Abstract
The dopamine hypothesis of schizophrenia (SZ) has motivated a large number of genetic association studies but few if any dopaminergic (DA) polymorphisms are accepted as credible risk factors at present. To evaluate whether dopamine-related genes have been investigated adequately, we surveyed public genetic databases and published SZ association studies with regard to 14 conventional DA genes and 7 selected dopamine-interacting proteins. We estimate that 325 polymorphisms would be required to evaluate the impact of common variation on SZ risk among Caucasian samples. To date, 98 polymorphisms have been analyzed in published association studies. We estimate that only 19 of these variations have been evaluated in samples with at least 50% power to detect an association of the effect size commonly found in genetically complex disorders. While it is possible that DA genes do not harbor genetic risk factors for SZ, our review suggests that satisfactory conclusions for most genes cannot be drawn at present. Whole-genome association studies have begun to fill this void, but additional analyses are likely to be needed. Recommendations for future association studies include analysis of adequately powered samples, judiciously selected polymorphisms, multiple ethnic groups, and concurrent evaluation of function at associated single-nucleotide polymorphisms.
Keywords: genetic association, schizophrenia, dopamine, meta-analysis
Introduction
Over the past 2 decades, schizophrenia (SZ)-mapping studies have grappled with several difficulties inherent to all studies of common, genetically complex disorders. Heritability estimates for the disorder vary from 60% to 70%,1,2 but complex segregation analyses have consistently rejected monogenic models of inheritance in favor of polygenic/multifactorial threshold models.2,3 A genetic model including multiple interacting loci of small effect may provide the best fit for the available data,4–6 making it difficult to identify individual genetic risk factors. Some analyses suggest that common genetic variants confer risk (also called the “common variant common disease” [CDCV] hypothesis), but others have argued in favor of rare variants.7–9 Aided by technological and statistical advances, genetic association studies have grown in size and sophistication.10,11 Thanks to these advances, some promising associations have been detected. For example, studies utilizing extended panels of single-nucleotide polymorphisms (SNPs) have identified associations with polymorphisms of dysbindin (DTNBP1), neuregulin 1 (NRG1), disrupted in SZ (DISC1), regulator of G protein signaling (RGS4), G72 and D-amino acid oxidase.12–15 Consistent with the polygenic model, the risk conferred by the associated alleles is modest (odds ratios [OR] ∼1.2).16
A sizable fraction of other association studies have focused on dopaminergic (DA) genes, but few credible genetic risk factors have emerged. Two broad conclusions are thus possible: either there are no significant associations between SZ and DA polymorphisms or sufficient evidence is not currently available. In this review, we evaluate the possible impact of DA gene polymorphisms on SZ risk. We summarize the motivation for, and details of, prior genetic association studies involving DA genes. We also survey public database information to determine the proportion of representative common variants that have actually been evaluated at these genes and the number of SNPs analyzed with adequate power to detect an association of the modest effect sizes expected. We conclude with suggested designs for future studies and discuss the relevance of such studies in the context of whole-genome association (WGA) studies.
The Dopamine Hypothesis
The DA hypothesis suggests hyperactivity of DA brain function in SZ pathogenesis. It originated from correlations between the clinical potency of antipsychotic drugs and their affinity for dopamine D2 receptors (DRD2).17–19 Two lines of enquiry have yielded relatively consistent results regarding the DA hypothesis of SZ. First, patients with SZ display increased sensitivity to the psychotogenic effects of agents that increase synaptic DA release.20–24 Second, acute amphetamine challenge to patients leads to increased DA transmission in vivo, as measured by radioligand binding to DRD2 during positron emission tomography (PET) scans.25–27 However, the DA hypothesis has not been supported consistently using measures such as postmortem DA receptor density or DA metabolite concentrations, in vivo measures of DA receptor density using PET scans, or DA metabolite concentrations in the cerebrospinal fluid.28–35 The discrepancies could be due to medication effects and sampling variation.36,37
Refining the DA Hypothesis
Subtle DA dysregulation could occur in SZ, rather than overall DA hyperactivity; eg, regional variation, selected receptor types, temporal sensitization, or variations during different phases of illness.23,37–39 Hypofunction in prefrontal neuronal circuits has been documented repeatedly in postmortem brain studies of SZ; this may also lead to disinhibition of the prefrontal drive to the limbic striatum with a resultant hyperdopaminergic state in the limbic striatum.36,40 These subtle changes likely reflect a chain of events, so a number of susceptibility factors may be present. This is consistent with the polygenic model of SZ.
Genetic Association Studies Using DA Polymorphisms
The extensive interest in the DA hypothesis has also motivated numerous association studies of DA genes under the rationale that credible genetic associations would motivate further studies of pathogenesis. However, most early association studies were hampered by significant deficiencies in technology and relatively modest sample sizes available. Despite these limitations, the gamut of genes involved in DA neurotransmission was investigated. We conducted PubMed searches using the following combinations of terms: (1) “(individual gene name)” and “schizophrenia”; (2) “(gene symbol)” and “schizophrenia”; (3) “dopamine” and “schizophrenia.” Genetic association studies were then extracted from these sets. As discussed below, most studies followed a similar pattern. An initial study reported on one or a few putatively functional polymorphisms, and subsequent studies analyzed only those variants. Some study designs, such as mutation detection followed by association tests in relatively small samples, are better suited to identify susceptibility loci harboring a substantial impact on risk. Thus, no consistent associations have been detected for a number of key DA genes, potentially leading to the conclusion that susceptibility variants are not present in the DA network.
The DA genes investigated in multiple independent samples include tyrosine hydroxylase,41–43 dopamine decarboxylase,44,45 dopamine beta hydroxylase,46–49 catechol-O-methyltransferase (COMT) (see below), MAOA,50–55 and 1 of the 2 isoforms of the vesicular monoamine transporter (SLC18A1 alias VMAT1).56–58 The dopamine receptors DRD1, DRD2, DRD3, DRD4, and DRD5 have also been investigated.59–64 The vesicular monoamine transporter, member 2 (VMAT2, SLC18A2), has only been investigated in one study to date.65
Other investigators have reported on dopamine-interacting proteins, with similarly inconsistent results. They include orphan nuclear receptor Subunit 4 (NURR, NR4A21); D1 receptor–interacting protein (CALCYON, DRD1IP); protein phosphatase 1, regulatory (inhibitory) subunit 1B (DARPP-32, PPP1R1B); syntaxin 1A (STX1A); protein interacting with PRKCA 1 (PICK1); synaptosomal-associated protein, 25 kDa (SNAP25); and beta adrenergic receptor kinase 2 (GRK3, ADRBK2).66–75
Because space restrictions preclude detailed discussion of each gene, we have reviewed 4 of the most extensively analyzed DA genes. While early association studies have been inconsistent for all of them, recently published studies have provided intriguing new facets. Each gene thus provides precepts for future association studies.
Dopamine D2 Receptor
The DRD2 was a logical early target for association studies because of the effects of therapeutic agents reviewed above. Two genetic variants have been the target of most studies. One is a cysteine to serine substitution at codon 311 (Cys311Ser) and the other an insertion/deletion of 141 bases in the 5′ region of the gene (−141C ins/del). Two independent meta-analyses identified a significant association between the rare Cys311 allele and SZ,76,77 a result that has since been confirmed by a more comprehensive meta-analysis including data from 3707 cases and 5363 controls.60 In contrast, a meta-analysis did not support an association with the insertion/deletion polymorphism. Other polymorphisms have been investigated more recently with significant results from 4 different studies,78–81 but significant associations were not detected when 5 SNPs were analyzed among a family cohort of Askhenazi Jewish families.82 It would be instructive if the same set of polymorphisms could be analyzed in all these samples, followed by meta-analysis.
Dopamine D3 Receptor
A large number of studies have sought associations at DRD3, but most have focused exclusively on rs6280 (Ser9Gly), a nonsynonymous SNP in the first exon with possible functional effects.83 Repeated meta-analyses have suggested a modest association, but all meta-analyses have not been consistent.61,84,85 Recent studies have evaluated other variations with somewhat more consistent results. Four studies focused on associations with SNPs upstream to exon 1.86–89 Three of these studies detected significant associations, suggesting that inconsistencies at rs6280 could represent associations with other, correlated SNPs. However, one large case-control study and analysis of a family-based sample did not reveal any significant associations.82,89 Two recent studies evaluated a larger proportion of representative variation; both detected significant haplotype-based associations. We found significant associations with SNPs and haplotypes spanning the gene in 2 independent samples.90 Another group reported significant haplotype-based associations in the 3′ region of DRD3 in a Galician population.91 In sum, the numerous association studies conducted at rs6280 appear to be equivocal with respect to SZ susceptibility; however, more recent results considering a greater proportion of common variation within the gene have been more encouraging. These recent findings may represent other liability loci at this gene and might highlight the value of comparative analyses of varied ethnic groups. Such studies lend themselves to evolutionary analyses that may identify ancient mutations.92–94
Catechol-O-methyltransferase
COMT is localized to chromosome 22q11, a region implicated in several linkage studies.95 Deletions in this region also lead to the velocardiofacial syndrome, with an increased risk of psychoses.96 Most association studies have investigated an exonic Met158Val polymorphism, which appears to influence COMT activity in vitro. Two different meta-analyses suggest that an association between this variant and SZ, if present, is complex and may be influenced by population substructure.97,98 Interest in the Met158Val polymorphism has continued because it may be correlated with working memory, a trait known to be impaired in SZ.50,99,100
Recent association studies have investigated a larger set of SNPs. Li examined 8 markers in a Chinese sample and detected a significant association with an extended haplotype including Met158Val.101 Another large study of Ashkenazi Jewish patients revealed a highly significant association with 2 COMT SNPs, as well as a haplotype comprising 3 SNPs spanning the 5′ to 3′ region of the gene (rs737865–rs4680–rs165599).102 However, a study among unrelated cases and controls did not replicate this finding,103 nor did a study of 274 Ashkenazi families investigating 7 COMT SNPs.82 Intriguingly, The Met158Val polymorphism was part of this haplotype and the association was more prominent among women. Gender-specific associations have been detected with a variant within this haplotype (rs737865) in Alzheimer disease as well.104 Notably, rs737865 is in proximity to an estrogen response element.104 These associations highlight the need to evaluate valid subgroups of SZ and the need to consider functional impacts of associated alleles.
Dopamine Transporter (DAT, DAT1, SLC6A3)
Most association studies have focused on a putatively functional variable number tandem repeat, 3′ to the stop codon in exon 15, but meta-analyses suggest no significant association.62,105–108 An association has been reported with an exonic SNP among Koreans (1389 C>T; rs2270912).109 A case-control study among Iranians identified a significant association with a putative promoter variant (−67A/T; rs2975226; P = .0003; OR = 2.25).110 The association is particularly intriguing because cis-acting variation in the 5′ region of this locus may contribute to differential SLC6A3 expression in vitro and in vivo.111,112 The Korean and Iranian studies need to be evaluated in additional samples. Additional studies using common polymorphisms spanning the gene are also required.
A Synthesis of Published DA Association Studies
We examined 14 DA genes and 7 dopamine-interacting proteins that have been used for prior association studies. Our goal was to identify a representative set of common SNPs that should be evaluated to enable a reasonable test of the CDCV hypothesis for each gene. The samples utilized were 60 unrelated Caucasians from the International HapMap project (CEPH; Utah residents with ancestry from northern and western Europe)113 or 90 unrelated individuals representative of the US population from the NIH Polymorphism Discovery Resource 90 individual subset (http://egp.gs.washington.edu/). Data were obtained using the Genome Variation Server resource (http://gvs.gs.washington.edu/GVS/).114 All SNPs with minor allele frequencies over 5% were identified because currently available samples may lack power to detect associations with less frequent polymorphisms. Because genotypes at many of these SNPs may be correlated due to linkage disequilibrium (LD), we selected representative “tag” SNPs using a conventional cutoff (r2 < 0.8 between loci). Based on these analyses, we found that 325 tag SNPs would be needed to tag all available common variations from these populations (table 1).
Table 1.
Published Dopaminergic Association Studies and Estimates of Their Comprehensiveness
Publicly Available SNP Datab | Published Studiesc | Largest Studyd | Meta-analysese | ||||||||
Gene | Location | Gene Name (alias) | Size (kb)a | Common SNPs | Tag SNPsf | No. of Markers Studiedg | Power > 50%h | Cases/Controlsi | Reference | SNPs | Result |
Dopamine Pathway Genes | |||||||||||
TH | 11p15.5 | Tyrosine hydroxylase | 17.9 | 14 | 10 | 2 | 1 | 334/391 | Pae et al139 | 1 | − |
DBH | 9q34 | Dopamine beta hydroxylase | 33.0 | 68 | 39 | 2 | 0 | 178/178 | Williams et al140 | ||
DDC | 7p11 | Dopamine decarboxylase | 112.6 | 204 | 36 | 2 | 0 | 173/204 | Borglum et al45 | ||
DRD1 | 5q35.1 | Dopamine D1 receptor | 13.1 | 12 | 7 | 2 | 1 | 407/399 | Dmitrzak-Weglarz et al141 | ||
DRD2 | 11q23 | Dopamine D2 receptor | 75.6 | 78 | 19 | 7 | 2 | 188/384 | Hanninen et al80 | 2 | +, −j |
DRD3 | 3q13.3 | Dopamine D3 receptor | 60.2 | 69 | 18 | 17 | 4 | 331/274, (292)k | Talkowski et al90 | 1 | +/− |
DRD4 | 11p15.5 | Dopamine D4 receptor | 13.4 | 4 | 2 | 5 | 5 | 570/570 | Nakajima et al142 | 2 | − |
DRD5 | 4p16.1 | Dopamine D5 receptor | 12.1 | 1 | 1 | 2 | 0 | 158/437 | Muir et al64 | ||
SLC18A1 | 8p21.3 | Vesicular monoamine transporter, 1 (VMAT1) | 48.4 | 60 | 20 | 4 | 0 | 354/365 | Richards et al57 | ||
SLC18A2 | 10q25 | Vesicular monoamine transporter, 2 (VMAT2) | 45.9 | 43 | 15 | 6 | 0 | (50) | Kunugi et al65 | ||
SLC6A3 | 5p15.3 | Neurotransmitter transporter, dopamine (DAT, DAT1) | 62.6 | 120 | 49 | 7 | 1 | 252/271 | Jeong et al109 | 1 | − |
COMT | 22q11.2 | Catechol-O-methyltransferase | 37.2 | 50 | 30 | 11 | 3 | 1643/3980 | Shifman et al102 | 1 | +/− |
MAOA | Xp11.3 | Monoamine oxidase A | 100.7 | 38 | 8 | 3 | 346/334 | Norton et al54 | |||
MAOB | Xp11.3 | Monoamine oxidase B | 125.8 | 16 | 12 | 0 | 0 | ||||
Dopamine-Interacting Genes | |||||||||||
NR4A2 | 2q24.1 | Orphan nuclear receptor subunit 4 (NURR1) | 18.3 | 6 | 3 | 2 | 0 | 180/180 | Iwayama-Shigeno et al66 | ||
DRD1IP | 10q26.3 | D1 receptor–interacting protein (CALCYON) | 21.5 | 5 | 4 | 1 | 0 | 276/253 | Luo et al68 | ||
PPP1R1B | 17q21.2 | Protein phosphatase 1, regulatory (inhibitory) subunit 1B (DARPP-32) | 19.7 | 3 | 1 | 3 | 0 | 249/273 | Li et al69 | ||
STX1A | 7q11.23 | Syntaxin 1A | 30.4 | 7 | 3 | 4 | 192/192, (238) | Wong et al75 | |||
PICK1 | 22q13.1 | Protein interacting with PRKCA 1 | 28.4 | 17 | 6 | 3 | 2 | 1765/1851 | Ishiguro et al72 | ||
SNAP25 | 20p12-p11.2 | Synaptosomal-associated protein, 25 kDa | 98.5 | 97 | 32 | 1 | 0 | 87/100 | Tachikawa et al73 | ||
ADRBK2 | 22q12.1 | Beta adrenergic receptor kinase 2 (GRK3) | 159.9 | 10 | 10 | 7 | 0 | (16) and (97)l | Yu et al74 |
Note: Minor allele frequency >5% for common SNPs; SNPs, single-nucleotide polymorphism.
Includes sequences 5 kb upstream (5′) and 5 kb downstream (3') of the gene.
Publicly available genotype data: HapMap build 36 (http://www.Hapmap.org/)143 and the NIH Polymorphism Discovery Resource 90 individual subset screening (http://gvs.gs.washington.edu/GVS/index.jsp).
Data from PubMed searches, see details in the text.
Studies with largest number of cases are included.
Number of SNPs at which meta-analysis has been conducted is provided. “+” indicates significant association detected, “−” indicates no significant association, and “+/−” indicates conflicting results among meta-analyses. Blank spaces indicate that meta-analyses have not been published.
Tag SNPs selected as described in the text. Repeat polymorphisms not included.
Indicates number of studied polymorphisms that were not redundant (r2 < 0.8, where feasible).
Number of SNPs for which individual study evaluating the SNP had 50% or greater power to detect an association; see details in the text.
Where family-based samples were used, the number of families is listed in parenthesis.
Significant results from Cys311Ser, but not for −141 ins/del (see text).
Study included samples from the United States (151 trios, 331 cases, 274 controls) and India (141 trios).
Study analyzed 16 Japanese families and 97 Chinese families.
These estimates were next compared with the published association studies. At each gene, we listed the number of variations evaluated in previous association studies (SNPs and other polymorphisms), as well as the largest individual association study for each gene (defined in terms of the number of cases, see table 1). If possible, LD between the polymorphisms was analyzed. We also estimated the number of studies that had 50% power to detect associations of modest effect size for each of the polymorphisms tested (alpha = .05). We assumed an additive risk model with a genotype relative risk of 1.5 for homozygous individuals, 1.25 for heterozygous individuals, and a disease prevalence of 1%. We also assumed that the marker being considered was the actual liability variant and that genotyping errors were negligible. Thus, our power estimates are relatively lax.
Ninety-eight different polymorphisms have been investigated in all the association studies to date. We find that only DRD4 has been comprehensively covered when considering the proportion of representative variations genotyped and power (table 1). If each of the published polymorphisms represents a tag SNP, 30.1% of the required tag SNPs may have been evaluated. In reality, the proportion of representative SNPs analyzed in the publications is almost certainly lower because we were unable to estimate LD between many of these polymorphisms, and several rare polymorphisms have been analyzed (data not shown). We estimate that 19 of the polymorphisms studied had greater than 50% power to detect a genotype relative risk expected at an alpha threshold of .05. Thus, most of the published studies lacked sufficient power, even using our relaxed criteria. Under more realistic conditions (D′ = 0.9 between the genotyped marker and liability locus, 0.5% error rate, 1:1 case-to-control ratio, and a risk allele frequency of 0.2), we estimate that 595 cases and 595 controls would be required for 50% power under an additive model and 275 cases and 275 controls would be required under a dominant model of inheritance (1217 cases and 561 cases, respectively, would be required for 80% power under each model).115,116 These estimates are with regard to single-marker analysis. Additional corrections would be required for multiple independent tests. Because analyses of epistatic interactions would require further corrections for multiple comparisons, the sample size requirements for identifying such effects will be even larger.
Suggestions for Future Analyses
Are More Genetic Association Studies Needed?
Given the difficulties outlined above, it is worthwhile to weigh the utility of further gene-mapping studies for SZ. We believe such studies are needed, primarily because it has been difficult to pinpoint environmental risk factors reliably.117,118 Gene-mapping studies have been recommended for such disorders, particularly if they have substantial heritability.119 The substantial body of evidence pointing to DA dysfunction in SZ suggests a natural starting point to reevaluate available evidence. Some may argue against the need for further DA genetic studies because DA function is already an area of intensive research, including drug development efforts. However, genetic association studies may provide additional value for such research. First, emerging evidence suggests that networks of functionally related genes may be involved in pathogenesis of many multifactorial disorders.120 Carefully designed genetic studies might enable the identification of such networks, including key nodes to which novel therapeutics can be targeted.121 Second, such analyses might help identify novel genes related functionally to “conventional” DA genes.
Which Genes Should Be targeted?
Apart from the genes involved in DA metabolism or those encoding DA receptors, a definition of “DA” genes is difficult because of the known cross talk between neurotransmitter systems. Any list of “DA genes” is also unlikely to remain static in the face of advances in neuroscience research. We recommend starting with genes for which prior association evidence is available. If further studies provide credible, consistent associations, additional functional interactants of the associated genes can be targeted.
Which Polymorphisms Should Be Investigated?
Different types of polymorphisms are known in the human genome, ranging from SNPs to large copy number variations.122 SNPs are obvious starting points because they have been characterized extensively and because they can be assayed cheaply and accurately. A secondary question is the choice of SNPs. While it is relatively easy to select representative tag SNPs, the allele frequency of the selected SNPs is a more difficult choice. The feasibility of detecting associations for common diseases using “common” SNPs has been questioned on the grounds that they may not mirror the primary associations accurately and/or because risk may be due to relatively rare alleles.8,123–125 While the possibility of rare variants predisposing to SZ cannot be discounted, currently available samples may not enable detection of statistical associations if such variants are examined directly. One practical solution may be to select common tag SNPs and follow up suggestive associations with more dense sets of SNPs, including rare variants. Such intensive analyses may enable us to detect causal variants.
Sample Configurations
The possibility of spurious associations due to ethnic admixture has motivated much debate and the espousal of family-based association studies.126,127 While family-based samples detect association only in the presence of linkage and are thus particularly valuable, it is now feasible to correct for population substructure.126,128,129 Though the choice of controls may be dictated by convenience, biased selection of controls has obvious implication for detecting associations. Hence, it is important to plan for follow up of initial associations in other independent samples.
Sample Size
The power analyses reviewed above suggest the need for relatively large samples. Given the possibility of false-positive associations, replicate analyses are also recommended.130 While sample size limitations remain significant hurdles for association studies, the availability of public repositories (http://www.nimh.nih.gov/) and the feasibility of staged analyses131 may make this issue more tractable.
Which Ethnic Group(s)?
The overwhelming majority of genetic association studies are being conducted among individuals of Caucasian ancestry. Our review suggests ethnic variation in the magnitude of some of the associations. Such variation is known in other disorders, eg, the association between ApoE alleles and Alzheimer disease.132 Evaluation of multiple ethnic groups may also enable us to identify primary associations based on ancestral recombinations.93
Functional Analyses
The majority of genetic associations for SZ have been reported with noncoding polymorphisms, making it difficult to attribute function to the associated alleles. Nevertheless, such analyses are critical for understanding pathogenesis and may also be helpful in determining primary associations. An interactive design, with genetic associations informing functional analyses, and vice versa, is desirable.
Should WGA Studies Supplant Candidate Gene Studies?
Recently, WGA have come to the fore, thanks to the availability of a comprehensive trove of common polymorphisms, rapid and accurate genotyping platforms, and sophisticated analytic techniques. By analyzing a representative set of SNPs among cases and controls, WGA studies seek to evaluate the relative impact of common polymorphisms. Judicious analyses may also provide insights into epistatic interactions. Remarkable consistencies have recently been attained for a diverse set of common diseases, including age-related macular degeneration, prostate cancer, Crohn disease, and type I diabetes mellitus.133–136 WGA studies have already been reported for SZ,137 and other independent studies are in progress. These studies are likely to yield important new insights, so it is reasonable to question the need for focused candidate gene studies.
It is important to note that WGA represent the beginning of a new effort, rather than an end point in the gene-mapping effort. For example, WGA studies will undoubtedly require replicate studies, followed by more detailed analysis of prioritized genes using more dense sets of polymorphisms. Thus, “candidate gene analyses” will still be needed. Indeed, common polymorphisms are not tagged uniformly across the genome in some arrays used for WGA. Thus, key associations may remain undetected, even with WGA. In other diseases, candidate gene analyses have also identified associations with SNPs that were not sufficiently large for detection using WGA; eg, associations between late-onset Alzheimer disease and SORL1 SNPs.138
Conclusions
Our review of published association studies involving DA genes highlights the lack of adequate analyses of variation at these genes. Our findings suggest that more comprehensive analyses are required in sufficiently powered samples, particularly in view of some promising recent results. Replicate analyses, as well as analyses of multiple ethnic groups, in conjunction with functional evaluation of associated SNPs would be preferable.
Funding
National Institute of Mental Health MH56242, MH63480, and MH66263 to V. Nimgaonkar and MH080582 to M. Talkowski.
References
- 1.Rao DC. Path analysis of qualitative data on pairs of relatives: application to schizophrenia. Hum Hered. 1981;31:325–333. doi: 10.1159/000153233. [DOI] [PubMed] [Google Scholar]
- 2.McGue M. The transmission of schizophrenia under a multifactorial threshold model. Am J Hum Genet. 1983;35:1161–1178. [PMC free article] [PubMed] [Google Scholar]
- 3.Carter CL. Segregation analysis of schizophrenia under a mixed genetic model. Hum Hered. 1980;30:350–356. doi: 10.1159/000153156. [DOI] [PubMed] [Google Scholar]
- 4.Risch N. Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol. 1990;7:3–16. doi: 10.1002/gepi.1370070103. discussion 17–45. [DOI] [PubMed] [Google Scholar]
- 5.Schliekelman P. Multiplex relative risk and estimation of the number of loci underlying an inherited disease. Am J Hum Genet. 2002;71(6):1369–1385. doi: 10.1086/344779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Sha Q. A combinatorial searching method for detecting a set of interacting loci associated with complex traits. Ann Hum Genet. 2006;70(pt 5):677–692. doi: 10.1111/j.1469-1809.2006.00262.x. [DOI] [PubMed] [Google Scholar]
- 7.Gottesman II. Complications to the complex inheritance of schizophrenia [Review] Clin Genet. 1994;46:116–123. doi: 10.1111/j.1399-0004.1994.tb04213.x. [DOI] [PubMed] [Google Scholar]
- 8.McClellan JM. Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry. 2007;190:194–199. doi: 10.1192/bjp.bp.106.025585. [DOI] [PubMed] [Google Scholar]
- 9.Jorde LB. Linkage disequilibrium and the search for complex disease genes. Genome Res. 2000;10:1435–1444. doi: 10.1101/gr.144500. [DOI] [PubMed] [Google Scholar]
- 10.Hirschhorn JN. A comprehensive review of genetic association studies. Genet Med. 2002;4:45–61. doi: 10.1097/00125817-200203000-00002. [DOI] [PubMed] [Google Scholar]
- 11.Collins FS. Variations on a theme: cataloging human DNA sequence variation. Science. 1997;278:1580–1581. doi: 10.1126/science.278.5343.1580. [DOI] [PubMed] [Google Scholar]
- 12.Craddock N. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet. 2005;42:193–204. doi: 10.1136/jmg.2005.030718. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Owen MJ. Schizophrenia: genes at last? Trends Genet. 2005;21:518–525. doi: 10.1016/j.tig.2005.06.011. [DOI] [PubMed] [Google Scholar]
- 14.Harrison PJ. Schizophrenia genes, gene expression. neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40–68. doi: 10.1038/sj.mp.4001558. image 45. [DOI] [PubMed] [Google Scholar]
- 15.Prasad KM. Gene mapping studies for schizophrenia: how useful are they for the clinician? In: Sawa A, editor. Neurogenetics of Psychiatric Disorders. New York: Taylor & Francis Group, LLC; 2007. [Google Scholar]
- 16.Shirts BH. The genes for schizophrenia: finally a breakthrough? Curr Psychiatry Rep. 2004;6:303–312. doi: 10.1007/s11920-004-0081-1. [DOI] [PubMed] [Google Scholar]
- 17.Carlsson A. Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol. 1963;20:140–144. doi: 10.1111/j.1600-0773.1963.tb01730.x. [DOI] [PubMed] [Google Scholar]
- 18.Creese I. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976;192:481–483. doi: 10.1126/science.3854. [DOI] [PubMed] [Google Scholar]
- 19.Seeman P. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261:717–719. doi: 10.1038/261717a0. [DOI] [PubMed] [Google Scholar]
- 20.Angrist B. CNS stimulants as a tool in the study of schizophrenia. Trends Neurosci. 1984;7:388–390. [Google Scholar]
- 21.Lieberman JA. Methylphenidate challenge as a predictor of relapse in schizophrenia. Am J Psychiatry. 1984;141:633–638. doi: 10.1176/ajp.141.5.633. [DOI] [PubMed] [Google Scholar]
- 22.Davidson M, et al. L-dopa challenge and relapse in schizophrenia. Am J Psychiatry. 1987;144:934–938. doi: 10.1176/ajp.144.7.934. [DOI] [PubMed] [Google Scholar]
- 23.Laruelle M. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46:56–72. doi: 10.1016/s0006-3223(99)00067-0. [DOI] [PubMed] [Google Scholar]
- 24.Laruelle M. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol. 1999;13:358–371. doi: 10.1177/026988119901300405. [DOI] [PubMed] [Google Scholar]
- 25.Laruelle M, et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA. 1996;93:9235–9240. doi: 10.1073/pnas.93.17.9235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Abi-Dargham A, et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry. 1998;155:761–767. doi: 10.1176/ajp.155.6.761. [DOI] [PubMed] [Google Scholar]
- 27.Breier A, et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA. 1997;94:2569–2574. doi: 10.1073/pnas.94.6.2569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Bird ED. Increased brain dopamine and reduced glutamic acid decarboxylase and choline acetyl transferase activity in schizophrenia and related psychoses. Lancet. 1977;2:1157–1158. doi: 10.1016/s0140-6736(77)91542-2. [DOI] [PubMed] [Google Scholar]
- 29.Cross AJ. 3H-Flupenthixol binding in post-mortem brains of schizophrenics: evidence for a selective increase in dopamine D2 receptors. Psychopharmacology. 1981;74:122–124. doi: 10.1007/BF00432676. [DOI] [PubMed] [Google Scholar]
- 30.Mackay AV, et al. Increased brain dopamine and dopamine receptors in schizophrenia. Arch Gen Psychiatry. 1982;39:991–997. doi: 10.1001/archpsyc.1982.04290090001001. [DOI] [PubMed] [Google Scholar]
- 31.Seeman P, et al. Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases. Neuropsychopharmacology. 1987;1:5–15. doi: 10.1016/0893-133x(87)90004-2. [DOI] [PubMed] [Google Scholar]
- 32.Hess EJ. Dopamine receptor subtype imbalance in schizophrenia. Life Sci. 1987;40:1487–1497. doi: 10.1016/0024-3205(87)90381-x. [DOI] [PubMed] [Google Scholar]
- 33.Wong DF, et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science. 1986;234:1558–1563. doi: 10.1126/science.2878495. [DOI] [PubMed] [Google Scholar]
- 34.Farde L. No D2 receptor increase in PET study of schizophrenia. Arch Gen Psychiatry. 1987;44:671–672. doi: 10.1001/archpsyc.1987.01800190091013. [DOI] [PubMed] [Google Scholar]
- 35.Widerlov E. A critical appraisal of CSF monoamine metabolite studies in schizophrenia. Ann N Y Acad Sci. 1988;537:309–323. doi: 10.1111/j.1749-6632.1988.tb42115.x. [DOI] [PubMed] [Google Scholar]
- 36.Lewis DA. Catching up on schizophrenia: natural history and neurobiology. Neuron. 2000;28:325–334. doi: 10.1016/s0896-6273(00)00111-2. [DOI] [PubMed] [Google Scholar]
- 37.Davis KL. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148:1474–1486. doi: 10.1176/ajp.148.11.1474. [DOI] [PubMed] [Google Scholar]
- 38.Greene JG. Gene expression profiles of brain dopamine neurons and relevance to neuropsychiatric disease. J Physiol. Jan 1 2006 doi: 10.1113/jphysiol.2006.112599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Seeman P, et al. Psychosis pathways converge via D2(High) dopamine receptors. Synapse. 2006;60:319–346. doi: 10.1002/syn.20303. [DOI] [PubMed] [Google Scholar]
- 40.Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–669. doi: 10.1001/archpsyc.1987.01800190080012. [DOI] [PubMed] [Google Scholar]
- 41.Ishiguro H, et al. Systematic search for variations in the tyrosine hydroxylase gene and their associations with schizophrenia, affective disorders, and alcoholism. Am J Med Genet. 1998;81:388–396. [PubMed] [Google Scholar]
- 42.Chao HM. Aromatic amino acid hydroxylase genes and schizophrenia. Am J Med Genet. 2002;114:626–630. doi: 10.1002/ajmg.10606. [DOI] [PubMed] [Google Scholar]
- 43.Li D. Meta-analysis shows association between the tryptophan hydroxylase (TPH) gene and schizophrenia. Hum Genet. 2006;120:22–30. doi: 10.1007/s00439-006-0190-5. [DOI] [PubMed] [Google Scholar]
- 44.Zhang B. No association between polymorphisms in the DDC gene and paranoid schizophrenia in a northern Chinese population. Psychiatr Genet. 2004;14:161–163. doi: 10.1097/00041444-200409000-00008. [DOI] [PubMed] [Google Scholar]
- 45.Borglum AD, et al. Dopa decarboxylase genotypes may influence age at onset of schizophrenia. Mol Psychiatry. 2001;6:712–717. doi: 10.1038/sj.mp.4000902. [DOI] [PubMed] [Google Scholar]
- 46.Tang Y, et al. A single nucleotide polymorphism at DBH, possibly associated with attention-deficit/hyperactivity disorder, associates with lower plasma dopamine beta-hydroxylase activity and is in linkage disequilibrium with two putative functional single nucleotide polymorphisms. Biol Psychiatry. 2006:7. doi: 10.1016/j.biopsych.2006.02.017. [DOI] [PubMed] [Google Scholar]
- 47.Cubells JF. Human genetics of plasma dopamine beta-hydroxylase activity: applications to research in psychiatry and neurology. Psychopharmacology (Berl) 2004;174:463–476. doi: 10.1007/s00213-004-1840-8. [DOI] [PubMed] [Google Scholar]
- 48.Jonsson EG, et al. No association between a putative functional promoter variant in the dopamine beta-hydroxylase gene and schizophrenia. Psychiatr Genet. 2003;13:175–178. doi: 10.1097/00041444-200309000-00007. [DOI] [PubMed] [Google Scholar]
- 49.Yamamoto K, et al. Dopamine beta-hydroxylase (DBH) gene and schizophrenia phenotypic variability: a genetic association study. Am J Med Genet B Neuropsychiatr Genet. 2003;117:33–38. doi: 10.1002/ajmg.b.10011. [DOI] [PubMed] [Google Scholar]
- 50.Tunbridge EM. Catechol-o-methyltransferase, cognition. Psychosis: val(158)met and beyond. Biol Psychiatry. 2006;60:141–151. doi: 10.1016/j.biopsych.2005.10.024. [DOI] [PubMed] [Google Scholar]
- 51.Sabol SZ. A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet. 1998;103:273–279. doi: 10.1007/s004390050816. [DOI] [PubMed] [Google Scholar]
- 52.Nolan KA. An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder. Psychiatr Genet. 2000;10:109–115. doi: 10.1097/00041444-200010030-00002. [DOI] [PubMed] [Google Scholar]
- 53.Syagailo YV, et al. Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders. Am J Med Genet. 2001;105:168–171. doi: 10.1002/ajmg.1193. [DOI] [PubMed] [Google Scholar]
- 54.Norton N, et al. Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. Am J Med Genet. 2002;114:491–496. doi: 10.1002/ajmg.10517. [DOI] [PubMed] [Google Scholar]
- 55.Jonsson EG, et al. Association between a promoter variant in the monoamine oxidase A gene and schizophrenia. Schizophr Res. 2003;61:31–37. doi: 10.1016/s0920-9964(02)00224-4. [DOI] [PubMed] [Google Scholar]
- 56.Bly M. Mutation in the vesicular monoamine gene, SLC18A1, associated with schizophrenia. Schizophr Res. 2005;78:337–338. doi: 10.1016/j.schres.2005.04.011. [DOI] [PubMed] [Google Scholar]
- 57.Richards M, et al. Association study of the vesicular monoamine transporter 1 (VMAT1) gene with schizophrenia in a Japanese population. Behav Brain Funct. 2006;2:39. doi: 10.1186/1744-9081-2-39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Chen SF, et al. Support for association of the A277C single nucleotide polymorphism in human vesicular monoamine transporter 1 gene with schizophrenia. Schizophr Res. 2007;90:363–365. doi: 10.1016/j.schres.2006.11.022. [DOI] [PubMed] [Google Scholar]
- 59.Cichon S, et al. Systematic screening for mutations in the 5′-regulatory region of the human dopamine D1 receptor (DRD1) gene in patients with schizophrenia and bipolar affective disorder. Am J Med Genet. 1996;67:424–428. doi: 10.1002/(SICI)1096-8628(19960726)67:4<424::AID-AJMG21>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
- 60.Glatt SJ. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. Am J Med Genet B Neuropsychiatr Genet. 2006;141:149–154. doi: 10.1002/ajmg.b.30273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Jonsson EG. Meta-analysis of the dopamine D3 receptor gene (DRD3) Ser9Gly variant and schizophrenia. Psychiatr Genet. 2004;14:9–12. doi: 10.1097/00041444-200403000-00002. [DOI] [PubMed] [Google Scholar]
- 62.Fanous AH, et al. Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. Am J Med Genet B Neuropsychiatr Genet. 2004;125:69–78. doi: 10.1002/ajmg.b.20103. [DOI] [PubMed] [Google Scholar]
- 63.Wong AH. Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol. 2000;410:183–203. doi: 10.1016/s0014-2999(00)00815-3. [DOI] [PubMed] [Google Scholar]
- 64.Muir WJ, et al. Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder. Am J Med Genet. 2001;105:152–158. doi: 10.1002/1096-8628(2001)9999:9999<::aid-ajmg1163>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
- 65.Kunugi H. Exon/intron boundaries, novel polymorphisms, and association analysis with schizophrenia of the human synaptic vesicle monoamine transporter (SVMT) gene. Mol Psychiatry. 2001;6:456–460. doi: 10.1038/sj.mp.4000895. [DOI] [PubMed] [Google Scholar]
- 66.Iwayama-Shigeno Y, et al. Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese patients with schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2003;118:20–24. doi: 10.1002/ajmg.b.10053. [DOI] [PubMed] [Google Scholar]
- 67.Chen YH. Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients. Am J Med Genet. 2001;105:753–757. doi: 10.1002/ajmg.10036. [DOI] [PubMed] [Google Scholar]
- 68.Luo X, et al. CALCYON gene variation, schizophrenia, and cocaine dependence. Am J Med Genet B Neuropsychiatr Genet. 2004;125:25–30. doi: 10.1002/ajmg.b.20092. [DOI] [PubMed] [Google Scholar]
- 69.Li CH. Mutation analysis of DARPP-32 as a candidate gene for schizophrenia. Schizophr Res. 2006;87(1–3):1–5. doi: 10.1016/j.schres.2006.04.003. [DOI] [PubMed] [Google Scholar]
- 70.Hong CJ. Association study of PICK1 rs3952 polymorphism and schizophrenia. Neuroreport. 2004;15:1965–1967. doi: 10.1097/00001756-200408260-00026. [DOI] [PubMed] [Google Scholar]
- 71.Fujii K, et al. Serine racemase binds to PICK1: potential relevance to schizophrenia. Mol Psychiatry. 2006;11:150–157. doi: 10.1038/sj.mp.4001776. [DOI] [PubMed] [Google Scholar]
- 72.Ishiguro H, et al. PICK1 is not a susceptibility gene for schizophrenia in a Japanese population: association study in a large case-control population. Neurosci Res. 2007;58:145–148. doi: 10.1016/j.neures.2007.02.008. [DOI] [PubMed] [Google Scholar]
- 73.Tachikawa H. Polymorphism of the 5′-upstream region of the human snap-25 gene: an association analysis with schizophrenia. Neuropsychobiology. 2001;43:131–133. doi: 10.1159/000054880. [DOI] [PubMed] [Google Scholar]
- 74.Yu SY, et al. Mutation screening and association study of the beta-adrenergic receptor kinase 2 gene in schizophrenia families. Psychiatry Res. 2004;125:95–104. doi: 10.1016/j.psychres.2003.12.003. [DOI] [PubMed] [Google Scholar]
- 75.Wong AH, et al. Association between schizophrenia and the syntaxin 1A gene. Biol Psychiatry. 2004;56:24–29. doi: 10.1016/j.biopsych.2004.03.008. [DOI] [PubMed] [Google Scholar]
- 76.Jonsson EG. Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: association study and meta-analysis. Am J Med Genet. 2003;119B:28–34. doi: 10.1002/ajmg.b.20004. [DOI] [PubMed] [Google Scholar]
- 77.Glatt SJ. Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia. Mol Psychiatry. 2003;8:911–915. doi: 10.1038/sj.mp.4001321. [DOI] [PubMed] [Google Scholar]
- 78.Dubertret C, et al. The 3′ region of the DRD2 gene is involved in genetic susceptibility to schizophrenia. Schizophr Res. 2004;67:75–85. doi: 10.1016/s0920-9964(03)00220-2. [DOI] [PubMed] [Google Scholar]
- 79.Kukreti R, et al. Association of DRD2 gene variant with schizophrenia. Neurosci Lett. 2006;392:68–71. doi: 10.1016/j.neulet.2005.08.059. [DOI] [PubMed] [Google Scholar]
- 80.Hanninen K, et al. Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia. Neurosci Lett. 2006;407:195–198. doi: 10.1016/j.neulet.2006.08.041. [DOI] [PubMed] [Google Scholar]
- 81.Parsons MJ, et al. A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate. Psychiatr Genet. 2007;17:159–163. doi: 10.1097/YPG.0b013e328017f8a4. [DOI] [PubMed] [Google Scholar]
- 82.Fallin MD, et al. Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet. 2005;77:918–936. doi: 10.1086/497703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Jeanneteau F, et al. A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor. Proc Natl Acad Sci USA. 2006;103:10753–10758. doi: 10.1073/pnas.0508189103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Shaikh S, et al. Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Hum Genet. 1996;97:714–719. doi: 10.1007/BF02346178. [DOI] [PubMed] [Google Scholar]
- 85.Ioannidis JP. Replication validity of genetic association studies. Nat Genet. 2001;29:306–309. doi: 10.1038/ng749. [DOI] [PubMed] [Google Scholar]
- 86.Ishiguro H, et al. Association between polymorphisms in the type 1 sigma receptor gene and schizophrenia. Neurosci Lett. 1998;257:45–48. doi: 10.1016/s0304-3940(98)00797-6. [DOI] [PubMed] [Google Scholar]
- 87.Sivagnanasundaram S. A cluster of single nucleotide polymorphisms in the 5′-leader of the human dopamine D3 receptor gene (DRD3) and its relationship to schizophrenia. Neurosci Lett. 2000;279:13–16. doi: 10.1016/s0304-3940(99)00921-0. [DOI] [PubMed] [Google Scholar]
- 88.Staddon S, et al. Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population. Schizophr Res. 2005;73:49–54. doi: 10.1016/j.schres.2004.06.011. [DOI] [PubMed] [Google Scholar]
- 89.Anney RJ, et al. Characterisation, mutation detection, and association analysis of alternative promoters and 5′ UTRs of the human dopamine D3 receptor gene in schizophrenia. Mol Psychiatry. 2002;7:493–502. doi: 10.1038/sj.mp.4001003. [DOI] [PubMed] [Google Scholar]
- 90.Talkowski ME, et al. Novel, replicated associations between dopamine D3 receptor gene polymorphisms and schizophrenia in two independent samples. Biol Psychiatry. 2006;60:570–577. doi: 10.1016/j.biopsych.2006.04.012. [DOI] [PubMed] [Google Scholar]
- 91.Dominguez E, et al. Extensive linkage disequilibrium mapping at HTR2A and DRD3 for schizophrenia susceptibility genes in the Galician population. Schizophr Res. 2007;90:123–129. doi: 10.1016/j.schres.2006.09.022. [DOI] [PubMed] [Google Scholar]
- 92.Templeton AR. A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. I. Basic theory and an analysis of alcohol dehydrogenase activity in Drosophila. Genetics. 1987;117:343–351. doi: 10.1093/genetics/117.2.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Templeton AR. Cladistic structure within the human lipoprotein lipase gene and its implications for phenotypic association studies. Genetics. 2000;156:1259–1275. doi: 10.1093/genetics/156.3.1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Seltman H. Evolutionary-based association analysis using haplotype data. Genet Epidemiol. 2003;25:48–58. doi: 10.1002/gepi.10246. [DOI] [PubMed] [Google Scholar]
- 95.Lewis CM, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet. 2003;73:34–48. doi: 10.1086/376549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Karayiorgou M, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA. 1995;92:7612–7616. doi: 10.1073/pnas.92.17.7612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Lohmueller KE. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003;33:177–182. doi: 10.1038/ng1071. [DOI] [PubMed] [Google Scholar]
- 98.Glatt SJ. Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. Am J Psychiatry. 2003;160:469–476. doi: 10.1176/appi.ajp.160.3.469. [DOI] [PubMed] [Google Scholar]
- 99.Egan MF, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA. 2001;98:6917–6922. doi: 10.1073/pnas.111134598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Barnett JH. Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry. 2007;12:502–509. doi: 10.1038/sj.mp.4001973. [DOI] [PubMed] [Google Scholar]
- 101.Li T, et al. Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry. 2000;5:77–84. doi: 10.1038/sj.mp.4000638. [DOI] [PubMed] [Google Scholar]
- 102.Shifman S, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet. 2002;71:1296–1302. doi: 10.1086/344514. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Williams HJ, et al. No association between schizophrenia and polymorphisms in COMT in two large samples. Am J Psychiatry. 2005;162:1736–1738. doi: 10.1176/appi.ajp.162.9.1736. [DOI] [PubMed] [Google Scholar]
- 104.Sweet RA, et al. Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease. Mol Psychiatry. 2005;10:1026–1036. doi: 10.1038/sj.mp.4001709. [DOI] [PubMed] [Google Scholar]
- 105.Vandenbergh DJ, et al. Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics. 1992;14:1104–1106. doi: 10.1016/s0888-7543(05)80138-7. [DOI] [PubMed] [Google Scholar]
- 106.Mitchell RJ, et al. Distribution of the 3′ VNTR polymorphism in the human dopamine transporter gene in world populations. Hum Biol. 2000;72:295–304. [PubMed] [Google Scholar]
- 107.VanNess SH. The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet. 2005;6:55. doi: 10.1186/1471-2156-6-55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Gamma F. Meta-analysis shows schizophrenia is not associated with the 40-base-pair repeat polymorphism of the dopamine transporter gene. Schizophr Res. 2005;73:55–58. doi: 10.1016/j.schres.2004.09.020. [DOI] [PubMed] [Google Scholar]
- 109.Jeong SH. Association study of dopamine transporter gene and schizophrenia in Korean population using multiple single nucleotide polymorphism markers. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:975–983. doi: 10.1016/j.pnpbp.2004.05.015. [DOI] [PubMed] [Google Scholar]
- 110.Khodayari N, et al. Association of the dopamine transporter gene (DAT1) core promoter polymorphism -67T variant with schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2004;129:10–12. doi: 10.1002/ajmg.b.30067. [DOI] [PubMed] [Google Scholar]
- 111.Kelada SN, et al. Dopamine transporter (SLC6A3) 5′ region haplotypes significantly affect transcriptional activity in vitro but are not associated with Parkinson's disease. Pharmacogenet Genomics. 2005;15:659–668. doi: 10.1097/01.fpc.0000170917.04275.d6. [DOI] [PubMed] [Google Scholar]
- 112.Drgon T, et al. Common human 5′ dopamine transporter (SLC6A3) haplotypes yield varying expression levels in vivo. Cell Mol Neurobiol. 2006:20. doi: 10.1007/s10571-006-9014-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.HapMap. The International HapMap Project. Nature. 2003;426:789–796. doi: 10.1038/nature02168. [DOI] [PubMed] [Google Scholar]
- 114.Carlson CS. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet. 2004;74:106–120. doi: 10.1086/381000. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.Purcell S. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19:149–150. doi: 10.1093/bioinformatics/19.1.149. [DOI] [PubMed] [Google Scholar]
- 116.Sham PC. Power of linkage versus association analysis of quantitative traits, by use of variance-components models, for sibship data. Am J Hum Genet. 2000;66:1616–1630. doi: 10.1086/302891. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Jablensky A. The 100-year epidemiology of schizophrenia. Schizophr Res. 1997;28:111–125. doi: 10.1016/s0920-9964(97)85354-6. [DOI] [PubMed] [Google Scholar]
- 118.Jablensky AV. Genetic epidemiology of schizophrenia: phenotypes, risk factors, and reproductive behavior. Am J Psychiatry. 2003;160:425–429. doi: 10.1176/appi.ajp.160.3.425. [DOI] [PubMed] [Google Scholar]
- 119.Merikangas KR. Genomic priorities and public health. Science. 2003;302:599–601. doi: 10.1126/science.1091468. [DOI] [PubMed] [Google Scholar]
- 120.Vogelstein B. Surfing the p53 network. Nature 16. 2000;408:307–310. doi: 10.1038/35042675. [DOI] [PubMed] [Google Scholar]
- 121.Goh KI. The human disease network. Proc Natl Acad Sci USA. 2007;104:8685–8690. doi: 10.1073/pnas.0701361104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122.Fanciulli M, et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet. 2007;39:721–723. doi: 10.1038/ng2046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Terwilliger JD. Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design. Hum Biol. 2000;72:63–132. [PubMed] [Google Scholar]
- 124.Terwilliger JD. An utter refutation of the “Fundamental Theorem of the HapMap”. Eur J Hum Genet. 2006;14:426–437. doi: 10.1038/sj.ejhg.5201583. [DOI] [PubMed] [Google Scholar]
- 125.Moskvina V. Detailed analysis of the relative power of direct and indirect association studies and the implications for their interpretation. Hum Hered. 2007;64:63–73. doi: 10.1159/000101424. [DOI] [PubMed] [Google Scholar]
- 126.Spielman RS. Transmission/disequilibrium test (TDT) for linkage and linkage disequilibrium between disease and marker. Am J Hum Genet. 1993;53a:863. [Google Scholar]
- 127.Wacholder S. Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J Natl Cancer Inst. 2000;14:1151–1158. doi: 10.1093/jnci/92.14.1151. [DOI] [PubMed] [Google Scholar]
- 128.Bacanu SA. The power of genomic control. Am J Hum Genet. 2000;66:1933–1944. doi: 10.1086/302929. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Pritchard JK. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet. 1999;65:220–228. doi: 10.1086/302449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Editorial. Freely associating. Nat Genet. 1999;22(1):1–2. doi: 10.1038/8702. [DOI] [PubMed] [Google Scholar]
- 131.Skol AD. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet. 2006;38:209–213. doi: 10.1038/ng1706. [DOI] [PubMed] [Google Scholar]
- 132.Farrer LA, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278:1349–1356. [PubMed] [Google Scholar]
- 133.Ennis S. Fine scale linkage disequilibrium mapping of age related macular degeneration in the complement factor H gene region. Br J Ophthalmol. 2007 doi: 10.1136/bjo.2007.114090. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 134.Gudmundsson J, et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet. 2007;39:631–637. doi: 10.1038/ng1999. [DOI] [PubMed] [Google Scholar]
- 135.Libioulle C, et al. Novel crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 2007;3:e58. doi: 10.1371/journal.pgen.0030058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 136.Saxena R, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316:1331–1336. doi: 10.1126/science.1142358. [DOI] [PubMed] [Google Scholar]
- 137.Lencz T, et al. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry. 2007;12:572–580. doi: 10.1038/sj.mp.4001983. [DOI] [PubMed] [Google Scholar]
- 138.Rogaeva E, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39:168–177. doi: 10.1038/ng1943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 139.Pae CU, et al. VNTR polymorphism of tyrosine hydroxylase gene and schizophrenia in the Korean population. Neuropsychobiology. 2003;47:131–136. doi: 10.1159/000070581. [DOI] [PubMed] [Google Scholar]
- 140.Williams HJ. No evidence for allelic association between schizophrenia and a functional variant of the human dopamine beta-hydroxylase gene (DBH) Am J Med Genet. 1999;88:557–559. doi: 10.1002/(sici)1096-8628(19991015)88:5<557::aid-ajmg22>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
- 141.Dmitrzak-Weglarz M, et al. Dopamine receptor D1 gene -48A/G polymorphism is associated with bipolar illness but not with schizophrenia in a Polish population. Neuropsychobiology. 2006;53:46–50. doi: 10.1159/000090703. [DOI] [PubMed] [Google Scholar]
- 142.Nakajima M, et al. Association and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics. J Hum Genet. 2007;52:86–91. doi: 10.1007/s10038-006-0084-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 143.Thorisson GA. The International HapMap Project Web site. Genome Res. 2005;15:1592–1593. doi: 10.1101/gr.4413105. [DOI] [PMC free article] [PubMed] [Google Scholar]