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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 2006 Jan 3;78(2):315–333. doi: 10.1086/500272

Genomewide Linkage Scan of 409 European-Ancestry and African American Families with Schizophrenia: Suggestive Evidence of Linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the Combined Sample

Brian K Suarez 1,,*, Jubao Duan 2,,*, Alan R Sanders 2, Anthony L Hinrichs 1, Carol H Jin 1, Cuiping Hou 2, Nancy G Buccola 3, Nancy Hale 4, Ann N Weilbaecher 5, Deborah A Nertney 7,8, Ann Olincy 9, Susan Green 10, Arthur W Schaffer 1, Christopher J Smith 11, Dominique E Hannah 7,8, John P Rice 1, Nancy J Cox 6, Maria Martinez 2,12, Bryan J Mowry 7,8, Farooq Amin 10,13,,, Jeremy M Silverman 11, Donald W Black 4, William F Byerley 14,15,,, Raymond R Crowe 4, Robert Freedman 9, C Robert Cloninger 1, Douglas F Levinson 16,,§, Pablo V Gejman 2
PMCID: PMC1380238  PMID: 16400611

Abstract

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees—263 of European ancestry (EA) and 146 of African American ancestry (AA)—together with the results of a genome scan (with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia (SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs (ASPs) (279 EA and 124 AA) and 100 all-possible half-sibling ASPs (15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 (empirical Z likelihood-ratio score [Zlr] threshold ⩾2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Zlr scores >2.0 in 8p were observed from 30.7 cM to 61.7 cM (Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Zlr of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 (NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Zlr scores was observed for 5p14.1-q12.1, where the maximum Zlr increased from 2.77 initially to 3.80 after fine mapping in the EA families.


Schizophrenia (SZ [MIM 181500]) is a disorder (or group of disorders) with onset typically in adolescence or young adulthood and characterized by disruption of thinking (e.g., delusions or disorganization), perception (hallucinations), mood, and behavior. The symptoms, if untreated, tend to persist, and the course of the disease tends to be chronic, even with treatment. Although psychotic symptoms can be detected in the general population, and a continuum of severity from normality to psychosis has been proposed (Strauss 1969; van Os et al. 2000; Johns et al. 2004), SZ, as defined by the DSM-IV criteria of the American Psychiatric Association (1994), is widely viewed as a discrete illness. Heritability is ∼80%, on the basis of twin studies (Cardno et al. 1999). There is a 10-fold increase in risk to first-degree relatives (Gottesman and Shields 1982), as well as a familial coaggregation of SZ with other psychotic disorders and with “schizophrenia spectrum” personality disorders (Kendler et al. 1993b, 1993c, 1993d; Stompe et al. 1998). SZ risk is also increased in adopted-away children who have a biological parent with SZ (Heston 1966; Kety et al. 1971; Rosenthal et al. 1971) and in the offspring of an unaffected MZ cotwin of a proband with SZ (Gottesman and Bertelsen 1989). Complex inheritance is suggested by the high MZ:DZ risk ratio (∼4:1) and by the rapid decrease in risk as biological relatedness to a proband decreases (O’Rourke et al. 1982).

For complex disorders such as SZ, it has proven difficult to obtain replicable positive evidence of genetic linkage, but careful analysis of the SZ literature suggests that there is considerable support for a set of potential susceptibility loci. Three types of evidence are available: linkage statistics from published studies and from two recent meta-analyses of genomewide linkage scans (Badner and Gershon 2002; Lewis et al. 2003), evidence from a chromosomal deletion syndrome on chromosome 22q (Lindsay et al. 1995), and reported associations with positional susceptibility genes, some of which have gathered independent support (Owen et al. 2004) and convergent support from independent neuropharmacological findings (Cloninger 2002). We anticipate that many SZ susceptibility genes remain unidentified and that some of these can be characterized using genetic linkage and association methods. Therefore, we have recruited a large sample of affected sibling pairs (ASPs) to search for susceptibility loci by whole-genome linkage screening, to prioritize regions for more-intensive study. The families were ascertained through probands with SZ who have a sibling with SZ or schizoaffective disorder (SA). The sample is part of the National Institute of Mental Health (NIMH) Genetics Initiative for Schizophrenia, and the NIMH will make available the DNA specimens and blinded clinical data (see NIMH Center for Collaborative Genetics Studies of Mental Disorders Web site).

We report here the results of a genome scan of 409 pedigrees with SZ—263 of European ancestry (EA) and 146 of African American ancestry (AA), all collected by the Molecular Genetics of Schizophrenia (MGS1) Collaboration—with the use of a 9-cM map of STRPs. Using nonparametric multipoint linkage analysis, we detected two chromosomal regions with suggestive evidence of linkage (Lander and Kruglyak 1995) on chromosomes 8p23.3-p12 and 11p11.2-q22.3 in the full sample and, in exploratory analyses, two regions that reached similar thresholds on chromosomes 4p16.1-p15.32 and 5p14.3-q11.2 in the AA and EA samples, respectively. Chromosome 8p is one of the most consistently observed regions in SZ genome scans, as discussed below. There have been several reports of significant association between SZ and polymorphisms in neuregulin 1 (NRG1) in this region (Craddock et al. 2005), but it is not, in fact, clear to what extent this gene accounts for the linkage signals, and replication has not been uniform (Duan et al. 2005). Most such linkage signals have been observed closer to the p-telomere than to NRG1. In the present sample, there is evidence of linkage across a broad region, and the two peaks observed primarily in EA families are both telomeric to NRG1. Also within this region is a paracentric inversion that is common in Europeans (Broman et al. 2003). A large block of linkage disequilibrium (LD) was observed in this region in our EA sample, presumably because of the absence of crossing-over when a parent is heterozygous for the inversion. The inversion also creates uncertainty about the location and order of certain markers. Previous SZ linkage reports on this region have not specifically addressed the effects of this inversion on the results. We discuss below our efforts to accommodate this inversion.

Material and Methods

Family Ascertainment

The study participants were enrolled at nine sites in the United States and one in Australia: University of Chicago, Chicago; University of California, Irvine; University of Colorado Health Sciences Center, Denver; Baylor College of Medicine, Houston; University of Iowa, Iowa City; Washington University, St. Louis; Mount Sinai School of Medicine, New York; University of Pennsylvania, Philadelphia (this site included a subcontract with the Louisiana State University Health Sciences Center, New Orleans); and the University of Queensland, Brisbane. The focus of recruitment efforts was on EA and AA families. EA populations in the United States and Australia have similar ethnic characteristics (Cavalli-Sforza et al. 1994). Families were identified from a variety of sources, including local treatment facilities, physician referrals, the National Alliance for the Mentally Ill and other advocacy groups, Web sites, media announcements, and advertisements. Participants gave informed consent to an interview, provided a blood specimen for DNA and cell lines, and granted permission to obtain their psychiatric records and (usually) to contact a family informant. Available parents were asked to provide a blood specimen. If one or both parents were not available, as many as two unaffected sibs were asked to provide blood specimens. Local institutional review board approval was obtained for each site.

Clinical Assessment

Subjects (aged ⩾18 years) were interviewed by trained clinicians using the semistructured Diagnostic Interview for Genetic Studies (DIGS) 2.0 (Nurnberger et al. 1994), to elicit information required to determine diagnoses of psychotic, mood, and substance-use disorders in accordance with DSM-IV criteria (American Psychiatric Association 1994), the comorbidity of these disorders, medical history, and ratings of positive and negative symptoms of SZ. A family informant was also interviewed, when possible, about each patient’s history and about the family psychiatric history, by use of the Family Interview for Genetic Studies (FIGS) (Gershon et al. 1988; Maxwell 1992). Two experienced research clinicians independently reviewed the DIGS, FIGS, interviewer’s narrative report, and all available psychiatric records and then assigned all relevant diagnoses (with a confidence level and age at onset identified for each one), a judgment about presence or absence of each DSM-IV criterion for SZ and SA, and the estimated lifetime duration of SZ and of mood syndromes. For all these items, the diagnosticians resolved any disagreements by discussion (or occasionally asked a third diagnostician to serve as a tiebreaker). Thus, a primary best-estimate final diagnosis (BEFD) (Leckman et al. 1982) was assigned on the basis of this consensus procedure. All individuals (interviewed or not) who did not receive an SZ or SA diagnosis were considered to have “diagnosis unknown” for the linkage analyses. One of the two diagnosticians also completed the Lifetime Dimensions of Psychosis Scale (LDPS), a 21-item scale for rating the lifetime duration and severity of positive, bizarre positive, negative, disorganized, and mood symptoms of psychotic disorders, on the basis of all available information for each patient (Levinson et al. 2002). Analyses using LDPS ratings will be presented elsewhere.

Inclusion and Exclusion Criteria

To be eligible, a family was required to be multiplex—minimally, to have a proband with a BEFD of SZ and one or more siblings with SZ or SA, with a confidence level of “likely” or “definite.” Additional first-degree relatives with SZ and SA were recruited when possible. Both SZ-affected and SA-affected relatives have been included in this and most other SZ linkage studies, on the basis of evidence from multiple-family studies showing that both disorders cluster in families ascertained through a proband with SZ (Gershon et al. 1988; Kendler et al. 1993a; Maier et al. 1993; Taylor et al. 1993). For an SA diagnosis, DSM-IV requires that criteria for SZ and for manic, mixed, and/or major depressive episodes be met simultaneously at some point, with persistence of psychotic symptoms without prominent mood symptoms for at least 2 wk, and with mood episodes persisting for “a substantial portion of the total duration” (Cloninger et al. 1998, p. 278) of illness, defined here as 30% for consistency with the first NIMH Genetics Initiative for Schizophrenia study. Subjects were excluded from receiving a final diagnosis of SZ or SA if psychosis was limited to periods of likely substance intoxication or withdrawal, if persistent psychotic symptoms were considered likely to be related to substance use (e.g., increasing paranoia after years of amphetamine use or symptoms limited to visual hallucinations and “flashbacks” after hallucinogen use), if psychosis might have been caused by another disorder (e.g., epilepsy predating SZ onset) as determined by consensus judgment, or if the individual had moderate or severe mental retardation.

Diagnostic Reliability and Supplemental Clinical Measures

The cross-site reliability of diagnoses was measured by comparing the original site’s consensus BEFD with a new consensus BEFD produced blindly by a second site using blinded copies of all available case material for 32 cases from the first NIMH Genetics Initiative for Schizophrenia from Washington University (Cloninger et al. 1998) and 36 cases from the present study (total N=68). The 68 total cases included 40 with a diagnosis of SZ from the original site, 10 with an SA diagnosis, and 18 with mood, personality, and/or substance-use diagnoses, most with at least some symptoms suggestive of an SZ spectrum disorder. Cohen’s kappas (Cohen 1960) were 0.88 for SZ and 0.89 for SA, indicating no notable variation across sites.

STRP Genotyping

DNA was extracted from lymphoblastoid cell lines by the Rutgers University Cell and DNA Repository and was delivered in two “waves” to the Center for Inherited Disease Research (CIDR) for genotyping. CIDR’s methods and details of the CIDR map are available online (see CIDR Web site). The marker set consisted of ∼400 STRPs, with mean spacing of 9 cM (the largest gap was 18 cM) and a mean marker heterozygosity of 0.76. Family relationships were checked prior to the scan with a forensic panel of 12 markers. Samples with failed or very low amplification and contaminated samples were identified, and sex checks and a review of Mendelian discrepancies were performed when required. Failed wave I specimens were replaced when possible, and the entire family was regenotyped (for 23 families) in wave II. Each gel included four CEPH controls, blind duplicates, and blank PCR products. Over 5% of wave I specimens were genotyped a second time in wave II. Analyses with RELCHECK (Boehnke and Cox 1997; Broman and Weber 1998) to assess family relationships were performed with the full set of genotypes. Genotypes were removed in cases of Mendelian inconsistencies or unlikely genotypes (P<.01), as determined by MERLIN (multipoint engine for rapid likelihood inference) (Abecasis et al. 2002). Quality control analyses for waves I and II, respectively, showed missing data rates of 3.96% and 3.48%, genotypewise error rates of 0.1% and 0.03% based on blind duplicates, and Mendelian inconsistency rates of 0.72% and 0.67%.

Analysis of Population Substructure

Accurate estimation of marker-allele frequencies is critical when DNA is unavailable for some parents and when population substructure exists (Curtis and Sham 1996), and allele frequencies can be significantly different for EA and AA subjects (Goddard et al. 2000; Grigull et al. 2001). It was decided that separate allele-frequency estimates for these two ethnic groups would be established for all analyses. Therefore, we used the program STRUCTURE (Pritchard et al. 2000) to identify and exclude families that were outliers with respect to the two main ethnic clusters, because these families would otherwise have been analyzed with inappropriate frequency estimates. Self-reported ancestries were EA or AA, plus 10 families with Hispanic ancestry. STRUCTURE analyses were completed assuming K=2, 3, or 4 clusters by use of all autosomal STRP genotypes. Each run consisted of 10,000 burn-ins and 10,000 subsequent iterations. There were clear EA and AA clusters regardless of the value of K, with no additional clusters that reflected self-reported ethnicity. Eight of the 10 Hispanic families consistently clustered (posterior P>.85) with either the EA or AA group (or showed approximately equal EA or AA admixture). Thus, K=2 was assumed, and 10 runs of K=2 with different starting seeds produced no changes in family assignments to the clusters. Thirteen families with 1 or 2 ungenotyped parents were removed from linkage analyses because they did not attain the selected threshold of a posterior probability of group membership of at least 0.85. Two families with self-reported Asian ancestry (without genotyped parents) were also removed.

Confirmation of Biological Relationships

All participant-reported genetic relationships were verified via RELCHECK (Boehnke and Cox 1997; Broman and Weber 1998) for autosomal and X-linked STRPs from the forensic tests, and Mendelian consistency was verified via PEDCHECK (O’Connell and Weeks 1998) for autosomal and X-linked STRPs from the genome scan, respectively. On the basis of these checks, 26 families were excluded because they no longer contained an ASP (full or half) or because the “siblings” proved to be not related, and 6 families were excluded because the siblings had identical genotypes (because of either an unreported MZ twin relationship or an error during phlebotomy, blood submission, or processing). For the retained families, two nuclear pedigrees contained self-reported full-sibling ASPs that were proven to be half-sibling ASPs in the EA sample; 18 nuclear pedigrees contained self-reported full-sibling ASPs that were proven to be half-sibling ASPs in the AA sample. Finally, one large pedigree was split into subfamilies so that they could be analyzed by GENEHUNTER-PLUS (GH+) (Kong and Cox 1997), resulting in the creation of a “new” family; the subfamilies were treated as if they were unrelated to one another.

STRP Maps and Allele Renumbering

The STRP genotyping was performed in two waves. Briefly, in addition to three Y-linked markers and one pseudoautosomal marker not used in linkage analysis, 393 autosomal and X-linked STRPs were typed in wave I, and 400 in wave II. Genotypes for the 387 markers common to both waves were hand-checked for consistency of allele designations, and alleles were renumbered when necessary, including 114 for which renumbering was complex (see tables A1 and A2 in appendix A for detailed examples). For the genome-scan analysis, we assumed map positions provided by CIDR, which are similar to Marshfield map positions (Broman et al. 1998). For the linkage fine-mapping analysis, all positions were drawn or interpolated from the deCODE map (Kong et al. 2002), as discussed below.

STRP Allele-Frequency Estimation

Maximum-likelihood allele-frequency estimates were obtainedfrom the USERM13 subroutine of MENDEL (Lange et al. 1988; Boehnke 1991) separately for the EA and AA families. By likelihood-ratio testing, EA and AA allele frequencies differed at P<10-16 for 82.5% of the markers, at 10-16P⩽.01 for 17% of the markers, and at P>.01 for only 0.5% (three) of the markers. Accordingly, for the linkage analysis of the combined EA and AA sample, we used separate allele-frequency estimates. For instance, if there were N alleles in the EA sample, we renumbered the AA alleles, starting with N+1. The sum of the EA and AA allele frequencies totaled 200% (table A2).

Linkage Analyses of STRPs and Determination of Empirical Significance Thresholds

Linkage analyses were performed using GH+ (Kong and Cox 1997) under the exponential-model option and the SALL scoring function, to compute Z likelihood-ratio (Zlr) scores for each map position. Zlr follows a normal distribution asymptotically under the null hypothesis of no linkage. All results are presented on the Zlr scale. The correspondence between Zlr and the log10 likelihood ratio of linkage is LOD=(Zlr)2/2ln(10). Information content (IC) was computed by GH+. The algorithm computes entropy for the probability distribution for the inheritance vectors of all pedigrees with or without genotypic data. IC is then computed by subtracting the ratio of these terms from 1. Map locations were drawn from the CIDR map (Broman et al. 1998) or were interpolated into that map.

The linkage analysis of all families combined was considered to be the primary analysis. Exploratory analyses of the EA and AA families separately were also performed. To determine empirical significance thresholds for Zlr scores, 5,000 replicates of the actual sample, map, and allele frequencies (including patterns of missing data) were generated using SIMULATE (Terwilliger et al. 1993) under the assumption of an absence of linkage. Each replicate was analyzed separately for all families (the planned primary analysis) and then for the AA and EA families separately. For the primary analysis, the Zlr threshold was 3.60 for “significant” linkage (expected in ⩽5% of genome scans) and 2.65 for “suggestive” linkage (expected ⩽1 times per genome scan) (Holmans et al. 2004). In comparison, the thresholds for EA and AA samples (without correction for multiple testing) were similar: 3.62 and 3.63, respectively, for significant linkage and 2.71 and 2.69, respectively, for suggestive linkage.

Also, as discussed below, a common paracentric inversion has been reported (Broman et al. 2003) in the region of chromosome 8p that produced the greatest evidence of linkage in the present study. One STRP in the CIDR map (D8S1469) is located in the middle of the typical inversion segment, and another STRP in the CIDR map (D8S1130) is close to the boundary of the typical inversion segment. The exact positions of these two STRPs, and the probability of recombination around them, would differ in individuals with and individuals without the inversion. The primary genome scan analysis results reported below excluded D8S1469, the less informative of the two inversion STRPs.

SNP Genotyping and Data Cleaning

For linkage fine mapping, genotyping of SNP markers was performed at Evanston Northwestern Healthcare’s Center for Psychiatric Genetics (Evanston, IL) by use of SNPlex (Applied Biosystems [ABI]). Using SNPbrowser software, version 1.0 (ABI), 585 SNPs (13 SNPlex pools) were selected to form a 0.5–0.6-cM map across 304 cM (255 Mb [Matise et al. 2003]) of chromosomes 4p16.3-p15.2 (44 cM; 27 Mb), 5p15.2-q13.3 (59 cM; 62 Mb), 8p23.3-q12.1 (78 cM; 59 Mb), 10p15.3-p14 (20 cM; 7 Mb), 10q25.3-q26.3 (36 cM; 18 Mb), and 11p13-q23.3 (67 cM; 82 Mb) from HapMap, Celera (Venter et al. 2001), or public databases (see National Center for Biotechnology Information [NCBI] dbSNP Web site, build 34) (table 1). Validated SNPs were selected if their minor-allele frequency (MAF) was reported to be >25% in databases for both EA and AA samples, and they were tested using bioinformatics for suitability for the SNPlex assay. Forty nanograms of fragmented DNA was dried down on each well of a 384-well plate. After phosphorylation of oligonucleotide ligation assay probes and universal linkers, allele-specific ligation and enzymatic clean-up were performed. PCR was performed with universal primers, and biotinylated amplicons were captured on streptavidin-coated plates. Single-stranded PCR products were hybridized with a set of fluorescently labeled, universal ZipChute probes that have a unique sequence corresponding to each SNP. ZipChute probes were eluted and separated on a 3730 DNA Analyzer (ABI), and genotypes were called by GeneMapper 3.5 (ABI), blind to diagnosis.

Table 1.

Fine-Mapping Summary

Chromosome
Value 4 5 8 10p 10q 11 Total Average
STRP Zlr peak group AA EA EA+AA EA EA+AA EA+AA
Peak STRP Zlr 2.72 2.77 3.25 2.04 2.23 2.74
Approximate 1-LOD linkage interval of STRP scan (cM)a:
 Start 0 33.6 2.1 0 120.3 61.9
 End 35.5 74.3 60.3 20.9 170.9 94.6
Total approximate 1-LOD interval (cM)a 35.5 40.7 58.2 20.9 50.6 32.7 238.6
Fine-mapping region chosen (cM)b:
 Start .0 24.9 .0 .0 134.7 43.2
 End 43.6 84.0 77.9 20.0 170.9 110.1
Total distance fine mapped (cM)b 43.6 59.1 77.9 20.0 36.2 67.0 304
Cytogenetic positionc 4p16.3–4p15.2 5p15.2–5q13.3 8p23.3–8q12.1 10p15.3–10p14 10q25.3–10q26.3 11p13–11q23.3
Physical distance (Mb)c:
 Start .3 14.0 .6 .3 116.4 34.9
 End 27.2 75.8 59.5 6.7 134.0 116.6
Total distance fine mapped (Mb) 26.8 61.8 58.9 6.4 17.7 81.8 253
No. of genotyped SNPs 91 120 131 33 71 139 585
Initial SNP interval (cM)b .48 .49 .59 .61 .51 .48 .52
No. of SNPs failed for assay 4 4 4 1 3 3 19
No. of SNPs failed for low (<90%) genotyping rates 6 5 5 3 0 4 23
No. of SNPs with excessive Mendelian errors 7 0 1 0 2 1 11
No. of SNPs remaining with clean genotypes 74 111 121 29 66 131 532
Cleaned SNP interval (cM)b .59 .53 .64 .69 .55 .51 .57
Average genotyping rate of cleaned SNPs (%) .987 .988 .980 .988 .988 .988 .986
Mendelian error rate (per genotype) of cleaned SNPs (%) .00015 .00023 .00012 .00012 .00017 .00018 .00017
Unlikely-recombinants rate (per genotype) of cleaned SNPs (%) .00048 .00030 .00042 .00069 .00075 .00033 .00044
Average MAF of cleaned SNPs:
 EA .37 .35 .36 .34 .35 .38 .36
 AA .35 .34 .35 .37 .34 .35 .35
No. of clean SNPs removed because of deviation from HWE:
 EA 1 2 0 0 1 2 6
 AA 0 1 3 1 0 1 6
No. of clean SNPs removed because of adjacent SNP LD:
 EA 9 21 12 6 11 13 72
 AA 6 5 9 3 7 12 42
No. of clean SNPs removed because of inversion (only chromosome 8):
 EA 0 0 5 0 0 0 5
 AA 0 0 5 0 0 0 5
No. of final SNPs analyzed for linkage:
 EA 64 88 104 23 54 116 449
 AA 68 105 104 25 59 118 479
Final SNP interval (cM)b:
 EA .68 .67 .75 .87 .67 .58 .68
 AA .64 .56 .75 .80 .61 .57 .63
Final fine-map IC:
 EA .83 .85 .85 .80 .83 .85 .84
 AA .77 .78 .79 .77 .78 .78 .76
Fine-mapping Zlr peak group AA EA EA EA EA EA+AA
Peak fine-mapping Zlr 3.09 3.80 3.33 2.52 2.08 3.08
SNP nearest to peak fine-mapping Zlr rs7681266 rs1027164 rs7834209 rs1155931 rs1343418 rs4275647
Approximate 1-LOD interval after fine mapping (cM)b:
 Start 1.0 44.9 5.1 .0 134.1 69.7
 End 32.0 76.7 46.0 23.2 153.5 89.2
Total approximate 1-LOD interval (cM)b 31.0 31.8 40.9 23.2 19.4 19.5 166
Total narrowing of fine-mapping peak achieved (cM)b 4.5 8.9 17.3 −2.3 31.2 13.2 73
Cytogenetic position of approximate 1-LOD interval after fine mappingc 4p16.3–4p15.32 5p14.1–5q12.1 8p23.2–8p21.2 10p15.3–10p14 10q25.3–10q26.13 11q13.1–11q14.1
Physical distance of approximate 1-LOD interval after fine mapping (Mb)c:
 Start .00 25.22 2.54 .00 115.78 63.69
 End 16.65 61.62 25.93 9.27 126.53 82.59
Total approximate 1-LOD interval (Mb)c 16.7 36.4 23.4 9.3 10.8 18.9 115
a

cM values refer to the STRP map of CIDR (used for linkage scan).

b

cM values refer to the deCODE map (used for fine mapping).

c

Cytogenetic locations and Mb values are from the UCSC July 2003 freeze.

Mendelian errors and unlikely genotypes were evaluated using MERLIN (Abecasis et al. 2002), as described above. We first excluded 19 SNPs because of failed assays and 23 SNPs because of low call rates (<90%). Then, we excluded 11 SNPs because of excessive Mendelian errors (>1%). The remaining 532 SNPs had 0.017% Mendelian errors per SNP (range 0.00%–0.66%) and 0.044% unlikely recombinants (range 0.00%–0.58%) for all fine-mapping regions (table 1). Two families were excluded—one because of excessive Mendelian errors (due to a specimen swap) and one without genotyped parents, because of excessive unlikely recombinants. The final call rate for all 532 cleaned SNPs was 98.6% (range 92.1%–100.0%), with a total of 729,158 cleaned genotypes remaining for further analysis. The average interval between neighboring SNPs was 0.59 Mb for chromosome 4, 0.53 Mb for chromosome 5, 0.64 Mb for chromosome 8, 0.69 Mb for chromosome 10p, 0.55 Mb for chromosome 10q, and 0.51 Mb for chromosome 11. There were several sizable centromeric gaps where the genome sequence information was incomplete (a 3.9-Mb gap for chromosome 5, a 3.8-Mb gap for chromosome 8, and a 4.1-Mb gap for chromosome 11). The average MAF was 0.35 (range 0.04–0.50) for AA subjects and 0.36 (range 0.00–0.50) for EA subjects. We also evaluated the repeatability with 121 SNPs from the chromosome 8 fine mapping, in which we observed repeatability of 99.9% when 268 DNA samples were blindly regenotyped. Of 31,931 genotypes that were nonzero in both experiments, 31 were discrepant, with 3 changes involving both alleles in a homozygous subject and 28 others involving a change of only one of the two alleles in a heterozygous individual.

Deviations from Hardy-Weinberg equilibrium (HWE) were analyzed separately in EA and AA samples in a set of as many unrelated individuals as possible. Six SNPs were removed because of significant deviations at P<.01 in the EA sample, and 6 SNPs were likewise removed in the AA sample, including 2 SNPs with highly significant deviations in the AA sample (P=.00006 for rs1355305; P=.0002 for rs896044) (table 1).

Selection of a Map for Linkage Fine Mapping

We therefore undertook to select a subset of markers for fine-mapping analyses that had the highest heterozygosity (and hence the highest IC). Pairwise marker LD between the cleaned fine-mapping SNPs was analyzed with a set of unrelated individuals, separately for EA and AA samples, by use of ASSOCIATE (Ott 1985), which computes maximum-likelihood estimates of the LD parameter by the expectation-maximization algorithm (Dempster et al. 1977). For example, of 121 SNPs in the chromosome 8 fine-mapping region, significant (P<.05) pairwise LD was observed between 40 and 20 adjacent marker pairs in the EA and AA samples, respectively, which is consistent with other reports of greater LD in EA than in AA samples (Hinds et al. 2005).

A contiguous block of highly significant LD was observed in the EA sample across 3.31 Mb (∼6 cM), with six adjacent SNPs extending from rs2980438 (at 8.132 Mb) to rs7824640 (at 11.442 Mb) on chromosome 8. It appears likely that this LD block is due to the large polymorphic inversion that is observed with a frequency >20% in the European (Giglio et al. 2001; Broman et al. 2003) and Japanese (Sugawara et al. 2003) populations. The inversion typically spans 4.7 Mb between two low-copy-repeat regions, each of which contains several olfactory receptor genes (Giglio et al. 2001). Direct demonstration of the inversion by use of FISH is beyond the scope of the present study, but we inferred that inversions could be present in some unknown but substantial proportion of our EA subjects on the basis of the large LD block and the fact that recombination cannot occur between chromosomes that are heterozygous for an inversion, leading to LD if the inversion is common. We detected no significant LD in this region in AA subjects, which suggests that this inversion is infrequent in sub-Saharan Africa, similar to the 17q21.31 paracentric inversion reported recently (Stefansson et al. 2005).

In families with missing parental genotypes, linkage scores can be inflated if substantial LD is present between marker pairs (Huang et al. 2004; Dunn et al., in press). Recent work by one of us (Levinson and Holmans, in press) indicates, however, that there is no appreciable inflation of linkage scores if dense SNP maps are trimmed to eliminate marker pairs whose LD (as measured by r2) is >0.05. Accordingly, we used this criterion to trim our SNP maps separately for the EA and AA families by removing one of each adjacent pair of SNPs that showed this level of LD. Removal of a SNP will create a new adjacent pair, and these new pairs were also evaluated for LD, until all adjacent pairs had r2 estimates <0.05. For chromosome 8, a total of 17 SNPs were trimmed from both EA and AA families. In the EA families, 12 SNPs were removed because r2 was >0.05, and 5 were removed because they are located in the inversion (where there was strong LD). In the AA families, three SNPs were removed because they deviated from HWE (at P<.01), nine were removed because r2 was >0.05, and five were removed because they are located in the inversion. We retained a single SNP (hCV1965865) from the inversion region. However, we deleted this SNP in analyses that included both SNPs and STRPs, since an STRP in the inversion (D8S1130) is more polymorphic. Similarly, we had already deleted the less-informative inversion STRP (D8S1469) for the combined SNP and STRP analysis, leaving a total of 104 SNPs and 9 STRPs for the final chromosome 8p fine map. Fine-mapping linkage results are reported for the EA and AA families separately and combined.

For other fine-mapping regions, we followed similar rules to exclude SNPs that may be in LD with adjacent SNPs (table 1). The final numbers of SNPs used in fine-mapping analyses for the EA and AA samples, respectively, were 64 and 68 for chromosome 4, 88 and 105 for chromosome 5, 104 and 104 for chromosome 8, 23 and 25 for chromosome 10p, 54 and 59 for chromosome 10q, and 116 and 118 for chromosome 11, for a total of 449 and 479 cleaned fine-mapping SNPs without significant intermarker LD that proceeded to linkage analyses (table 1).

Correct specifications of marker-marker genetic distances are also critical for accurate multipoint linkage analysis. Genetic-mapping information was not available for most of our fine-mapping SNPs, and our sample did not include the kinds of complete and multigenerational pedigrees that ideally should be used to estimate genetic distances. The deCODE map includes genetic locations for a larger number of markers, on the basis of more meioses, than does the CIDR map. Therefore, we created a genetic and a physical map of the STRPs in the region, using the UniSTS database (see UniSTS Web site), deCODE map information for genetic locations, and the NCBI sequence map for physical positions. Genetic locations were assigned to SNPs by use of linear interpolation of physical positions in relation to the genetic locations of flanking STRPs.

Sharing of Biomaterials and Clinical Data

Biological materials, genotypes, and blinded clinical data will be made available to the scientific community by the NIMH Center for Collaborative Genetics Studies of Mental Disorders (see the Center's Web site).

Results

We report here results of the clinical characteristics of the sample, a genomewide linkage scan of SZ, and the fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 8p23.3-q12.1, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3.

Families and Individuals Included in Linkage Analyses

A total of 459 families met eligibility criteria and were included in the two waves of CIDR genotyping, although 4 of these families were removed because one of the siblings was no longer considered to be affected after further diagnostic review in preparation for dimensional analyses. After removal of families as described above, 409 families (408 independent families) were included in the linkage analysis: 263 (64.3%) EA and 146 (35.7%) AA. The 409 families resulted from the splitting of 1 family that was too large to be analyzed by GH+. A full description of the DNA specimens available from this data set, including those excluded from the present analysis, will be made available on the NIMH Human Genetics Initiative for Schizophrenia Web site. Table 2 describes the number of statistically independent affected full-sib pairs (AFSPs) and the number of all possible affected half-sib pairs (AHAPs) used in the linkage analysis. Statistically independent AFSPs were counted as S-1 for S affected full sibs in a sibship with only full sibs; all possible AHAPs were counted as S(S-1)/2 for S affected half sibs in a sibship with only half sibs. Because there is no optimal method for counting independent AHAPs when there are full and half sibs in the same family, all possible half-sib pairs have been counted in these cases (see fig. A1 in appendix A for an illustration and explanation). Linkage analyses included 403 independent AFSPs (279 EA and 124 AA), 100 AHAPs (15 EA and 85 AA), and 26 other genotyped affected relatives (parents, aunts, uncles, and offspring). Genotypes were available for 33% of all parents (45% EA and 17% AA), and 156 unaffected full or half sibs were genotyped (96 EA and 60 AA). Linkage analyses included genotypes from 1,380 subjects.

Table 2.

Counts of Families and Individuals Genotyped[Note]

No. of Genotyped Parents
Sample andNo. of AFSPs per Family AFSPsa AHAPsb AffectedNonsibsc UnaffectedSibsd 0 1 2 3 4
EA sample:
 0 AFSPs 0 15 2 5 5 8 1 0 0
 1 AFSPs 226 0 6 77 81 75 70 0 0
 2 AFSPs 18 0 1 5 7 7 4 0 0
 3 AFSPs 4 0 1 9 2 0 1 0 1
 4 AFSPs 0 0 0 0 0 0 0 0 0
 5 AFSPs 1 0 0 0 1 0 0 0 0
  No. of families 249 NA NA NA 96 90 76 0 1
  No. of individuals or pairs 279 15 10 96 0 90 152 0 4
AA sample:
 0 AFSPs 0 53 7 15 27 20 0 0 0
 1 AFSPs 80 17 8 29 57 18 5 0 0
 2 AFSPs 15 11 1 9 6 7 1 0 1
 3 AFSPs 2 4 1 2 0 2 0 0 0
 4 AFSPs 2 0 0 5 1 1 0 0 0
 5 AFSPs 0 0 0 0 0 0 0 0 0
  No. of families 99 NA NA NA 91 48 6 0 1
  No. of individuals or pairs 124 85 16 60 0 48 12 0 4
Total sample:
  No. of families 348 NA NA NA 187 138 82 0 2
  No. of individuals or pairs 403 100 26 156 0 138 164 0 8

Note.— All counts reflect genotyped individuals only. A total of 1,380 individuals were genotyped in 409 families. The number of all (genotyped or not) parents was 920 (552 EA and 368 AA). NA = not applicable.

a

Genotyped independent AFSPs (n-1).

b

Genotyped AHAPs, all possible pairs; see main text for description of this counting method.

c

Genotyped affected nonsiblings; this includes persons who are not siblings or half siblings of affected individuals, so it includes parents, aunts, uncles, and offspring.

d

Genotyped unaffected siblings (and also unaffected half siblings) of affected individuals.

Descriptions of the 1,380 individuals who were genotyped are given in tables 3 and 4. Of the 409 families, 263 were EA, and 146 (from 145 independent families) were AA. The mean age at enrollment was 39.1 and 41.4 years for the EA and AA probands, respectively, with onset at ∼20 years of age for all groups of male and female probands, both EA and AA. As noted in table 3, 35% of fathers and 56% of mothers of the EA probands and 7% of fathers and 33% of mothers of the AA probands were genotyped. Overall, 4.9% of fathers and 6.6% of mothers received a diagnosis of SZ, and 1% of mothers received a diagnosis of SA. The “other” group consisted of 61 half sibs plus other non–first-degree relatives. In table 4, we display the characteristics of probands and siblings with SZ. The percentage of SZ-affected subjects with a mood disorder did not differ by ethnicity or between probands and relatives, but females had a higher percentage than males did (64.5% vs. 46.2%; χ21=24.8; P<.0001). All SA-affected subjects had mood episodes (manic, mixed, and/or major depressive), by definition. We used a general linear model to examine differences in age at enrollment, age at onset, duration of psychosis, and duration of mood episodes in the subjects with SZ and those with SA. The independent variables were ethnicity, sex, and familial relationship (probands vs. siblings). Both sex and ethnicity were significant predictors of duration of nonaffective psychosis (P<.01), with females and AA subjects having longer durations. No other variables were significant at the P<.01 level. There was a trend toward females having a longer duration of mood episodes (P=.03). Next, we compared the siblings with SZ and those with SA. The subjects with SA had a longer duration of mood episodes (P<.0001). The only other significant variable was ethnicity as a predictor of the duration of nonaffective psychosis (P=.02).

Table 3.

Clinical Characteristics of All Genotyped Individuals

Probands
Siblings
Fathers
Mothers
Othersa
Characteristic EA AA EA AA EA AA EA AA EA AA
No. of individuals 263 145 368 193 92 10 148 48 38 78
Percentage male 68.8 53.4 57.7 48.2 100 100 0 0 60.5 44.3
Mean (SD) age at enrollment (years) 39.1 (10.8) 41.4 (10.5) 40.6 (10.8) 43.3 (10.4) 65.5 (10.2) 69.6 (11.1) 63.3 (11.1) 60.8 (12.9) 33.9 (17.5) 38.5 (12.3)
Percentage with SZ 100 100 62.7 63.2 4.4 10.0 2.7 18.8 50.0 64.6
Percentage with SA 0 0 12.1 10.4 0 0 .7 2.1 13.2 6.3
Percentage with substance dependence:
 Any:
  Males 24.6 42.3 24.7 31.2 4.3 20.0 17.4 34.3
  Females 16.9 23.5 15.3 20.0 4.1 8.3 13.3 25.0
 Alcohol 15.8 26.7 12.4 15.5 4.3 20.0 2.7 4.2 5.3 16.5
 Cannabis 7.5 8.2 7.0 7.3 0 0 0 2.1 5.3 6.3
 Cocaine 2.3 12.3 1.6 10.9 0 0 0 0 0 8.8
 Amphetamine 2.6 1.4 1.9 1.0 0 0 1.0 0 2.6 0
a

The “Others” group consists of half siblings and other non–first-degree relatives.

Table 4.

Additional Clinical Characteristics of Genotyped Affected Subjects

Probands
Siblings
EA
AA
EA
AA
Affected Groupand Characteristic Males Females Males Females Males Females Males Females
SZ:
 No. of individuals 182 81 78 67 155 77 66 54
 Mean age at enrollment (years) 37.7 42.2 40.0 43.1 38.2 42.1 43.2 42.5
 Mean age at illness onset (years) 20.3 20.3 19.6 22.2 20.1 21.1 19.3 20.3
 Mean duration of nonaffective psychosis (mo) 207.5 258.9 238.1 253.9 215.4 246.6 276.4 253.9
 Percentage of subjects with mood episodes 46.4 64.6 38.2 61.8 51.3 64.9 42.4 69.1
 Mean duration of mood episodes (mo) 11.6 23.5 13.1 13.1 13.2 13.1 14.0 16.8
SA:
 No. of individuals 24 21 8 12
 Mean age at enrollment (years) 40.0 41.8 35.4 41.8
 Mean age at illness onset (years) 21.1 21.9 18.1 19.3
 Mean duration of nonaffective psychosis (mo) 218.4 234.3 182.6 222.4
 Mean duration of mood episodesa (mo) 94.8 123.6 89.3 115.7
a

All subjects with SA had one or more mood episodes (manic, mixed, and/or major depressive), by definition.

Genome Scan

For the STRP genome scan, the CIDR map was used, although, for purposes of display alongside the fine-mapping SNPs, we converted to the deCODE map. Figure 1 displays the multipoint Zlr graph across the genome for all families, and table 5 lists the STRPs that attained a multipoint Zlr with nominal significance at P<.01 (results for all STRPs are found in table 6). We detected two chromosomal regions with suggestive evidence (Zlr⩾2.65) of linkage in the primary analyses of all families: 8p23.3-p12 and 11p11.2-q22.3. The mean IC for the STRP scan was 0.60 for the EA sample and 0.55 for the AA sample.

Figure 1.

Figure  1

Results of the STRP genome scan for SZ. Zlr scores for the entire sample are plotted on the Y-axis, and genomic position (cM on CIDR map) by chromosome (p-ter to q-ter) is plotted on the X-axis.

Table 5.

STRPs with a Multipoint Zlr of Nominal Significance at P < .01[Note]

Zlr
Chromosomeand Marker Alias Position(cM)a EA Sample AA Sample Total Sample
3:
 D3S2406 GGAT2G03 103 2.33
4:
 D4S2366 GATA22G05 13 2.66
 D4S403 AFM157xg3 26 2.43
5:
 D5S2848 GATA145D09 40 2.65
 D5S1470 GATA7C06 45 2.72 2.52
 D5S2500 GATA67D03 69 2.37
6:
 D6S2427 GGAA15B08 54 2.54
8:
 D8S264 AFM143xd8 1 2.56
 D8S262 AFM127xh2 7 3.33
 D8S1130 GATA25C10 22 3.06
 D8S1106 GATA23D06 26 2.72
 D8S1145 GATA72C10 37 3.09 2.47
 D8S560 AFMa127ye5 43 2.96 2.51
 D8S1771 AFMb320va5 50 2.95 3.24
 D8S1477 GGAA20C10 60 2.64
11:
 D11S2371 GATA90D07 76 2.66 2.74
 D11S2002 GATA30G01 85 2.36
20:
 D20S851 AFMa218yb5 25 2.34

Note.— A nominal P<.01 is a Zlr>2.326 here.

a

cM values refer to the STRP map of CIDR.

Table 6.

STRPs by Map Position and Multipoint Zlr for Linkage Scan

Zlr
Chromosomeand Marker Alias Position(cM)a EA Sample AA Sample Total Sample
1:
D1S2845 AFM344we9 9 −.63 −.18 −.62
D1S2660 AFMa203yc1 11 −.70 −.05 −.60
D1S1612 GGAA3A07 16 −.26 −.22 −.34
D1S1597 GATA27E01 30 −.46 −1.14 −1.05
D1S3669 GATA29A05 37 −.72 −1.88 −1.70
D1S552 GGAT2A07 45 −1.22 −2.84 −2.64
D1S1622 ATA20F08 57 −.74 −1.79 −1.64
D1S255 AFM260zg5 65 −.15 −1.46 −.99
D1S3721 GATA129H04 73 −.23 −1.34 −.96
D1S2134 GATA72H07 76 .09 −.84 −.41
D1S3728 GATA165C03 89 2.04 −.06 1.62
D1S1665 GATA61A06 102 .14 .15 .20
D1S1728 GATA109 109 −.54 −.36 −.65
D1S551 GATA6A05 114 −.71 −.29 −.75
D1S1588 ATA2E04 126 −.02 −.30 −.19
D1S1631 ATA29D04 137 1.59 −1.43 .47
D1S3723 GATA176G01 140 2.13 −1.37 .96
D1S534 GATA12A07 152 1.28 .04 1.06
D1S1653 GATA43A04 164 1.03 −.03 .83
D1S1679 GGAA5F09 171 .70 −.12 .50
D1S1677 GGAA22G10 176 .58 −.17 .37
D1S1619 ATA14D03 188 .61 −.98 −.08
D1S1589 ATA4E02 192 .76 −1.00 .03
D1S518 GATA7C01 202 .67 −.59 .20
D1S1660 GATA48B01 212 .87 −.74 .27
D1S1647 GATA25A11 216 .96 −.23 .64
C1S1248 GATA124F08 226 .86 .41 .94
D1S2141 GATA87F04 233 .03 .48 .30
D1S549 GATA4H09 240 .23 −.14 .10
D1S3462 ATA29C07 247 .38 −.12 .23
D1S235 AFM203yg9 255 1.29 .57 1.38
D1S547 GATA4A09 268 1.16 1.24 1.66
D1S1609 GATA50F11 275 1.10 1.30 1.65
D1S2682 AFMa272xc9 288 −.25 1.22 .45
2:
D2S2976 GATA165C07 4 −.50 −1.04 −1.01
D2S1780 GATA72G11 10 −.91 −.88 −1.25
D2S2952 GATA116B01 18 −.61 −.59 −.84
D2S1400 GGAA20G10 28 −.39 .28 −.13
D2S1360 GATA11H10 38 −.98 .68 −.37
D2S405 GATA8F07 48 −.57 .42 −.22
D2S1788 GATA86E02 56 −.64 .50 −.25
D2S1356 ATA4F03 64 −.60 −.40 −.72
D2S1352 ATA27D04 74 −.14 −.39 −.33
D2S441 GATA8F03 87 .25 −1.35 −.57
D2S1394 GATA69E12 91 .69 −1.09 −.06
D2S1777 GATA71G04 99 1.34 −1.38 .25
D2S1790 GATA88G05 103 1.84 −.91 .95
D2S2972 GATA176C01 114 1.45 −.51 .87
D2S410 GATA4E11 125 1.66 −.23 1.21
D2S1328 GATA27A12 133 1.71 .43 1.64
D2S442 GATA8H05 147 1.70 .77 1.82
D2S1399 GGAA20G04 152 1.45 .24 1.32
D2S1353 ATA27H09 165 1.02 −.95 .31
D2S1776 GATA71D01 173 1.58 −1.43 .51
D2S1391 GATA65C03 186 2.25 −.50 1.61
D2S1384 GATA52A04 200 1.38 .40 1.36
D2S2944 GATA30E06 210 1.65 .46 1.61
D2S434 GATA4G12 216 .57 −.12 .40
D2S1363 GATA23D03 227 .25 −.38 −.01
D2S427 GATA12H10 237 −.19 −.08 −.20
D2S2968 GATA178G09 252 −.44 1.38 .47
D2S125 AFM112yd4 261 −.22 1.32 .60
3:
D3S2387 GATA22G12 6 .15 −1.23 −.62
D3S1560 AFM217xd6 19 .90 −1.87 −.37
D3S4545 GATA164B08 26 1.93 −.87 1.04
D3S1259 AFM036yb8 37 1.35 .55 1.43
D3S3038 GATA73D01 45 1.85 .43 1.76
D3S2432 GATA27C08 58 1.91 .08 1.60
D3S1768 GATA8B05 62 2.33 −.10 1.82
D3S2409 ATA10H11 71 1.54 −.65 .88
D3S1600 AFM308xc9 86 1.77 −.18 1.31
D3S4542 GATA148E04 90 1.73 −.40 1.16
D3S2406 GGAT2G03 103 2.33 −.86 1.37
D3S4529 GATA128C02 112 .96 −.25 .62
D3S2459 GATA68D03 119 .34 .66 .66
D3S3045 GATA84B12 124 .21 .86 .67
D3S2460 GATA68F07 135 −.98 .03 −.78
D3S4523 ATA34G06 138 −1.47 −.25 −1.34
D3S1764 GATA4A10 153 −.08 −.83 −.56
D3S1744 GATA3C02 161 −.35 −1.23 −.99
D3S1746 GATA8F01 170 −.41 −.98 −.89
D3S1763 GATA3H01 177 −.87 −.71 −1.12
D3S3053 GATA92B06 182 −.83 −.38 −.90
D3S2427 GATA22F11 188 −.77 −.10 −.67
D3S1262 AFM059xa9 201 .48 −.11 .32
D3S2398 GATA6G12 209 .58 −.33 .27
D3S2418 ATA22E01 216 .80 −.37 .42
D3S1311 AFM254ve1 225 .35 −.27 .12
4:
D4S2366 GATA22G05 13 .35 2.66 1.78
D4S403 AFM157xg3 26 .57 2.43 1.88
D4S2639 GATA90B10 33 .85 2.15 1.95
D4S391 AFM016xf3 44 .16 .52 .44
D4S2632 GATA72G09 51 .54 .23 .56
D4S1627 GATA7D01 60 .32 .71 .67
D4S3248 GATA28F03 73 .94 −.17 .67
D4S2367 GATA24H01 78 .58 −.49 .20
D4S3243 GATA10G07 88 .29 −1.22 −.46
D4S2361 ATA2A03 93 .57 −.75 .02
D4S1647 GATA2F11 105 −.06 .06 −.02
D4S2623 GATA62A12 114 .16 .72 .56
D4S2394 ATA26B08 130 −.30 −.76 −.67
D4S1644 GATA11E09 143 −.73 −1.87 −1.67
D4S1625 GATA107 146 −.50 −1.93 −1.52
D4S1629 GATA8A05 158 −.36 −2.47 −1.69
D4S2368 GATA27G03 168 −1.05 −1.69 −1.83
D4S2431 GGAA19H07 176 −.89 −1.59 −1.64
D4S2417 GATA42H02 182 −.08 −1.46 −.90
D4S408 AFM165xc11 195 −1.39 −1.22 −1.84
D4S1652 GATA5B02 208 .28 −1.92 −.85
5:
D5S2488 ATA20G07 0 1.17 −1.09 .32
D5S2849 GATA145D10 8 1.87 −1.28 .75
D5S2505 GATA84E11 14 1.33 −1.45 .23
D5S817 GATA3E10 23 .39 −1.28 −.40
D5S2845 GATA134B03 36 1.97 −.35 1.38
D5S2848 GATA145D09 40 2.65 −.32 1.95
D5S1470 GATA7C06 45 2.72 .52 2.52
D5S1457 GATA21D04 59 2.10 .48 2.00
D5S2500 GATA67D03 69 2.37 .33 2.14
D5S424 AFM214zg9 82 .40 .06 .36
D5S641 AFM284VD1 92 −.90 .52 −.43
D5S1725 GATA89G08 98 −.67 .76 −.10
D5S1503 GATA61B11 108 −1.14 .27 −.76
D5S1453 ATA4D10 115 −1.75 .82 −.96
D5S2501 GATA68A03 117 −1.30 .76 −.62
D5S1505 GATA62A04 130 −1.00 1.14 −.15
D5S816 GATA2H09 139 .27 −.23 .09
D5S1480 ATA23A10 147 −.27 −.42 −.46
D5S820 GATA6E05 160 .85 −.92 .17
D5S1471 GATA7H10 172 1.44 −2.69 −.42
D5S1456 GATA11A11 175 1.82 −2.17 .25
D5S211 Mfd154 183 2.23 −1.26 1.09
D5S408 AFM164xb8 195 2.01 −.34 1.41
6:
D6S942 UT654 0 −1.46 .27 −1.03
F13A1 SE30 9 −.93 .01 −.74
D6S2434 ATA50C05 25 .79 1.36 1.44
D6S1660 AFMb355wg5 40 −.02 1.16 .66
D6S2439 GATA163B10 42 −.05 .66 .35
D6S2427 GGAA15B08 54 −.45 2.54 1.18
D6S1017 GGAT3H10 63 −.43 1.72 .70
D6S2410 GATA11E02 73 .04 .91 .55
D6S1053 GATA64D02 80 −.74 −.13 −.68
D6S1031 ATA28B11 89 −.89 .87 −.24
D6S1056 GATA68H04 103 −.50 1.06 .20
D6S1021 ATA11D10 112 −1.04 .35 −.63
D6S474 GATA31 119 −1.16 −.08 −1.00
D6S1040 GATA23F08 129 −.45 −1.71 −1.30
D6S1009 GATA32B03 138 −.57 −1.98 −1.58
C6S1848 GATA184A08 146 −1.57 −1.41 −2.10
D6S2436 GATA165G02 155 −1.79 −.84 −1.94
D6S1035 ATA6C09 165 −1.05 −.23 −.98
D6S1277 GATA81B01 173 −.09 −.64 −.45
D6S1027 ATA22G07 187 −.82 .08 −.61
7:
D7S2477 AFMb035xb9 0 −.23 1.52 .75
D7S3056 GATA24F03 7 .65 1.09 1.16
D7S513 AFM217yc5 18 −.19 .22 −.02
D7S3051 GATA137H02 29 −.28 −.07 −.26
D7S1802 GATA41G07 33 .33 .27 .43
D7S1808 GGAA3F06 42 .61 −.16 .40
D7S817 GATA13G11 50 .58 −.35 .28
D7S2846 GATA31A10 58 1.00 −.15 .75
D7S1818 GATA24D12 70 .73 −.01 .60
D7S3046 GATA118G10 79 .48 −.60 .04
D7S2204 GATA73D10 91 −.20 −.90 −.69
D7S2212 GATA87D11 95 −.46 −.29 −.55
D7S821 GATA5D08 109 −.42 .26 −.20
D7S1799 GATA23F05 114 −.40 .45 −.06
D7S3061 GGAA6D03 128 .13 .16 .20
D7S1804 GATA43C11 137 −.32 .33 −.06
D7S1824 GATA32C12 150 .94 1.20 1.47
D7S2195 GATA112F07 155 .69 1.13 1.22
D7S3070 GATA189C06 163 .37 1.80 1.37
D7S3058 GATA30D09 174 −.29 2.20 1.05
D7S559 Mfd265 182 1.12 1.60 1.85
8:
D8S264 AFM143xd8 1 2.56 −2.34 .75
D8S262 AFM127xh2 7 3.33 −2.61 1.19
D8S1130 GATA25C10 22 3.06 −1.92 1.43
D8S1106 GATA23D06 26 2.72 −.86 1.76
D8S1145 GATA72C10 37 3.09 −.04 2.47
D8S560 AFMa127ye5 43 2.96 .28 2.51
D8S1771 AFMb320va5 50 2.95 1.45 3.24
D8S1477 GGAA20C10 60 2.28 1.36 2.64
D8S1110 GATA8G10 67 .51 .27 .57
D8S1113 GGAA8G07 78 .08 .09 .12
D8S1136 GATA41A01 82 −.53 .57 −.10
D8S2324 GATA14E09 94 −1.81 −.26 −1.62
D8S1119 ATA19G07 101 −1.91 −.44 −1.80
C8S14 GAAT1A4 110 −1.26 −.24 −1.18
D8S1132 GATA26E03 119 .49 −1.12 −.24
D8S592 GATA6B02 125 .60 −1.03 −.11
D8S1179 GATA7G07 135 −.51 −1.60 −1.34
D8S1720 AFMa197wg5 141 −.40 −2.64 −1.88
D8S256 AFM073yb7 148 −.37 −2.35 −1.71
D8S1108 GATA50D10 154 −.86 −2.28 −2.06
D8S373 UT721 164 −1.34 −2.05 −2.26
9:
D9S1779 AFM026tg9 0 −.46 −.21 −.49
D9S1871 AFM345ta9 8 −.68 .67 −.14
D9S2169 GATA62F03 14 −.78 .42 −.37
C9S1879 GATA187D09 22 −.97 −.06 −.83
D9S925 GATA27A11 32 −1.47 −.97 −1.76
D9S1121 GATA87E02 44 −1.31 −.36 −1.28
D9S1118 GATA71E08 58 .44 .21 .48
D9S301 GATA7D12 66 1.22 −.59 .63
D9S1122 GATA89A11 76 .71 .02 .59
D9S922 GATA21F05 80 .64 .21 .64
D9S1120 GATA81C04 89 .63 .91 1.04
D9S1796 AFMa210ze5 98 −.06 .59 .30
D9S1786 AFMa137yb9 104 .03 .79 .49
D9S938 GGAA22E01 111 −.39 .77 .13
D9S930 GATA48D07 120 −.31 .32 −.07
D9S934 GATA64G07 128 .04 −.90 −.48
D9S1825 AFMb029xg1 136 .28 −1.43 −.60
D9S2157 ATA59H06 147 −.26 −1.70 −1.20
D9S1826 AFMB030ZG9 160 −.57 −1.20 −1.17
D9S1838 AFMb303zg9 164 −.15 −1.00 −.71
10:
D10S1435 GATA88F09 4 2.01 .68 2.02
D10S189 AFM063xf4 19 1.44 .22 1.30
D10S1412 ATA31G11 28 .84 .31 .87
D10S2325 GAAT5F06 33 .88 −.23 .58
D10S1423 GATA70E11 46 1.14 .83 1.41
D10S1426 GATA73E11 59 .19 1.27 .88
D10S1208 ATA5A04 63 −.42 .39 −.11
D10S1221 ATA21A03 76 −1.59 .54 −.99
D10S1225 ATA24F10 81 −1.61 .51 −1.01
C10S1218 GATA121A08 88 −1.58 1.07 −.66
D10S1432 GATA87G01 94 −1.37 .49 −.83
D10S2327 GGAT1A4 101 −1.43 .28 −.99
D10S2470 GATA115E01 113 −.35 .60 .06
D10S1239 GATA64A09 125 1.06 .13 .94
D10S1237 GATA48G07 135 .94 −.03 .75
D10S1656 AFMa184xd9 149 1.55 1.66 2.23
D10S217 AFM212XD6 158 .68 2.10 1.79
D10S1248 GGAA23C05 165 1.32 1.44 1.92
D10S212 AFM198zb4 171 1.48 1.18 1.89
11:
D11S2362 ATA33B03 9 −.69 .13 −.49
D11S1999 GATA23F06 17 1.85 −.13 1.42
D11S1981 GATA48E02 21 .96 −.69 .38
C11S348 ATA34E08 33 −.20 −.04 −.18
D11S1392 GATA6B09 43 .69 .14 .64
D11S1993 ATA1B07 54 1.45 .64 1.54
D11S1344 AFM298vc9 58 1.18 .56 1.28
D11S2371 GATA90D07 76 2.66 .98 2.74
D11S2002 GATA30G01 85 1.94 1.34 2.36
D11S2000 GATA28D01 101 .20 1.39 .99
D11S1391 GATA4E01 105 −.12 1.61 .86
D11S1998 GATA23E06 113 −.51 1.02 .20
D11S4464 GATA64D03 123 −.63 .92 .04
D11S912 AFM157xh6 131 −1.47 .14 −1.11
D11S968 AFM109xc3 148 −1.58 −.54 −1.60
12:
D12S372 GATA4H03 6 .26 1.21 .90
C12S4912 GATA49D12 18 .48 1.15 1.06
D12S391 GATA11H08 26 −.22 .21 −.05
D12S373 GATA6C01 36 −.25 .03 −.19
D12S1042 ATA27A06 49 −.06 .16 .04
C12S916 GATA91H06 56 .45 .25 .51
D12S398 GGAT2G06 68 .24 .63 .57
D12S1294 GATA73H09 78 1.01 .37 1.04
D12S375 GATA3F02 81 1.25 .33 1.21
D12S1052 GATA26D02 83 1.31 .25 1.20
D12S1064 GATA63D12 95 .99 .28 .97
D12S1300 GATA85A04 104 2.08 −.62 1.33
PAH PAH.PCR9 109 1.52 −.49 .97
D12S2070 ATA25F09 125 .24 −.66 −.19
D12S395 GATA4H01 137 .12 .34 .29
D12S2078 GATA32F05 150 1.11 −.70 .51
D12S1045 ATA29A06 161 1.05 −.86 .38
D12S392 GATA13D05 166 .57 −1.34 −.30
13:
D13S1243 AFMa217yb5 10 −.62 −.12 −.58
D13S217 AFM205XH12 17 −.55 .70 −.03
D13S1493 GGAA29H03 26 −.03 1.03 .59
D13S894 GATA86H01 33 .42 1.32 1.11
D13S325 GATA6B07 39 .42 .37 .56
D13S788 GATA29A09 46 .61 −.97 −.09
D13S800 GATA64F08 56 1.82 .09 1.53
D13S317 GATA7G10 64 1.78 .79 1.92
D13S793 GATA43H03 76 .47 −.06 .36
D13S779 ATA26D07 83 −.08 .03 −.05
D13S796 GATA51B02 94 .09 1.30 .85
D13S1265 AFMb318xh5 99 −.39 1.14 .37
D13S285 AFM309va9 111 .11 1.44 .96
14:
D14S742 GATA74E02 12 −.99 −1.35 −1.58
D14S1280 GATA31B09 26 −1.89 −1.80 −2.58
D14S608 GATA43H01 28 −1.65 −1.74 −2.35
D14S599 ATA29G03 41 −1.40 −.94 −1.68
D14S306 GATA4B04 44 −.42 −1.07 −.96
D14S587 GGAA10C09 56 .95 −.17 .67
D14S592 ATA19H08 67 .85 −.99 .10
D14S588 GGAA4A12 76 .86 −.76 .23
D14S53 Mfd190 86 1.01 .61 1.17
D14S606 GATA30A03 92 −.21 .72 .26
C14S1937 GATA193A07 96 −.35 1.84 .81
D14S617 GGAA21G11 106 .33 1.09 .92
D14S1434 GATA168F06 113 .23 1.36 1.00
D14S1426 GATA136B01 126 .87 .05 .74
D14S1007 AFMb002zf1 138 .22 .52 .48
15:
D15S128 AFM273yf9 6 1.57 −2.18 .02
D15S822 GATA88H02 12 .88 −1.85 −.38
D15S165 AFM248vc5 20 .79 −2.12 −.64
C15S503 GATA50C03 35 −.48 −1.03 −1.00
D15S659 GATA63A03 43 1.11 −1.19 .21
D15S643 GATA50G06 52 1.50 .20 1.35
D15S1507 GATA151F03 60 .91 .48 1.02
D15S131 AFM262xb1 71 .90 .76 1.18
D15S655 ATA28G05 83 .54 .28 .61
D15S652 ATA24A08 90 .26 .13 .29
D15S816 GATA73F01 101 −.62 −.37 −.72
D15S657 GATA22F01 105 −1.28 −.56 −1.36
D15S966 AFMa140ye5 112 −.55 −1.08 −1.08
D15S642 GATA27A03 122 −.72 −1.27 −1.32
16:
D16S3401 16PTEL06 0 .65 −1.54 −.39
D16S2616 ATA41E04 11 1.02 −1.57 −.10
D16S748 ATA3A07 23 1.26 −1.66 .08
D16S3103 AFMb337zc9 32 1.51 −.38 1.00
D16S403 AFM049xd2 44 1.17 −.40 .74
D16S769 GATA71H05 51 .08 −1.32 −.70
D16S540 GATA7B02 58 −.58 −.89 −.99
D16S3396 ATA55A11 64 −.77 −.82 −1.10
D16S3253 GATA22F09 72 −.67 −.15 −.63
C16S1385 GATA138C05 81 .13 .04 .13
D16S2624 GATA81D12 88 .27 −.52 −.07
D16S3096 AFMb322wb9 99 .98 −.16 .70
D16S3091 AFMB297ZC1 111 1.52 −.57 .89
D16S539 GATA11C06 125 .54 −.65 .07
D16S2621 GATA71F09 130 .31 −.51 −.03
17:
D17S1308 GTAT1A05 1 −.02 .00 −.01
D17S1298 GAAT2C03 11 −.23 −.59 −.54
D17S974 GATA8C04 22 .10 −.64 −.29
D17S1303 GATA64B04 24 .46 −.93 −.17
D17S799 AFM192yh2 32 1.00 −1.38 −.01
D17S2196 GATA185H04 45 −.03 −.67 −.41
D17S975 GGAT2C07 51 −.68 −1.50 −1.43
D17S1880 AFMa072zh9 53 −.66 −1.85 −1.61
D17S1299 GATA25A04 62 −1.25 −1.46 −1.85
D17S2180 ATC6A06 67 −1.41 −.97 −1.71
D17S1290 GATA49C09 82 −1.42 −.54 −1.46
D17S2193 ATA43A10 89 −1.12 −.29 −1.07
D17S1301 GATA28D11 100 −1.20 −.01 −.99
D17S784 AFM044xg3 117 −.12 −.95 −.66
D17S928 AFM217yd10 126 −.41 −.84 −.83
18:
C18S1781 GATA178F11 3 −.13 −.57 −.43
D18S976 GATA88A12 13 1.82 −.34 1.28
D18S843 ACT1A01 28 .97 .42 1.03
D18S542 GATA11A06 41 .58 1.77 1.49
D18S877 GATA64H04 54 .65 .30 .70
D18S535 GATA13 64 .19 −.15 .07
D18S851 GATA6D09 75 .42 −.04 .32
D18S858 ATA23G05 80 .81 .03 .68
D18S862 ATA7D07 89 1.74 −.06 1.37
D18S1364 GATA7E12 99 1.26 .52 1.33
C18S822 ATA82B02 107 1.39 .20 1.24
D18S1371 GATA177C03 116 1.32 −.02 1.06
D18S1390 18QTEL11 126 .79 .09 .70
19:
D19S591 GATA44F10 10 .86 1.24 1.41
D19S1034 GATA21G05 21 1.35 1.67 2.07
D19S586 GATA23B01 33 1.31 1.00 1.65
D19S714 GATA66B04 42 1.28 1.30 1.80
D19S433 GGAA2A03 52 1.01 −.02 .81
D19S245 Mfd235 59 1.23 .00 1.01
D19S178 Mfd139 68 1.20 −.39 .73
D19S246 Mfd232 78 −.52 .20 −.32
D19S589 GATA29B01 88 −1.09 .26 −.75
D19S254 Mfd238 101 −.75 −.70 −1.01
20:
D20S103 AFM077xd3 2 1.09 −.86 .38
D20S482 GATA51D03 12 .42 −1.48 −.48
D20S851 AFMa218yb5 25 2.34 −1.12 1.26
D20S604 GATA81E09 33 2.21 −1.19 1.10
D20S470 GGAA7E02 39 1.55 −1.49 .39
D20S477 GATA29F06 48 1.56 −.65 .89
D20S478 GATA42A03 54 .71 −.95 .02
D20S481 GATA47F05 62 1.30 −1.72 .08
D20S480 GATA45B10 80 −.17 −1.65 −1.07
D20S451 UT254 90 −.32 −1.61 −1.20
21:
D21S1432 GATA11C12 3 .20 −.18 .05
D21S1437 GGAA3C07 13 .93 −.60 .41
D21S2052 GATA129D11 25 .49 −1.38 −.37
D21S1440 ATA27F01 37 .25 −.33 .01
D21S266 AFM234xg9 46 −.18 −.70 −.56
D21S1446 GATA70B08 58 −.52 .08 −.38
22:
D22S420 AFM217xf4 4 1.22 −.70 .59
D22S345 MFD313 19 1.10 −1.23 .16
D22S689 GATA21F03 29 1.29 −1.65 .07
D22S685 GATA6F05 32 1.19 −1.88 −.15
D22S683 GATA11B12 36 1.11 −1.82 −.16
D22S683 GGAT3C10 46 .34 −1.34 −.53
D22S1169 AFMb337zh9 61 −.31 .00 −.26
23:
DXS9895 GATA124B04 9 −.39 .20 −.22
DXS9902 GATA175D03 22 −.52 .14 −.37
DXS9896 GATA124E07 40 .02 −.55 −.34
DXS1068 AFM238yc11 53 −.68 −.20 −.68
DXS6810 GATA69C12 64 −1.63 −.22 −1.49
CXS1444 GATA144D04 71 −1.67 .34 −1.17
DXS7132 GATA72E05 83 −1.47 −.22 −1.34
DXS6800 GATA31D10 93 −1.33 −.57 −1.43
DXS6789 GATA31F01 104 −.82 −1.39 −1.51
DXS6797 GATA10C11 112 −.10 −.98 −.69
CXS1725 GATA172D05 116 −.02 .27 .11
DXS1001 AFM248we5 130 1.53 .55 1.53
DXS1047 AFM150xf10 143 .49 .48 .65
DXS8044 AFM203ze11 143 .48 .47 .64
CXS318 GATA31E08 154 −.56 .66 −.08
DXS9908 GATA182E04 165 −1.73 .31 −1.26
DXS998 AFM224zg11 173 −1.23 .25 −.90
a

cM values refer to the STRP map of CIDR.

On chromosome 8p23.3-p12 (fig. 2), Zlr scores >2.0 were observed across 31 cM, from 30.7 to 61.7 cM on the CIDR map (∼26.6–58.5 cM on the deCODE map used for fine-mapping analyses; see below). The maximum multipoint evidence of linkage was a Zlr score of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM). Although the meaning of a 1-LOD interval is not clear for complex disorders, we note that here the 1-LOD interval (on the CIDR map) extended from 37.0 cM (18.36 Mb, at D8S1145) to 60.3 cM (32.12 Mb, at D8S1477). The linkage signal in this region was observed primarily in EA families, in which two peaks of similar magnitude were observed, at 11.5 cM (Zlr=3.52) and at 39.6 cM (Zlr=3.19), with a 1-LOD interval extending from 2.15 cM (∼3.03 Mb, centromeric to D8S264) to 58.3 cM (∼30.11 Mb, telomeric to D8S1477). In AA families, negative Zlr scores were observed from 8pter to 37.0 cM, with a maximum Zlr of 1.55 at 54.2 cM.

Figure 2.

Figure  2

Results of the STRP genome scan for SZ on chromosome 8 and the subsequent SNP fine mapping. Positive Zlr scores for the STRP scan for the entire sample (yellow line), EA subsample (blue line), and AA subsample (red line) are plotted on the Y-axis, and genomic position (CIDR cM converted to deCODE cM from p-ter, to allow plotting of the fine-mapping data) on chromosome 8 is plotted on the X-axis (0–80 cM). Similarly, positive Zlr scores for the scanning STRPs plus the fine-mapping SNPs for the entire sample (orange line), EA sample (green line), and AA sample (purple line) are plotted on the Y-axis, and genomic position (deCODE cM from p-ter) on chromosome 8 is plotted on the X-axis (0–80 cM). The PPP3CC gene is located at 39 deCODE cM, and the NRG1 (GGF2 isoform) gene spans 53–54 deCODE cM. The common inversion on chromosome 8p spans ∼18–22 deCODE cM and is marked.

Suggestive linkage was also observed in the entire sample at 11p11.2-q22.3 (fig. 3), with a Zlr of 2.74 at D11S2371 (76.1 cM; equivalent LOD of 1.63), with a 1-LOD interval from 61.9 cM (∼60.55 Mb, centromeric to D11S1344) to 94.6 cM (∼94.39 Mb, centromeric to D11S2000). Again, greater evidence of linkage was observed in EA families (Zlr=2.66 at D11S2371, 76.1 cM) than in AA families (Zlr=1.61 at D11S1391, 104.6 cM).

Figure 3.

Figure  3

Results of the STRP genome scan for SZ on chromosome 11 and the subsequent SNP fine mapping. Positive Zlr scores for the STRP scan for the entire sample (yellow line), EA subsample (blue line), and AA subsample (red line) are plotted on the Y-axis, and genomic position (CIDR cM converted to deCODE cM from p-ter, to allow plotting of the fine-mapping data) on chromosome 11 is plotted on the X-axis (30–120 cM). Similarly, positive Zlr scores for the scanning STRPs plus the fine-mapping SNPs for the entire sample (orange line), EA subsample (green line), and AA subsample (purple line) are plotted on the Y-axis, and genomic position (deCODE cM from p-ter) on chromosome 11 is plotted on the X-axis (30–120 cM).

In the exploratory analysis, uncorrected suggestive evidence of linkage was observed in AA families on chromosome 4p16.1-p15.32 (fig. 4) and in EA families on chromosome 5p14.3-q11.2 (fig. 5). For chromosome 4, the maximum Zlr of 2.72 was at 15.5 cM (6.92 Mb, centromeric to D4S2366), with a 1-LOD interval from 4pter to 35.5 cM (∼22.65 Mb, centromeric to D4S2639) in AA families. Zlr did not exceed 1.0 in the EA families on chromosome 4. For chromosome 5, the maximum Zlr of 2.77 was at 43.2 cM (∼31.61 Mb, telomeric to D5S1470), with a 1-LOD interval from 33.6 cM (∼17.50 Mb, telomeric to D5S2845) to 74.3 cM (∼66.62 Mb, telomeric to D5S2500) in EA families. Zlr did not exceed 1.0 in the AA families in this region of chromosome 5.

Figure 4.

Figure  4

Results of the STRP genome scan for SZ on chromosome 4 and the subsequent SNP fine mapping. Positive Zlr scores for the STRP scan for the entire sample (yellow line), EA subsample (blue line), and AA subsample (red line) are plotted on the Y-axis, and genomic position (CIDR cM converted to deCODE cM from p-ter, to allow plotting of the fine-mapping data) on chromosome 4 is plotted on the X-axis (0–60 cM). Similarly, positive Zlr scores for the scanning STRPs plus the fine-mapping SNPs for the entire sample (orange line), EA subsample (green line), and AA subsample (purple line) are plotted on the Y-axis, and genomic position (deCODE cM from p-ter) on chromosome 4 is plotted on the X-axis (0– 60 cM).

Figure 5.

Figure  5

Results of the STRP genome scan for SZ on chromosome 5 and the subsequent SNP fine mapping. Positive Zlr scores for the STRP scan for the entire sample (yellow line), EA subsample (blue line), and AA subsample (red line) are plotted on the Y-axis, and genomic position (CIDR cM converted to deCODE cM from p-ter, to allow plotting of the fine-mapping data) on chromosome 5 is plotted on the X-axis (10–100 cM). Similarly, positive Zlr scores for the scanning STRPs plus the fine-mapping SNPs for the entire sample (orange line), EA subsample (green line), and AA subsample (purple line) are plotted on the Y-axis, and genomic position (deCODE cM from p-ter) on chromosome 5 is plotted on the X-axis (10–100 cM).

Linkage Fine-Mapping Analysis

For the fine-mapping analysis, the deCODE map was used. We performed fine mapping for the four suggestive regions (4p16.3-p15.2, 5p15.2-q13.3, 8p23.3-q12.1, and 11p13-q23.3) and two other regions that had multiple markers with a Zlr >2.0 (10p15.3-p14 and 10q25.3-q26.3) (table 1). The average IC across the fine-mapping region for EA and AA families was 0.64 and 0.59, respectively, for the STRP map and was 0.85 and 0.79, respectively, for the map of 104 SNPs and 9 STRPs on chromosome 8p. The average IC for other fine-mapping regions for EA and AA families, respectively, was 0.83 and 0.77 for chromosome 4, 0.85 and 0.78 for chromosome 5, 0.80 and 0.77 for chromosome 10p, 0.83 and 0.78 for chromosome 10q, and 0.85 and 0.78 for chromosome 11 (table 1).

Figure 2 shows Zlr scores for the full sample and for EA and AA families separately, with a combination of STRPs and SNPs on chromosome 8p. In the full sample, the maximum Zlr score of 3.32 was observed at 44.4 cM (deCODE), just telomeric to D8S1771, where a similar peak (Zlr = 3.24) was observed in the scan analysis. In EA families, two peaks were again observed, although at slightly different locations than in the scan analysis: a telomeric peak (Zlr = 3.33) at 16.4 cM (deCODE), near the boundary of the inversion region (D8S1130), and a more centromeric peak (Zlr=3.10) at 35.7 cM (deCODE), telomeric to D8S560. In AA families, a maximum Zlr score of 1.68 was observed at 43.1 cM (deCODE), contributing to the peak result for the full sample. Results were essentially identical for analyses with the SNPs alone.

Therefore, fine mapping did not significantly increase or decrease the overall significance or length of the linkage peak in chromosome 8, despite an increase in IC. We note that the effect of the inversion on the analysis remains unclear. The genome-scan map contains two STRPs in the inversion region, as discussed above. We removed D8S1469 from the linkage analysis of STRPs alone (and also in the fine mapping) so that only one STRP (D8S1130) remained in this region. In EA families, the peak Zlr in this analysis remains very close to the inversion region. Until a more comprehensive analysis of the presence and sequence of inversions in this region can be performed, their effect on linkage results cannot be clearly understood. We consider the results of our analysis of 9 STRPs and 104 SNPs, with only 1 STRP within the inversion region, to be the most conservative estimation possible from the present data, and we conclude that genomewide suggestive linkage has been observed in the full sample, with two somewhat distinct peaks observed in the EA families.

However, we observed a more noticeable increase in significance for fine mapping of 5p15.2-q13.3 (fig. 5). In EA families, the 1-LOD interval was narrowed from 40.7 cM to 31.8 cM (table 1). It became clear that the centromere separated the linkage region into two peaks, and the maximum Zlr score of the more significant peak increased from 2.77, telomeric to D5S1470 (43.2 cM and ∼31.6 Mb) (5p peak), to 3.80 at rs1027164 (73.8 cM and 57.3 Mb) (5q peak) (fig. 5). Zlr did not exceed 1 before or after fine mapping in the AA families (data not shown).

With regard to the fine mapping of chromosome 4p16.3-p15.2 that showed suggestive linkage in AA families and of chromosome 11p13-q23.3 that showed suggestive linkage in both the EA and the combined samples, the significance remained almost the same as before fine mapping (table 1 and figs. 3 and 4). However, we were able to narrow the 1-LOD interval for chromosome 11 from 32.7 cM to 19.5 cM in the full sample. For chromosome 10 regions, fine mapping did not improve any significance of linkage beyond a Zlr score of 3 (table 1).

Discussion

Genetic factors appear to predominate in the etiology of SZ, given a heritability estimated at 0.8. Most studies of the molecular genetics of SZ have investigated possible associations with functional polymorphisms in loci relevant to monoamine neurotransmission, which have been considered candidate genes on the basis of simple pharmacological models of SZ. Linkage studies have the advantage of not depending on any knowledge of the pathophysiology of the disorder. The most recent meta-analysis of SZ genome scans, including 20 analyses from 16 individual projects, showed significant evidence, across these studies, of linkage in a number of chromosomal regions (Lewis et al. 2003). In several of these regions, plausible candidate genes have been identified for which substantial evidence of association with SZ has been reported more than once (Craddock et al. 2005).

We have reported here one of the largest genome scans of SZ to date. The primary linkage analyses included predominantly EA or AA families. To take into account the possibility that these groups might differ in the effects of different SZ susceptibility loci, separate exploratory analyses of EA and AA families were also performed. Genomewide suggestive evidence of linkage was observed in the primary analysis on chromosomes 8p23.3-p12 and 11p11.2-q22.3, and, in the exploratory analyses, this threshold was also exceeded (without correction for multiple tests) on chromosome 4p16.1-p15.32 in AA families and on chromosome 5p14.3-q11.2 in EA families.

There are some limitations to our conclusions. For example, it is not known how to best define the phenotype for genetic studies of SZ. There is considerable support for the approach of combining the DSM-IV categories of SZ and SA, on the basis of their high relative risk in families of probands with SZ compared with the general population, their similar clinical characteristics in our (and other) samples, and the high reliability with which these diagnoses have been assigned. However, more-optimal phenotypes or endophenotypes might be identified in the future. Furthermore, despite the fact that this is a very large single sample of pedigrees with SZ, it lacks sufficient power to reliably detect loci with small effects.

The strongest evidence of linkage was at chromosome 8p23.3-p12. However, the presence of a common paracentric inversion in our strongest linkage region has complicated our analyses and the interpretation of results. It is possible, for example, that SZ is associated either with the presence of certain specific inversions or with one or more genes within the inversion segment. Also, failure to account for the presence of the inversion might have influenced the results of previous linkage analyses in this region (e.g., the location of the peak signals) in ways that are not yet clear. We evaluated the sensitivity of our linkage analyses to the genetic map assumptions, and linkage results remained basically unchanged whatever the assumed order of the SNPs located within the inverted region. Our results appeared to be more sensitive to the map length. Unsurprisingly, Zlr scores varied with the assumed length, but these variations remained relatively moderate. For instance, a twofold decrease in map length led to a 6% reduction in Zlr score. Conversely, the assumption of a twofold longer map led to a 5% increase in Zlr score. In spite of these perhaps modest limitations related to the map effects of the inversion, evidence of a susceptibility locus for SZ in 8p has been detected in other family samples (table A3), and two positional candidate genes—NRG1 and protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoform (calcineurin A gamma) (PPP3CC)—have been proposed to account for the linkages (Stefansson et al. 2002; Gerber et al. 2003), although neither can be considered definitively established (for example, see the detailed analysis of the reported association between NRG1 and SZ [Duan et al. 2005]). The linkage signal in the present sample was extremely broad: nine STRP markers across 60 cM produced linkage signals at nominal P<.01 (Zlr>2.326) in the combined sample and in the EA families separately (table 5). We continued to observe suggestive evidence of linkage in the fine-mapping analysis, and it is improbable that a denser SNP map would substantially increase the linkage signal. In the EA families, which are largely responsible for the positive signal in this region, there appear to be two peaks. Given this, plus the repeated observation of evidence of SZ linkage in this region and the diverse locations of the peak evidence of linkage across studies, there might be more than one SZ susceptibility gene in this region. The 8p23-p12 region contains 239 annotated genes (UCSC Genome Bioinformatics, May 2004 freeze); this includes 137 genes that are annotated as full length, with an initiating ATG and valid stop-codon, that can be translated from the genome without frameshifts, and that use consensus splice sites (Consensus Coding DNA Sequence [CCDS] database, March 2005 report; see CCDS Web site). In addition to NRG1 and PPP3CC in 8p, a substantial number of the genes in this region might be considered positional candidates because of their roles in brain function, and, given that the pathophysiology of SZ is largely unknown, there could be additional relevant genes. Therefore, large and systematic case-control and/or family-based LD mapping experiments should be undertaken in this region.

In summary, a genome scan of a large sample of pedigrees with SZ has produced suggestive evidence of linkage in two regions and evidence of two other suggestive regions in exploratory analyses of AA and EA families (see table 7 for results of fine mapping in our sample). Some of these regions have support from multiple other SZ linkage scans (see tables A3 and A4). The present study increases support for the hypothesis that one, or possibly more than one, SZ susceptibility gene is located on chromosome 8p. The SZ candidate regions observed in multiple samples should be studied systematically in large samples with the use of LD mapping methods.

Table 7.

STRPs and SNPs by Map Position and Multipoint Zlr for Fine-Mapping Regions


Zlr
Chromosomeand Marker Alias Position(cM)a EA Sample AA Sample Total Sample
4:
rs11727981 hCV11282864 .3 −.71 2.09 .65
rs1135945 hCV9657182 .6 −.73 2.15 .66
rs13138362 hCV1884907 1.0 −.77 2.22 .67
rs2290404 hCV9039853 1.2 −.81 2.24 .65
rs2236995 hCV3253724 2.2 −.97 2.26 .55
rs231200 rs231200 2.5 −.99 2.32 .57
rs4974665 hCV3176043 2.9 −.92 2.36 .67
rs445160 hCV3243313 3.7 −.89 2.45 .77
rs1475977 hCV7565657 3.9 −.88 2.46 .78
rs916171 hCV7565369 4.3 −.87 2.49 .80
rs1741553 hCV1269876 5.2 −.91 2.50 .79
rs910643 hCV2523717 6.2 −.93 2.51 .76
rs873924 rs873924 7.2 −.69 2.49 .92
rs4689174 rs4689174 7.4 −.65 2.46 .94
rs6833060 hCV2876203 7.5 −.79 2.44 .82
rs4361326 hCV376560 8.0 −.77 2.45 .86
rs1812310 rs1812310 8.6 −.58 2.33 .94
rs4689261 hCV2881264 9.8 −.32 2.33 1.15
rs984576 rs984576 10.7 −.10 2.28 1.29
rs7664611 hCV2979334 11.5 .01 2.34 1.41
D4S2366 GATA22G05 12.5 .07 2.49 1.54
rs2279195 hCV1900723 21.3 −.33 2.96 1.49
rs938563 hCV1216607 22.2 −.08 3.06 1.76
rs747357 hCV2400825 22.4 −.05 3.08 1.79
rs2868942 hCV2643298 22.7 .02 3.09 1.85
rs7681266 hCV369676 23.1 .11 3.09 1.94
rs7662694 rs7662694 23.5 .06 3.06 1.89
rs7674470 hCV2976961 24.9 .05 3.00 1.84
rs1388875 hCV11990265 25.4 −.07 2.95 1.72
rs717376 hCV1895671 25.6 −.10 2.94 1.69
rs961996 hCV8842641 25.7 −.12 2.92 1.66
rs763318 hCV2308179 26.1 −.08 2.82 1.64
rs6838908 hCV2967286 26.6 −.02 2.78 1.65
D4S403 AFM157xg3 26.7 −.04 2.77 1.63
rs1019271 hCV1192337 26.8 −.03 2.65 1.57
rs558473 rs558473 27.1 −.05 2.71 1.59
rs6449004 hCV2900115 27.4 −.09 2.67 1.54
rs1032732 hCV7563531 27.9 −.02 2.71 1.62
rs11728802 hCV2878633 28.2 .17 2.66 1.75
rs923985 hCV9512533 28.5 .32 2.61 1.82
rs6449126 rs6449126 29.3 .59 2.66 2.06
rs1861048 hCV2672580 29.5 .65 2.69 2.12
rs6834674 hCV1216865 30.0 .81 2.71 2.27
rs717176 hCV343178 30.3 .81 2.55 2.18
rs10034719 hCV8281272 30.5 .83 2.62 2.24
rs2036358 hCV1485501 30.9 .75 2.63 2.18
rs1496747 hCV3031687 31.2 .48 2.59 1.94
rs7671482 hCV3142167 32.0 .41 2.24 1.68
rs7671329 hCV1321122 33.5 .21 2.07 1.43
rs13104297 hCV2801460 34.3 .32 1.83 1.37
rs7668417 hCV1704075 34.5 .39 1.79 1.41
rs1861125 hCV11989661 34.6 .45 1.76 1.43
D4S2639 GATA90B10 34.7 .46 1.75 1.44
rs2643435 rs2643435 34.8 .47 1.75 1.46
rs1452554 rs1452554 35.0 .52 1.74 1.49
rs312364 rs312364 35.0 .52 1.74 1.49
rs901123 hCV1970471 35.1 .49 1.80 1.50
rs1323067 hCV2946946 35.4 .43 1.84 1.49
rs525684 hCV2946855 35.7 .37 1.83 1.42
rs1019997 hCV8289078 36.3 .33 1.65 1.27
rs1364836 hCV8847912 36.9 .28 1.56 1.18
rs925570 hCV7462900 37.4 .27 1.50 1.14
rs2270851 hCV11544446 37.6 .23 1.47 1.09
rs10030690 rs10030690 38.0 .21 1.38 1.01
rs989631 hCV9512541 38.1 .21 1.32 .98
rs6857002 hCV2645274 38.7 .26 1.19 .94
rs4407488 hCV1216773 39.8 .36 .93 .87
rs7684572 hCV2668686 40.3 .36 .91 .85
rs1035091 hCV336230 41.7 .12 .68 .51
rs6831932 hCV3038799 42.3 .05 .64 .44
rs11731086 hCV1222538 43.3 .01 .64 .40
rs2048506 hCV1219482 44.9 −.12 .70 .32
rs13144326 hCV1585404 45.2 −.15 .70 .30
rs260960 hCV1228386 45.7 −.15 .72 .31
rs6833149 hCV7672079 46.3 −.11 .70 .33
rs1947508 hCV11938279 47.1 .04 .57 .37
D4S391 AFM016xf3 47.3 .04 .57 .38
5:
D5S817 GATA3E10 29.9 .78 −1.09 .05
rs1530495 hCV7572662 31.9 .87 −.95 .20
rs30623 hCV2936976 32.8 1.11 −.86 .45
rs153931 hCV3088146 33.8 1.44 −.76 .77
rs983889 hCV1401088 34.7 1.77 −.74 1.04
rs162859 hCV2935668 35.9 1.91 −.56 1.25
rs31463 hCV1162271 37.8 1.83 −.29 1.33
rs2036848 hCV1454666 38.1 1.83 −.18 1.40
rs1443404 hCV7580382 38.5 1.91 −.19 1.46
rs6870006 rs6870006 38.9 1.84 −.23 1.38
rs10472818 rs10472818 39.4 1.77 −.04 1.43
rs1911864 hCV12086585 40.0 1.70 −.03 1.38
rs2434772 hCV2941094 40.5 1.75 −.05 1.42
rs248186 rs248186 40.9 1.82 −.03 1.48
rs7725275 hCV198613 41.3 1.89 −.06 1.52
rs995178 hCV9621778 41.9 1.85 −.02 1.51
D5S2845 GATA134B03 42.5 1.84 .09 1.55
rs7716862 hCV2939263 42.6 1.90 .06 1.59
rs1402426 rs1402426 43.0 2.06 −.03 1.67
rs1366262 hCV1399202 43.7 2.40 −.06 1.93
rs1505874 hCV2935236 44.0 2.48 −.11 1.97
rs2014790 hCV8796946 44.9 2.86 −.16 2.23
rs1566037 hCV2708385 46.2 3.35 −.19 2.61
D5S2848 GATA145D09 46.4 3.42 −.19 2.66
rs10942230 hCV2940113 46.6 3.52 −.19 2.75
rs1501680 hCV1399439 47.5 3.54 −.19 2.78
rs397425 hCV1028719 47.9 3.51 −.09 2.83
rs9292323 hCV2933709 48.2 3.50 −.01 2.87
rs4867029 hCV28011100 48.9 3.41 .11 2.86
rs2133764 rs2133764 50.0 3.38 .18 2.89
rs2068015 hCV1428649 50.5 3.36 .19 2.87
rs500557 hCV2940056 51.8 3.10 .33 2.74
rs641221 hCV605081 53.8 2.92 .78 2.87
D5S1470 GATA7C06 53.9 2.91 .78 2.86
rs6864434 hCV1488765 54.2 2.80 .74 2.75
rs1981968 hCV11324483 54.6 3.01 .71 2.91
rs7705177 rs7705177 54.8 3.04 .65 2.91
hCV2838186 hCV2838186 55.7 3.00 .48 2.79
rs213583 hCV655159 56.0 3.03 .44 2.79
rs13189166 hCV1114849 56.3 2.84 .43 2.65
rs460053 hCV3172343 57.0 2.83 .47 2.69
hCV3020978 hCV3020978 57.5 2.78 .47 2.63
rs7731139 rs7731139 57.7 2.68 .41 2.51
rs10454863 hCV1999272 57.9 2.59 .42 2.44
rs1549681 hCV1400831 58.7 2.57 .43 2.41
rs158409 hCV2935131 58.8 2.60 .40 2.42
rs11958226 rs11958226 59.2 2.61 .32 2.37
rs2910797 hCV1395027 59.6 2.61 .29 2.35
rs2289779 hCV11360428 62.0 2.52 −.09 2.09
rs379707 hCV646794 63.5 2.75 −.22 2.20
rs495237 hCV1002294 64.6 2.78 −.39 2.14
rs1564269 hCV7581372 64.7 2.78 −.44 2.11
rs1376178 hCV1321333 65.0 2.79 −.48 2.11
rs1801033 hCV115685 65.3 2.80 −.58 2.05
rs11740946 hCV264064 65.5 2.80 −.61 2.04
rs2972408 hCV1567451 66.2 2.70 −.45 2.06
D5S1457 GATA21D04 66.3 2.67 −.23 2.15
rs2972756 hCV2841551 66.3 2.68 −.34 2.10
rs6895327 hCV450793 66.5 2.69 −.34 2.12
rs4285229 hCV11553362 66.7 2.66 −.33 2.12
rs900379 hCV8291179 66.8 2.66 −.31 2.13
rs10035564 hCV11554044 67.1 2.64 −.25 2.17
rs2337954 hCV2127591 67.3 2.71 −.25 2.21
rs166863 hCV2994177 67.4 2.75 −.20 2.29
rs2288468 hCV11371816 67.4 2.75 −.19 2.30
rs929819 hCV8289991 67.4 2.75 −.19 2.30
rs1345981 hCV2865963 67.7 2.82 −.13 2.39
rs12521153 hCV2838776 68.7 3.03 −.13 2.54
rs10940347 hCV3186696 68.9 3.09 −.16 2.57
rs250387 hCV2386214 69.1 3.12 −.17 2.58
rs714459 hCV2840288 69.5 3.16 −.24 2.56
rs1363864 hCV3019869 70.1 3.29 −.37 2.58
rs3804264|s hCV1401643 70.5 3.43 −.46 2.63
rs191205 hCV1025536 70.9 3.59 −.47 2.76
rs30000 hCV807035 71.5 3.70 −.44 2.86
rs252890 hCV2840868 72.4 3.63 −.47 2.79
rs2972355 hCV1238506 72.9 3.72 −.49 2.85
rs1027164 hCV8886893 73.8 3.80 −.56 2.85
rs159729 hCV3099052 74.8 3.72 −.69 2.68
D5S2500 GATA67D03 75.2 3.62 −.73 2.56
rs27548 hCV3248153 75.2 3.62 −.73 2.56
rs159195 rs159195 75.2 3.53 −.72 2.50
rs1995780 hCV11486548 75.4 3.51 −.68 2.50
rs153067 hCV8963983 75.5 3.49 −.68 2.48
rs34634 hCV1144877 75.7 3.45 −.71 2.43
rs4078970 hCV7573130 76.2 3.33 −.85 2.26
rs2344396 hCV1561870 76.7 3.16 −1.00 2.07
rs7715472 hCV3248309 76.8 3.12 −1.02 2.03
rs346437 hCV3045752 77.0 3.03 −1.04 1.94
rs4527551 hCV1497859 77.1 2.97 −1.04 1.89
rs272629 hCV2765438 77.5 2.79 −.78 1.89
rs12651884 hCV7693739 77.7 2.75 −.67 1.92
rs10042323 hCV1186571 77.9 2.69 −.61 1.91
rs37347 hCV3166294 78.1 2.49 −.62 1.74
rs1317632 hCV37054 78.6 2.33 −.66 1.57
rs257712 hCV2841358 78.7 2.31 −.67 1.55
rs984091 hCV7447368 79.2 2.11 −.67 1.38
rs7705123 rs7705123 80.0 2.23 −.49 1.58
rs28155 hCV946441 81.2 2.13 −.36 1.59
rs164578 hCV918494 81.6 2.15 −.34 1.62
rs2561183 hCV2934686 81.7 2.13 −.36 1.59
rs7448990 hCV2837195 82.7 1.75 −.49 1.22
rs1531312 hCV1698516 83.4 1.62 −.67 1.01
rs6886010 rs6886010 83.7 1.55 −.83 .86
rs4041421 hCV1393623 84.0 1.49 −.90 .79
rs1403728 hCV3060555 84.4 1.46 −.98 .72
rs347245 hCV2828781 84.9 1.39 −1.06 .63
rs282381 hCV544172 85.5 1.21 −1.05 .49
rs890995 hCV2938484 86.6 .94 −1.22 .21
rs7734427 hCV74896 87.8 .95 −1.40 .17
rs7717355 rs7717355 88.9 .90 −1.39 .19
rs4374745 hCV174414 89.5 .86 −1.33 .16
rs10045155 rs10045155 90.2 .90 −1.25 .22
D5S424 AFM214zg9 90.9 .67 −1.20 .04
8:
rs1979176 hCV12003528 .0 1.89 −2.34 .21
rs6558451 hCV2769705 1.8 1.90 −2.25 .25
rs4354330 hCV2062160 2.6 1.83 −2.29 .17
D8S264 AFM143xd8 4.0 1.99 −2.46 .19
rs17515 hCV12004129 5.1 2.51 −2.59 .55
rs10088378 hCV1423079 7.0 3.03 −2.82 .83
D8S262 AFM127xh2 7.9 3.28 −2.93 .95
rs2740898 hCV8849739 8.6 3.26 −2.94 .94
rs1560428 hCV7533717 9.6 3.17 −2.95 .86
rs9314540 rs9314540 11.0 3.00 −2.78 .87
rs11779265 hCV8315417 12.0 2.82 −2.62 .83
rs10503309 rs10503309 13.1 2.84 −2.54 .94
rs6559058 rs6559058 14.1 3.05 −2.44 1.16
rs2442581 rs2442581 15.9 3.27 −2.20 1.42
rs7834209 rs7834209 16.4 3.33 −2.20 1.46
rs2980438 hCV11587790 17.8 3.19 −2.34 1.23
rs506960 hCV725401 18.5 3.09 −2.28 1.19
D8S1130 GATA25C10 19.3 2.93 −2.18 1.13
D8S1106 GATA23D06 24.7 2.25 −1.96 .75
rs609020 hCV1380 25.9 2.42 −1.87 .92
rs7006666 hCV1160271 26.6 2.46 −1.76 1.02
rs2017470 hCV1854379 26.7 2.49 −1.75 1.06
rs1355305 hCV283932 27.1 2.52 −1.69 1.11
rs4383970 hCV10024049 27.3 2.56 −1.66 1.16
rs352783 hCV2038032 28.0 2.49 −1.43 1.21
rs1871573 hCV12104846 28.6 2.35 −1.42 1.08
rs822300 rs822300 29.3 2.37 −1.35 1.12
rs2239879 hCV2441245 30.4 2.62 −1.22 1.40
rs2904748 hCV16157316 31.1 2.85 −.98 1.73
rs2237851 rs2237851 31.5 2.82 −.87 1.77
rs1041983 hCV8684085 32.1 2.80 −.72 1.85
D8S1145 GATA72C10 32.2 2.90 −.69 1.94
rs3736273 hCV1199888 32.9 2.94 −.54 2.06
rs4486225 hCV11848800 34.0 2.96 −.33 2.20
rs7005767 hCV9639133 34.7 3.03 −.23 2.33
 NA hCV1167258 35.7 3.10 .06 2.55
rs896044 hCV1313416 36.3 3.05 .18 2.59
rs11991767 hCV1682164 37.5 3.01 .40 2.66
D8S560 AFMa127ye5 38.8 2.97 .76 2.84
rs7490 hCV8805141 39.4 2.96 .93 2.93
rs9886594 rs9886594 40.0 3.02 1.10 3.09
rs2055824 hCV12106772 41.9 2.86 1.35 3.10
rs1002791 hCV75221 42.3 2.94 1.46 3.23
rs2928679 hCV1382529 42.7 2.83 1.62 3.24
rs1436148 hCV8470964 43.1 2.70 1.68 3.17
rs7836430 hCV2995961 43.9 2.82 1.65 3.25
rs196886 hCV796208 44.4 2.91 1.66 3.32
rs11998492 hCV11857651 44.8 2.89 1.62 3.28
D8S1771 AFMb320va5 44.8 2.88 1.62 3.28
rs2467698 hCV2895454 45.1 2.66 1.56 3.07
rs4872389 hCV1158898 45.8 2.56 1.44 2.92
 NA hCV3094290 46.2 2.53 1.38 2.85
rs442103 hCV1126721 46.8 2.51 1.33 2.81
rs1351499 hCV1714124 47.5 2.70 1.04 2.78
rs11783299 hCV2152299 47.5 2.70 1.04 2.78
rs2071575 hCV2045384 47.6 2.69 1.03 2.78
rs2294092 hCV1374353 48.1 2.61 .97 2.67
rs4732838 hCV1140451 48.8 2.18 .90 2.28
 NA hCV2049967 49.2 2.13 .91 2.25
rs6558073 hCV3275985 49.6 2.02 .94 2.17
rs12056328 hCV25645594 50.4 1.74 1.04 2.01
rs12676327 hCV444094 51.2 1.76 1.10 2.06
rs12386822 hCV1584515 52.1 1.78 1.09 2.08
rs2979487 hCV15880850 52.9 1.68 1.14 2.02
 NA hCV1379657 53.2 1.63 1.25 2.04
 NA hCV2779153 53.5 1.67 1.32 2.13
rs763551 hCV2259922 53.9 1.80 1.46 2.31
rs1481762 hCV8868705 54.2 1.89 1.42 2.35
D8S1477 GGAA20C10 54.3 1.90 1.41 2.36
 NA hCV2870374 54.5 1.91 1.32 2.31
rs4733142 hCV8280633 54.8 1.96 1.28 2.33
rs938641 hCV445693 55.1 1.98 1.20 2.30
rs7463110 hCV1943749 55.4 1.94 1.10 2.21
rs6468305 rs6468305 55.6 1.80 .98 2.02
rs7826624 hCV1374319 56.1 1.71 .95 1.93
rs670603 hCV2446103 56.5 1.62 1.04 1.92
 NA hCV2445923 56.8 1.57 1.03 1.88
rs1111387 hCV2445746 56.9 1.54 1.05 1.86
rs2298320 hCV2445274 57.4 1.26 1.04 1.63
rs7812866 hCV1718918 57.6 1.18 1.02 1.56
rs1043782 hCV8844184 57.8 1.13 .99 1.50
rs7816768 hCV2159104 58.2 1.05 .93 1.39
rs7832578 hCV95287 58.4 1.05 .89 1.37
rs3852339 hCV8896420 58.8 1.03 .92 1.37
rs2589916 hCV2045597 60.1 .74 .84 1.10
rs868586 hCV1593263 60.5 .72 .77 1.05
rs7823929 hCV448973 61.0 .64 .66 .92
rs7837006 hCV2896129 61.1 .63 .67 .91
rs906290 hCV3201067 61.2 .57 .64 .85
rs732612 hCV2533651 61.3 .47 .50 .69
rs2304297 hCV15974192 61.5 .40 .49 .63
 NA hCV2896764 61.5 .39 .48 .61
rs7003908 hCV1841761 63.2 .02 .20 .16
rs1027966 hCV8809457 63.3 .02 .20 .15
rs2279301 hCV333405 63.3 .01 .19 .15
rs11990854 hCV1563801 63.7 −.05 .20 .09
rs4873375 rs4873375 64.0 −.11 .24 .07
rs7002235 hCV1145366 64.0 −.11 .24 .07
rs4382493 hCV174458 64.5 −.14 .26 .07
rs1367819 hCV2049503 65.2 −.28 .00 −.20
rs718251 hCV9319187 65.5 −.26 −.01 −.19
rs1365245 hCV7478079 66.1 −.09 −.04 −.07
D8S1110 GATA8G10 66.6 −.12 −.09 −.11
rs10504146 rs10504146 66.8 −.13 −.10 −.13
rs545125 hCV3140037 67.1 −.13 −.10 −.12
rs1477958 hCV7480634 68.0 −.11 −.20 −.17
rs7824575 hCV1951523 68.5 −.18 −.25 −.25
rs311390 hCV3034570 68.5 −.19 −.19 −.22
 NA hCV2770809 68.6 −.19 −.10 −.18
rs7837220 hCV1854535 69.2 .04 .15 .14
rs867531 hCV8967543 69.3 .08 .14 .17
rs12678930 hCV1320563 69.4 .11 .15 .19
rs1821814 hCV11365409 69.7 .16 .11 .21
rs1834413 hCV11922708 70.2 .13 −.03 .10
rs1317836 rs1317836 70.7 .07 −.12 .00
rs4397388 hCV117013 71.0 .10 −.17 .00
rs6471680 hCV2826238 71.3 −.11 −.19 −.18
rs1023651 hCV2914108 71.6 −.17 −.21 −.25
10p:
rs2448384 hCV1904568 1.2 1.77 .86 1.99
rs7912017 rs7912017 1.5 1.74 .82 1.93
rs10904587 hCV27050 2.0 1.67 .80 1.88
rs4256905 hCV358407 2.2 1.61 .80 1.83
rs1500965 hCV7886666 2.4 1.56 .80 1.78
rs2387662 hCV488722 2.5 1.58 .81 1.81
rs2813440 hCV241818 2.6 1.62 .86 1.86
rs1029182 rs1029182 4.4 2.26 .85 2.36
rs10751855 hCV1759096 5.5 2.36 .82 2.41
rs826472 hCV7431936 5.7 2.37 .81 2.41
rs729397 hCV3162530 5.8 2.36 .79 2.40
rs2279768 hCV11648249 9.5 1.99 .49 1.91
D10S1435 GATA88F09 10.1 1.95 .45 1.85
rs9630129 hCV1904916 11.0 2.20 .22 1.92
rs1325586 hCV1977337 11.5 2.30 .13 1.94
rs10795055 hCV3003439 12.2 2.45 .10 2.05
rs1886946 hCV11373985 13.5 2.50 .05 2.08
rs1022768 hCV8914257 14.2 2.50 −.01 2.05
rs1751277 hCV1853650 14.6 2.51 −.05 2.04
rs4266965 hCV7873798 15.6 2.49 .00 2.07
rs1155931 hCV1803410 16.2 2.52 −.01 2.10
rs4881450 hCV399566 16.9 2.42 .05 2.06
rs2386638 hCV278985 17.5 2.31 .07 2.00
rs7072398 hCV1882638 18.3 2.10 .09 1.87
rs3750671 hCV9615599 18.6 2.01 .06 1.79
rs7902155 rs7902155 18.8 1.90 .06 1.69
rs3815975 rs3815975 19.4 1.72 .03 1.51
rs2255088 hCV16011810 19.6 1.64 .04 1.44
D10S189 AFM063xf4 19.8 1.65 .04 1.45
10q:
D10S1237 GATA48G07 134.1 1.49 .23 1.42
rs11196798 hCV1765605 134.2 1.52 .14 1.40
rs703349 hCV3085761 134.8 1.58 .29 1.58
rs658530 hCV10013467 134.8 1.58 .29 1.58
rs1264798 rs1264798 134.8 1.58 .29 1.58
rs10159620 hCV2647718 135.3 1.52 .35 1.57
rs1017822 hCV3088272 135.6 1.47 .38 1.54
rs180552 hCV3088334 135.9 1.61 .48 1.70
rs2420257 hCV15801819 136.3 1.76 .59 1.87
rs11197672 hCV2065828 136.6 1.72 .61 1.83
rs1867991 hCV12127228 136.9 1.76 .51 1.80
rs740598 hCV3254784 137.1 1.78 .42 1.76
rs2118207 hCV15820611 137.4 1.81 .42 1.78
hCV55714 hCV55714 137.6 1.87 .44 1.84
rs1935168 hCV11744008 137.8 1.92 .40 1.85
rs71003 hCV2981626 138.0 2.04 .36 1.93
rs1343418 hCV11212949 139.2 2.07 .42 1.99
rs853600 rs853600 140.1 1.94 .47 1.90
rs1857269 hCV11757499 140.6 1.88 .51 1.87
rs4752182 hCV8171237 140.9 1.85 .49 1.83
rs7905458 hCV1484613 141.5 1.94 .47 1.89
rs884970 hCV1802876 142.0 1.71 .44 1.69
rs10886515 hCV2101894 142.2 1.68 .56 1.73
rs378150342 hCV1310103 142.5 1.66 .50 1.68
rs1537219 hCV2731394 143.2 1.61 .59 1.70
rs12769643 hCV8174365 143.8 1.47 .71 1.65
rs7082695 hCV8175290 144.4 1.36 .62 1.51
rs732640 hCV2118990 144.9 1.36 .53 1.46
rs2288336 hCV11309727 146.2 1.36 .57 1.49
rs12571870 hCV1821946 147.0 1.34 .38 1.36
rs7920046 hCV3006292 147.2 1.34 .36 1.34
rs6599619 hCV1821764 148.0 1.20 .31 1.19
rs9804347 hCV367398 148.2 1.17 .31 1.17
rs10751744 hCV2102486 148.4 1.16 .29 1.15
rs766295 hCV2102652 148.6 1.01 .30 1.04
rs11597880 hCV1250945 151.3 .60 .88 1.06
D10S1656 AFMa184xd9 151.4 .61 .91 1.08
rs12569498 hCV251049 151.6 .62 1.02 1.17
rs10736889 hCV1662136 152.0 .53 1.16 1.20
rs2015178 rs2015178 152.6 .47 1.20 1.20
rs875748 hCV8892668 153.8 .35 1.31 1.14
rs768761 hCV1703535 154.3 .39 1.35 1.19
rs2281955 hCV2017094 155.2 .45 1.31 1.19
rs10901596 hCV1419866 156.7 .44 1.31 1.17
rs1436804 rs1436804 157.3 .36 1.35 1.13
rs7909756 rs7909756 157.8 .37 1.35 1.13
rs10741150 hCV372978 158.5 .47 1.34 1.21
rs2483853 hCV1779324 158.7 .47 1.37 1.25
rs943207 hCV8197363 159.2 .48 1.41 1.27
D10S217 AFM212XD6 159.9 .54 1.31 1.23
rs1410064 hCV2009015 160.4 .46 1.16 1.08
rs10764754 hCV1801130 160.7 .45 1.16 1.07
rs1001990 hCV8901459 163.1 .52 .77 .90
rs7085203 rs7085203 164.8 .62 .90 1.05
rs1869251 hCV3014410 165.4 .68 .90 1.11
rs1861860 rs1861860 166.4 .71 .91 1.13
rs7898151 hCV3158009 168.1 .75 1.00 1.20
rs573370 hCV1769819 168.8 .79 .91 1.19
D10S1248 GGAA23C05 169.2 .93 .72 1.18
rs447363 rs447363 170.0 1.04 .75 1.29
rs448669 hCV1166802 170.4 1.07 .71 1.29
rs964681 rs964681 172.0 1.37 .65 1.49
rs11017736 hCV363155 172.8 1.43 .61 1.52
rs754575 hCV3232964 173.2 1.46 .62 1.55
hCV94022 hCV94022 175.4 1.59 .66 1.68
rs870552 hCV9496352 176.0 1.66 .68 1.75
rs11146353 hCV12058853 176.6 1.67 .66 1.75
D10S212 AFM198zb4 177.2 1.61 .58 1.65
11:
D11S1392 GATA6B09 50.6 .73 −.66 .20
rs2288667 hCV15879519 51.2 .75 −.54 .29
rs1570214 hCV7619035 51.8 .99 −.51 .50
rs650693 hCV995778 52.7 1.38 −.41 .87
rs10836555 hCV2898958 53.7 1.72 −.16 1.29
rs179801 rs179801 55.4 1.50 .34 1.39
ss2946400 hCV12037009 56.0 1.40 .46 1.38
rs1038254 hCV9821215 56.3 1.35 .47 1.34
rs10837120 hCV1177638 56.3 1.35 .47 1.34
rs2953308 hCV1625511 57.0 1.32 .46 1.32
rs1371671 hCV8894006 57.2 1.32 .45 1.32
rs1381578 hCV1204510 57.5 1.33 .47 1.34
rs959632 hCV2162237 57.8 1.43 .51 1.45
rs1484960 rs1484960 58.2 1.42 .51 1.46
rs2042684 hCV2897320 58.8 1.37 .56 1.47
D11S1993 ATA1B07 59.2 1.34 .58 1.46
rs10838149 hCV289210 59.3 1.34 .56 1.45
rs178503 hCV12032785 59.8 1.34 .59 1.46
rs1344709 hCV2836372 61.5 1.10 .87 1.44
rs2289448 hCV9653411 63.0 .87 .92 1.29
rs2945999 hCV1717146 63.4 .90 .96 1.34
D11S1344 AFM298vc9 63.5 .90 .97 1.35
rs12284298 hCV2898441 63.5 .93 .99 1.39
rs1055447 hCV9636495 63.7 .84 1.06 1.37
rs11039402 rs11039402 63.8 .88 1.06 1.41
rs753095 hCV11668059 63.8 .88 1.06 1.41
rs692607 hCV1182084 63.9 .95 1.07 1.46
rs11227802 hCV1870167 64.0 .87 1.07 1.40
rs514385 hCV1000052 64.2 .86 1.03 1.36
rs2441952 rs2441952 64.2 .81 1.03 1.31
rs1938596 hCV3185821 64.2 .80 1.03 1.31
rs1938781 hCV3160372 64.5 .96 1.03 1.43
rs507035 hCV2138493 64.9 1.07 1.01 1.51
rs198436 hCV2575631 67.0 1.42 .96 1.76
rs10897237 hCV1243327 67.6 1.71 1.02 2.03
rs2428549 hCV3186395 68.0 1.72 1.03 2.04
rs515213 hCV826909 68.9 1.69 1.01 2.01
rs11231531 rs11231531 69.2 1.79 1.01 2.09
rs7938819 hCV9153521 69.7 1.94 1.00 2.21
rs7940569 hCV3012560 70.3 2.01 .99 2.25
rs1467110 hCV8376844 70.6 2.02 .99 2.26
rs1784223 hCV3093494 71.0 2.05 1.03 2.31
rs593525 rs593525 71.3 2.14 1.01 2.38
rs2279861 hCV11667604 71.6 2.23 1.04 2.47
rs7108388 hCV1346738 71.9 2.28 1.03 2.51
rs1638588 hCV1250035 72.1 2.32 1.05 2.55
rs105147 hCV2623925 72.3 2.34 1.21 2.66
rs10896364 hCV209229 73.2 2.61 1.21 2.87
rs1551305 hCV8762660 74.0 2.83 1.21 3.04
rs4275647 hCV12034770 74.6 2.80 1.32 3.08
rs734102 rs734102 75.7 2.66 1.24 2.92
rs2276068 hCV12039531 76.2 2.55 1.15 2.79
rs1207142 hCV8896286 76.9 2.62 1.09 2.81
rs3924047 hCV12040954 77.5 2.60 1.11 2.80
hCV2139440 hCV2139440 78.4 2.38 1.08 2.60
rs1000620 hCV8893770 78.8 2.43 .99 2.58
D11S2371 GATA90D07 79.3 2.35 .96 2.50
rs11235876 hCV153313 80.4 2.45 .80 2.49
rs1044782 hCV7985452 80.7 2.48 .83 2.53
rs1315265 hCV7625202 80.9 2.41 .85 2.49
rs554202 hCV1045980 81.2 2.27 .97 2.45
rs663746 hCV3245441 81.6 2.32 1.03 2.51
rs7926553 hCV3242281 83.0 2.31 1.03 2.50
rs595654 hCV1249332 83.3 2.39 1.11 2.61
rs230656 hCV3152042 83.7 2.23 1.09 2.47
rs663520 hCV8749748 83.8 2.21 1.10 2.46
rs552604 hCV1514816 85.4 1.87 1.47 2.40
rs672600 hCV573098 86.4 1.66 1.58 2.30
D11S2002 GATA30G01 87.3 1.78 1.76 2.49
rs1037398 hCV8755557 87.4 1.82 1.75 2.52
rs1013273 hCV8755635 88.4 2.01 1.61 2.61
rs605335 hCV949590 88.5 1.99 1.59 2.57
rs7940296 hCV3245775 89.0 1.72 1.49 2.30
rs11233632 hCV2077671 89.2 1.58 1.50 2.19
rs10751099 hCV11327826 89.5 1.49 1.51 2.12
rs1399619 hCV7624437 89.8 1.33 1.50 1.99
rs290202 hCV1379796 90.3 1.12 1.45 1.81
ss1510291 hCV8753222 90.4 1.08 1.48 1.79
rs4144615 hCV2946456 90.9 .82 1.56 1.63
rs2226844 hCV1511121 91.8 .62 1.68 1.55
rs12270038 hCV2965095 92.3 .69 1.81 1.69
rs11020488 rs11020488 92.4 .71 1.82 1.71
rs10830237 hCV1423593 92.5 .80 1.85 1.80
rs1369953 hCV8371719 92.6 .72 1.86 1.74
rs1892887 rs1892887 92.9 .65 1.86 1.71
rs10830528 rs10830528 93.0 .60 2.00 1.76
rs1528767 rs1528767 93.5 .55 1.87 1.65
rs2514288 rs2514288 93.8 .52 1.68 1.49
rs1793089 hCV8370494 93.9 .55 1.62 1.47
rs606462 hCV3160944 95.4 .76 1.25 1.40
rs493390 hCV2134445 95.5 .75 1.19 1.36
rs10501817 hCV1558437 96.1 .71 1.05 1.23
rs568878 hCV3243095 97.5 .55 1.09 1.11
rs483884 hCV8366620 98.1 .49 .99 .99
rs1023849 hCV1374954 99.7 .49 .73 .83
rs1840054 hCV3013255 100.7 .44 .45 .62
rs2597565 hCV1828315 100.9 .47 .40 .61
rs7925640 rs7925640 101.6 .40 .37 .54
rs901540 hCV1832533 102.0 .32 .23 .38
rs1494471 rs1494471 102.5 .33 .25 .39
rs6590589 hCV1369078 102.8 .27 .20 .32
rs1502277 hCV1505893 103.1 .22 .10 .22
rs566351 hCV3182870 103.5 .15 .15 .19
rs10791487 hCV372177 104.0 −.23 .48 .08
rs10895277 hCV12072893 104.1 −.22 .55 .14
rs1784410 hCV7492851 104.3 −.22 .70 .22
rs634192 hCV944666 104.7 −.21 .90 .35
rs716273 hCV1335221 104.9 −.12 1.06 .52
D11S2000 GATA28D01 105.2 −.21 1.23 .55
rs10750684 hCV1951845 105.3 −.49 1.25 .33
rs578169 hCV3148094 105.7 −.41 1.30 .43
rs2028816 hCV3247421 106.4 −.31 1.37 .57
rs6591147 hCV1636106 106.6 −.26 1.36 .61
rs2000930 hCV3014100 106.9 −.18 1.32 .63
rs669715 hCV3250963 107.5 −.32 1.17 .43
rs228592 hCV2609424 107.9 −.48 1.11 .26
rs10890898 hCV1849328 108.2 −.57 1.08 .16
rs7116461 hCV9412214 108.6 −.54 1.09 .19
rs11606636 hCV3096929 109.0 −.63 1.18 .16
rs1509317 hCV8910331 109.5 −.70 1.40 .25
D11S1391 GATA4E01 109.7 −.71 1.40 .24
rs167685 hCV2073302 110.0 −.73 1.36 .19
rs7926485 hCV1366793 110.6 −.87 1.25 .02
rs2043055 hCV11481682 111.2 −.85 1.25 .04
rs321146 rs321146 112.5 −.61 1.20 .20
rs1022084 hCV1568571 113.1 −.46 1.18 .32
rs387977 hCV1057713 114.7 −.27 1.10 .44
rs1792379 hCV1717400 115.2 −.22 1.11 .48
rs4445669 hCV12072002 115.8 −.20 1.09 .49
rs1961328 hCV1254535 116.5 −.20 1.02 .45
rs2846903 hCV1683155 116.5 −.20 1.01 .45
rs1263149 hCV2679516 117.6 −.17 1.04 .48
rs528508 hCV7501076 118.7 −.25 1.01 .40
D11S1998 GATA23E06 120.0 −.34 .85 .23
a

cM values refer to the STRP map of deCODE.

Acknowledgments

We thank the patients and families for their participation. Data and biomaterials from the NIMH Genetics Initiative for Schizophrenia MGS1 families were collected in nine projects. From 1999 to 2004, the principal investigators (PIs) and coinvestigators were: University of Chicago, Chicago (grant R01 MH59571): P.V.G. (collaboration coordinator and PI) and A.R.S.; Baylor College of Medicine, Houston (grant R01 MH59587): F.A. (PI); University of California at Irvine, Irvine (grant R01 MH60870): W.F.B. (PI); University of Iowa, Iowa City (grant R01 MH59566): D.W.B. (PI) and R.R.C.; Washington University, St. Louis (grant R01 MH60879): C.R.C. (PI); University of Colorado, Denver (grant R01 MH59565): R.F. (PI) and A.O.; University of Pennsylvania, Philadelphia (grant R01 MH61675): D.F.L. (PI), and subcontract to Louisiana State University, New Orleans: N.G.B. (subcontract PI); University of Queensland, Brisbane (grant R01 MH59588): B.J.M. (PI); and Mt. Sinai School of Medicine, New York (grant R01 MH59586): J.M.S. (PI). We also thank the individuals at each participating institution for their laboratory, database, and/or clinical contributions, especially Roberta Fishman, Layla Kassem, Eric B. Carpenter, Gregory J. Burrell, Christos Pantelis, Robert J. Barrett, and Douglas A. Fugman. Genotyping was performed at CIDR (for STRPs) and at Evanston Northwestern Healthcare Research Institute (for SNPs).

Appendix A

Table A1.

Example of Renumbering to Assure that Allelic Designations Are Comparable between Waves I and II for D6S2427[Note]

Allele Frequency
OriginalAllelicDesignation
RenumberedAllelicDesignation
FragmentSize(bp) Wave I Wave II Wave I Wave II Wave I Wave II
187 .003 .003 1 1 1 1
195 .004 2 2
199 .025 .019 3 2 3 3
200 .002 3 4
202 .057 4 5
203 .028 4 5
206 .116 5 6
207 .003 .148 6 5 7 6
209 .001 6 8
210 .283 .247 7 7 9 9
211 .003 .003 8 8 10 10
213 .001 9 11
214 .229 .256 9 10 12 12
215 .005 .002 10 11 13 13
218 .153 .153 11 12 14 14
219 .001 13 15
222 .060 .072 12 14 16 16
226 .038 .045 13 15 17 17
227 .001 14 18
230 .021 .016 15 16 19 19
234 .001 .002 16 17 20 20

Note.— The presence of rare alleles in one wave but not the other means that the original allelic designations from CIDR cannot be used when the waves are combined. For instance, allele 10 in wave I has a frequency of 0.5%, whereas, in wave II, it has a frequency of 25.6%. In fact, the fragment of size 214 bp (relabled as allele 12 when the waves are combined) has a frequency of 24.7% in this sample. When a large proportion of families have ungenotyped parents, as is the case here, the results of a linkage analysis necessarily will depend on the estimates of the allele frequencies. Accordingly, when genotypes are produced in different waves, by different laboratories, or by use of different technologies, it is critically important to assure that the alleles align correctly.

Table A2.

Example of Allelic Renumbering for D15S128 Used to Combine the EA and AA Families[Note]

Allele Frequency
FragmentSize(bp) AlleleNumber EA AA Renumbered Allele(AA Only)
196 1 .0005
198 2 .0011
200 3 .0643 .0141 14
202 4 .0050 .1141 15
204 5 .0050 .1043 16
206 6 .2494 .3424 17
208 7 .2629 .0826 18
210 8 .1661 .1065 19
212 9 .1275 .0576 20
213/214 10 .0833 .0620 21
215/216 11 .0263 .0185 22
217 12 .0062 .0011 23
219 13 .0022 .0032 24
221 14 .0924 25
225 15 .0011 26

Note.— Shown are the allele frequencies for D15S128 in the EA and AA families. The original recoding of this STRP resulted in 15 alleles. Alleles 1–13 are the only alleles present in the EA sample. Accordingly, we renumbered the alleles of the genotypes in the AA families, as indicated. In the linkage analysis of the combined sample, the allele frequencies sum to 200%, resulting in the correct computation of conditional probabilities of the genotypes of missing parents.

Figure A1.

Figure  A1

Illustration of the counting of sib pairs. Because there is no optimal method for counting independent affected half sib pairs when there are full and half sibs in the same family, all possible half sib pairs (AHAPs) have been counted in these cases. Consider, for instance, the two families shown here. Pedigree A is counted as two statistically independent AFSPs and three AHAPs. Pedigree B is counted as two AFSPs and four AHAPs.

Table A3.

Previous Chromosome 8p SZ Linkage Reports[Note]

Best Single-Point Result
Best Multipoint Result
Study Ethnicity No. of ASPs No. of Families Affection P Marker Cytogenetic cM Mb P Marker Cytogenetic cM Mb
Initial major study:
 Blouin et al. 1998a EA 54 SZ and SA .00019 D8S1771 8p21.2 50.05 25.5
 Follow-up sample, Blouin et al. 1998b EA 51 SZ and SA .023 D8S1752 8p21.2 46.26 22.7
Supportive studies:
 SLCG 1996 (for chromosomes 3, 6, and 8)c EA 633 384 SZ and SA .0014 D8S261 p22 37.04 17.8 .005 D8S133 p21.3 41.55 22.0
 Kaufmann et al. 1998d AA 42 30 SZ and SADT .01333 D8S1819 p23.1 9.96 6.7
 Brzustowicz et al. 2000e EA 22 SZ, SA, and SSD >.05 D8S136 p21.3 43.96 22.5 >.05 D8S136 p11.21 64.96 40.3
 Gurling et al. 2001f EA 13 SZ, SA, and UFP .0001 D8S503 p23.1 16.19 9.3 .0005 D8S1771 p21.2 50.05 25.5
 Straub et al. 2002g EA 270 Very broad (D1–D9) .005 D8S1731 p22 31.73 15.2
 Stefansson et al. 2002h EA 33 SZ, SA, and UFP Suggestive D8S278 p12 60.87 32.6
 DeLisi et al. 2002i EA 130 95 Broad .016 Unknown p23.1 18.20 9.8
 Moises et al. 1995j EA 5 SZ and SA .04 D8S298 p21.3 43.96 21.8
 Lindholm et al. 2001k EA 1 SZ Suggestive D8S550 p23.1 21.33 10.9
 Park et al. 2004l EA 40 Psychotic BP Suggestive D8S382 p12 51.15 26.0 Suggestive D8S382 p12 51.15 26.0

Note.— cM values refer to the Marshfield map; cytogenetic locations and Mb on chromsome 8 are from the UCSC July 2003 freeze. Predominant ethnicities are listed; see footnotes for each study for more detail. ASPs are noted when available; otherwise, the number of families is listed. Affection status is listed for the most significant model if there is more than one. Psychotic BP = bipolar I, SA manic type (Park et al. 2004); SADT = SA depressed type; SSD = schizophrenia spectrum disorders (nonaffective psychotic disorder, schizotypal personality disorder, or paranoid personality disorder); UFP = unspecified functional psychosis. Very broad (D1–D9) refers to SZ, SA–poor outcome, “simple SZ,” schizotypal personality disorder (PD), schizophreniform disorder, delusional disorder, atypical psychosis, SA–good outcome, psychotic affective disorders, paranoid PD, avoidant PD, schizoid PD, nonpsychotic affective disorders, anxiety disorders, alcoholism, and the rest of the PDs. Broad refers to SZ, SA, psychosis not otherwise specified, schizotypal PD, and paranoid PD (DeLisi et al. 2002). The lowest P values—sometimes limited to a notation of “suggestive,” per standard criteria (Lander and Kruglyak 1995)—are listed, when available, for single- and multipoint analyses, along with marker and location information.

a

The initial major study by Blouin et al. (1998) (also reported earlier by Pulver et al. [1995]), both genome scan and replication samples, was performed on mostly EA samples (the 54 scan families and the 51 replication families derived from a total of 105 families composed of 44 EA from Maryland, 31 additional EA from throughout the United States, along with 6 AA, 5 Ashkenazim, 1 Amish, 10 Italian, 3 Polish, and 5 Greek families). The genome-scan nonparametric linkage (NPL) Zall=3.64 (P=.00019) near D8S1771, and the 95% CI was noted to be 18 cM wide.

b

The same study by Blouin et al. (1998) also had a replication sample. The replication study NPL Zall=1.95 (P=.023) at D8S1752.

c

This was a large multisite replication study (SLCG 1996), analyzed with and without the Johns Hopkins families reported elsewhere (Pulver et al. 1995; Blouin et al. 1998), that was composed of predominantly EA families (samples from 13 EA sites and 1 South African Bantu-speaking sample). The replication portion—that is, the “new” families, as far as linkage reported for chromosome 8—comprised (depending on available genotypes) 633 ASPs (independent) and 384–463 families. The single-point analysis showed a recessive heterogeneity LOD (HLOD) of 2.22 (P=.0014) for the new sample at D8S261. The multipoint analyses showed a maximum LOD score (MLS) for ASPs of 1.58 (P=.005) for the new sample near D8S133.

d

In this study (Kaufmann et al. 1998), 42 ASPs (some half siblings) from 30 families showed the strongest single-point finding in the region with NPL Zmax=2.27 (P=.0133) at D8S1819.

e

In this study (Brzustowicz et al. 2000), 22 families (21 Celtic and 1 German) were reported without P values, but all linkages were noted to be nonsignificant on empirical testing. The best single-point score was at D8S136, with a homogeneity Zmax=2.09 and a heterogeneity Zmax=2.16 (0.80 linked), and the best multipoint (three-point) score was at ∼21 cM centromeric to D8S136, with a heterogeneity Zmax=2.80 (0.90 linked).

f

In this study (Gurling et al. 2001), 13 families (5 British and 8 Icelandic) were reported with a recessive HLOD=3.6 (P=.0001) at D8S503 (note that there was a broad region with positive markers) and a recessive five-point HLOD=3.2 (P=.0005) at D8S1771 (note that homogeneity LOD=3.0).

g

In this study (Straub et al. 2002), 270 EA (Irish) families showed a maximum multipoint NPL score of 2.56 (P=.005) near D8S1731.

h

In this study (Stefansson et al. 2002), 33 EA (Icelandic) families were reported without P values, but linkage was clearly stated to be at the “suggestive” level. Both multipoint analyses showed peaks at D8S278: allele-sharing LOD=2.53 and parametric affecteds-only LOD=3.48.

i

In this study (DeLisi et al. 2002), 130 ASPs (independent, some half siblings) from 95 EA families (from the central valley of Costa Rica surrounding the city of San Jose, which originated from Spanish settlers, with some characteristics of a population isolate) showed a nonparametric multipoint MLS=1.19 (P=.016), with the multipoint peak reported to be at 18.2 cM.

j

In this study (Moises et al. 1995), five large EA (Icelandic) families showed a weighted-rank pairwise correlation (WRPC) score of 120.05 and WRPC variance of 4,630 (P=.04) at D8S298.

k

In this study (Lindholm et al. 2001), one very large EA (northern Sweden) family was reported without P values, but the linkage finding was clearly stated to be at the “suggestive” level via simulations that pointed to an MLS >2.2 as suggestive and an MLS >3.7 as significant. At D8S550, an MLS of 2.90 at recombination fraction 0.15 was noted when allele frequencies from the local control population were used; when the allele frequencies from the pedigree itself were used, the MLS was 0.70.

l

In this study (Park et al. 2004), 40 mostly EA families (29 EA and 11 Middle-Eastern) were reported without P values, but the linkage finding was clearly stated to be at the “suggestive” level by identification of a two-point LOD >1.9 as suggestive (and a two-point LOD >3.3 as significant). At D8S382, LOD=2.09 and MLS=3.46.

Table A4.

Previous Chromosome 5 Pericentromeric SZ Linkage Reports[Note]

Best Single-Point Result
Best Multipoint Result
Study Ethnicity No. of Families Affection P Marker Cytogenetic cM Mb P Marker Cytogenetic cM Mb
Initial major study:
 Bespalova et al. 2005a EA 1 SZ and STPD Sig. D5S111 5p13.3 47.09 33.3 Significant D5S111 5p13.3 47.09 33.3
Supportive studies:
 Cooper-Casey et al. 2005b EA 1 SZ and SA Suggestive D5S426 5p13.2 51.99 34.8 Suggestive D5S426 5p13.2 51.99 34.8
 Garver et al. 2001c AA and EA 30 SZ, SADT, and CA .015 D5S426 5p13.2 51.99 34.8
 Straub et al. 2002d EA 90 Narrow (D1–D2) D5S1470 5p13.3 45.34 32.5
 Paunio et al. 2001e EA 53 Broad (LC4) D5S2504 5q11.1 59f 49.9
 Gurling et al. 2001g EA 13 SZ, SA, UFP, STPD, and SDPD .002 D5S407 5q11.2 64.67 56.0 .003 D5S407 5q11.2 64.67 56.0

Note.— cM values refer to the Marshfield map; cytogenetic locations and Mb on chromsome 8 are from the UCSC July 2003 freeze. Predominant ethnicities are listed; see notes for each study for more detail. ASPs are noted when available; otherwise, the number of families is listed. Affection status is listed for the most significant model if there is more than one. CA = cluster A personality disorders (SDPD, STPD, and paranoid personality disorder); SADT = SA depressed type; SDPD = schizoid personality disorder; STPD = schizotypal personality disorder; UFP = unspecified functional psychosis. Narrow (D1–D2) refers to SZ, SA–poor outcome, and “simple SZ.” Broad (LC4) refers to SZ, SA, CA, schizophreniform disorder, delusional disorder, brief psychotic disorder, psychosis not otherwise specified, and severe major affective disorders. The lowest P values—sometimes limited to a notation of “suggestive” or “significant,” per standard criteria (Lander and Kruglyak 1995)—are listed, when available, for single- and multipoint analyses, along with marker and location information.

a

The fine-mapping follow-up (Bespalova et al. 2005) of the initial major study (Silverman et al. 1996) was performed on a single large Puerto Rican family, primarily descended from Spanish ancestors. Analyses showed a maximum two-point LOD=3.72 at D5S111 under dominant inheritance at a recombination fraction of 0.01 and a 90% penetrance (Silverman et al. 1996); at the same marker, the multipoint LOD=4.37 (Bespalova et al. 2005), although no P values were provided.

b

This study was performed (Cooper-Casey et al. 2005) on a single large family from the central valley of Costa Rica primarily descended from Spanish ancestors. Analyses showed a maximum two-point LOD=1.80 at D5S426 under dominant inheritance; the nonparamteric multipoint LOD=2.70 at the same marker, with the results characterized as suggestive evidence, although no P values were provided.

c

This study (Garver et al. 2001) of 30 families (23 AA and 7 EA) showed a multipoint nonparametric linkage score of 2.21 (P=.015) at D5S426.

d

This study (Straub et al. 2002) of 270 EA (Irish) families showed a maximum pairwise heterogeneity LOD (HLOD) of 2.18 at D5S1470 under dominant inheritance and the narrow (D1–D2) affection status in the family set A (90 families).

e

This study (Paunio et al. 2001) of 53 EA (Finnish) families from the country’s “internal isolate” showed Zmax=2.33 at D5S395 and Zmax=2.36 at D5S2504 under dominant inheritance and affection liability class 4 (LC4), which was the broadest affection status model (Paunio et al. 2001).

f

Estimated.

g

This study (Gurling et al. 2001) of 13 EA families (5 British and 8 Icelandic) reported a dominant HLOD=2.5 (P=.002) at D5S407 under the spectrum affection status and a dominant five-point HLOD=2.2 (P=.003) peaking at the same marker (note that LOD=2.3 in a single pedigree as well).

Web Resources

The URLs for data presented herein are as follows:

  1. Center for Inherited Disease Research (CIDR), http://www.cidr.jhmi.edu/
  2. Consensus Coding DNA Sequence (CCDS) database, http://www.ncbi.nlm.nih.gov/projects/CCDS/ (for March 2005 report)
  3. dbSNP, http://www.ncbi.nlm.nih.gov/SNP/ (for build 34)
  4. HapMap, http://www.hapmap.org/
  5. NIMH Center for Collaborative Genetics Studies of Mental Disorders, http://zork.wustl.edu/nimh/
  6. NIMH Human Genetics Initiative for Schizophrenia, http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html
  7. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for SZ) [PubMed]
  8. UCSC Genome Bioinformatics, http://genome.ucsc.edu/ (for May 2004 assembly of the human genome)
  9. UniSTS, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unists (for comprehensive database of sequence-tagged sites)

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