Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Oct 1.
Published in final edited form as: Eur J Med Genet. 2012 Jun 27;55(10):510–514. doi: 10.1016/j.ejmg.2012.06.005

GWAS reveals new recessive loci associated with non-syndromic facial clefting

Mauricio Camargo a, Dora Rivera a, Lina Moreno b,c, Andrew C Lidral b, Ursula Harper d, Marypat Jones d, Benjamin D Solomon e, Erich Roessler e, Jorge I Vélez e, Ariel F Martinez e, Settara C Chandrasekharappa d, Mauricio Arcos-Burgos e,f,*
PMCID: PMC3521569  NIHMSID: NIHMS407263  PMID: 22750566

Abstract

We have applied a GWAS to 40 consanguineous families segregating cases of non-syndromic cleft lip with or without cleft palate (NS CL/P) (a total of 160 affected and unaffected individuals) in order to trace potential recessive loci that confer susceptibility to this common facial malformation. Pedigree-based association test (PBAT) analyses reported nominal evidence of association and linkage over SNP markers located at 11q25 (rs4937877, P = 2.7 × 10−6), 19p12 (rs4324267, P = 1.6 × 10−5), 5q14.1 (rs4588572, P-value = 3.36 × 10−5), and 15q21.1 (rs4774497, P = 1.08 × 10−4). Using the Versatile Gene-Based Association Study to complement the PBAT results, we found clusters of markers located at chromosomes 19p12, 11q25, and 8p23.2 overcome the threshold for GWAS significance (P < 1 × 10−7). From this study, new recessive loci implicated in NS CL/P include: B3GAT1, GLB1L2, ZNF431, ZNF714, and CSMD1, even though the functional association with the genesis of NS CL/P remains to be elucidated. These results emphasize the importance of using homogeneous populations, phenotypes, and family structures for GWAS combined with gene-based association analyses, and should encourage. other researchers to evaluate these genes on independent patient samples affected by NS CL/P.

Keywords: Non-syndromic clefting, Facial, GWAS, Recessive loci, B3GAT1, CSMD1

1. Introduction

Orofacial clefts (OFC) are a major public health problem, affecting one every 500–1000 births worldwide[1]. The etiology of OFC is complex, and the genetic contributions are heterogeneous, likely relating to interacting effects of multiple loci with environmental covariates[2]. Non-syndromic (sometimes termed ‘isolated’) cleft lip with or without cleft palate (NS CL/P) is the most prevalent type of OFC[3].

Segregation analyses of CL/P have supported models that include genes of major effect[4]. Analyses of recurrence risk patterns estimate that between 3 and 14 genes (possibly interacting) are involved in the etiology of CL/P[5]. Mutation analysis of candidate genes revealed that 2–6% of individuals with NS CL/P are identified as having mutations in several genes including MSX1, FOXE1, GLI2, JAG2, LHX8, SATB2, RYK1[6,7]. In addition to analyses of candidate genes/loci, numerous genome-wide linkage screens of NS CL/P have been reported[1,8,9]. Meta-analysis of several of these published genome scans revealed genome-wide significant regions that best fit a recessive model of inheritance[1].

Over the past 20 years, one member of our research group (MA–B) conducted population genetics studies of the isolated Paisa community inhabiting the northwestern region of Colombia [10–12]. This community exhibits high degrees of endogamy, is genetically homogeneous, and the number of sibs is traditionally larger compared to families from other areas of the country [10,11,13]. Furthermore, race composition studies have shown that more than 90% of the genes are of Caucasian ancestry [10]. The study and recruitment of thousands of members from multigenerational and extended families in the Paisa community have been instrumental for the discovery of new gene associations that predispose this population to complex genetic conditions such as idiopathic epilepsy[14–16], Alzheimer’s disease and other dementias[17,18], attention deficit/hyperactivity disorder (ADHD) [19–22], and rheumatologic and autoimmune conditions[23–26], among others. In the particular case of NS CL/P, data from more than 600 multigenerational and extended Paisa pedigrees clustering NS CL/P were instrumental in identifying several loci associated with facial malformation. These loci include IRF6 and FOXE1[1,8,27,28] and the replication of loci identified in the GWAS as significantly associated with NS CL/P[29].

The purpose of this study is to contrast the hypothesis that NS CL/P loci following a recessive model of inheritance might be suitable for mapping using the GWAS technology applied to consanguineous extended and multigenerational Paisa families. To achieve this goal, families segregating for NS CL/P were ascertained by identifying affected probands who were recruited at Clínica Noel, in Medellin, Colombia. Clinical aspects, ascertainment methodology, and phenotype characterization of probands and their biological relatives have been reported previously[1,8,27–30]. Most of the families involve extended multiplex kindreds, i.e., multigenerational families with several affected individuals.

2. Methods

2.1. Subjects

To date, we have recruited 661 total pedigrees consisting of 2718 individuals (792 affected by clefting and 1926 unaffected), of which 1370 are female and 1291 are male. In 57 cases, mostly from very early generations, an accurate gender determination was not possible. Individuals with dysmorphic syndromes that included CL/P as a characteristic feature (e.g. van der Woude syndrome) were excluded from this study to restrict the analysis to NS CL/P. Because of our ad hoc hypothesis of recessive inheritance, we limited our study to pedigrees of known consanguinity or those in which, as a potential indicative of endogamy, spouses shared the same last name. As a result, a total of 40 pedigrees were selected.

2.2. Genotyping and genetic analysis

Blood samples were collected during home visits or during patients’ appointments at the clinic. Consent for future genetic and clinical analyses was specifically obtained. DNA was extracted using the QIAamp DNA Blood Maxi kit (Qiagen, Valencia, California, USA) and stored at −20 °C until use. Genotyping was performed at the NHGRI Genome Technology Branch using 370CNV-Quad SNP-chips from Illumina (www.illumina.com) and the Illumina Infinium assay protocol[31]. In brief, the DNA was whole-genome amplified, fragmented, hybridized, fluorescently tagged, and scanned. Standard quality control was applied.

All genotype data sets underwent the same rigorous quality checks both before and after the affected and unaffected NS CL/P patients were compared. SNPs were excluded from the analysis if they violated Hardy–Weinberg equilibrium (P < 0.05 for all genotyped SNPs), had a call rate below 90%, or had a minor allele frequency below 1%. All analyses were carried out with the use of established procedures implemented in the SVS 7.3.1 PBAT module (Golden Helix, Inc. Bozeman, MT, USA. Golden Helix PBAT Software, http://www.goldenhelix.com). PBAT employs a unified approach to calculate the Family Based Association Test (FBAT) statistic, a generalization of the Transmission Disequilibrium Test (TDT) method[32]. The FBAT statistic is based on a linear combination of offspring genotypes and traits, and for this particular set of families is exceptionally well suited as it maximizes the exquisite information provided by these pedigrees. Furthermore, we used FBAT because it is robust against the effects of population stratification and admixture[32]. To deal with the intensive computations needed to analyze these complex pedigrees, we used the PBAT module that identifies clusters of nuclear families in extended pedigrees, which are directly linked (i.e. that share a family member) and analyzes such clusters as extended pedigrees, avoiding the problem of overestimating any parameter and reducing both the complexity and computation time (Golden Helix, Inc. Bozeman, MT, USA. Golden Helix PBAT Software, http://www.goldenhelix.com). We also used the recessive model to test the null hypothesis of no linkage and no association as it maximized the power of the FBAT-statistic, and also because it suits our initial hypothesis of recessive transmission for this trait. Because NS CL/P occurs more often in men than women, ~2:1 ratio, sex was included as a modifier variable because covariates for the selected phenotype are known to substantially increase the power of the FBAT statistic [32,33].

The total set of results from the PBAT analysis (331,352 SNP marker loci that pass quality control) was subjected to a gene-based association test using Versatile Gene-Based Associated Study (VEGAS)[34]. Currently, gene-based tests are popular as an important complementary methodology in GWAS as they combine the markers’ implicit linkage disequilibrium information and the structural information on the genes. As a consequence of combining these methods, marginal levels of significance are often confused with random noise may add up to reveal significant signals of association[34]. Specifically, VEGAS performs gene-based association tests that produce a gene-based test statistic and then uses a simulation-based approach to calculate an empirical gene-based P-value. By default, patterns of linkage disequilibrium for each gene were estimated using the HapMap2 CEU population because the Paisa community is mostly Caucasian[10]Since 331,352 SNP marker loci were available for analysis after quality control (threshold P-value for GWAS significance was set at 0.05/331,352 = 1.5 × 10−7), we performed 107 permutations to set up empirical threshold values after using VEGAS.

3. Results

From the 40 extended pedigrees primarily selected for the GWAS, 34 passed quality control and were informative for genetic analyses. A total of 373 individuals, 287 unaffected and 86 affected NS CL/P, 174 females and 199 males, constituted these 34 pedigrees. From the 86 NS CL/P affected individuals, 31 were females and 55 males (χ2 = 5.05, P = 0.025, Odds Ratio = 1.76 males/females, 95% C.I. 1.04–3.00). The family size ranged from 3 to 34 individuals. A detailed description in terms of size, sex composition as well as status is presented in Table 1 of the supplementary information.

PBAT analysis reported nominal evidence of association and linkage over SNPs located at 5q14.1 (rs4588572, P = 3.36 × 10−5), 11q25 (rs4937877, P = 2.7 × 10−6), 15q21.1 (rs4774497, P = 1.08 × 10−4), and 19p12 (rs4324267, P = 1.6 × 10−5) (Table 1).

Table 1.

P-values for the top 30 SNPs reporting nominal evidence of association and linkage.

SNP Chromosome Allele (frequency) avHet Position (bp) Closest gene(s)a P-value
rs4937877 11 G (0.2542) 0.3565 133,740,601 GLB1L2 2.70 × 10−6
rs4324267 19 A (0.2208) 0.2241 21,116,188 ZNF431 1.60 × 10−5
rs4707479 6 A (0.4083) 0.3776 68,787,829 BAI3 3.18 × 10−5
rs4588572 5 G (0.3621) 0.1951 77,667,389 SCAMP1 3.36 × 10−5
rs787499 1 A (0.375) 0.4571 67,843,969 SERBP1/GNG12 4.11 × 10−5
rs10063742 5 A (0.375) 0.1963 77,795,117 SCAMP1 5.01 × 10−5
rs7700390 5 A (0.3708) 0.2442 77,825,287 LHFPL2 5.01 × 10−5
rs7309401 12 A (0.2417) 0.4444 106,418,919 BTBD11 5.33 × 10−5
rs2133471 10 A (0.3458) 0.4997 54,831,303 PRKG1/DKK1/PCDH15 5.75 × 10−5
rs2115498 19 A (0.3458) 0.3855 21,147,312 ZNF431 6.10 × 10−5
rs6873144 5 G (0.4583) 0.3872 77,777,539 SCAMP1 7.41 × 10−5
rs1159930 5 A (0.4583) 0.4066 77,804,698 SCAMP1 7.41 × 10−5
rs1428864 5 G (0.4542) 0.3927 77,816,018 SCAP1/LHFPL2 7.41 × 10−5
rs239649 21 A (0.3375) 0.4598 27,717,245 BC043580 7.70 × 10−5
rs2398587 5 G (0.3625) 0.4275 142,600,718 ARHGAP26 9.62 × 10−5
rs3933797 9 A (0.2833) 0.3878 95,225,151 FAM120A 9.62 × 10−5
rs7036984 9 A (0.2417) 0.3477 95,240,360 CR618537 9.62 × 10−5
rs2058191 19 A (0.3125) 0.3736 33,528,681 CCNE1 9.67 × 10−5
rs1800977 9 G (0.4625) 0.4173 106,730,270 ABCA1 9.72 × 10−5
rs3797390 5 G (0.4667) 0.477 75,942,820 IQGAP2 1.02 × 10−4
rs1035791 11 A (0.2417) 0.4913 124,697,490 PKNOX2 1.08 × 10−4
rs1344542 12 G (0.3833) 0.4871 108,566,536 MMAB/MVK 1.08 × 10−4
rs4774497 15 A (0.35) 0.4216 45,645,546 SEMA6D 1.08 × 10−4
rs1898110 15 C (0.3305) 0.4328 45,677,641 SEMA6D 1.08 × 10−4
rs4796902 18 G (0.2833) 0.431 10,698,597 FAM38B 1.08 × 10−4
rs4239291 18 A (0.2833) 0.4129 10,699,970 FAM38B 1.08 × 10−4
rs6028738 20 A (0.3333) 0.4458 38,012,703 DHX35 1.08 × 10−4
rs958523 20 A (0.3083) 0.4455 38,015,758 DHX35 1.08 × 10−4
rs928163 20 A (0.2375) 0.4989 55,823,159 PMEPA1 1.08 × 10−4
rs4748264 10 G (0.1875) 0.3945 16,296,342 PTER 1.28 × 10−4
Open in a new tab
a

As in the UCSC Genome Browser GRCh37/hg19 assembly.

After using VEGAS, clusters of significant markers located at chromosomes 8p23.2,11q25, and 19p12 overcame the threshold for GWAS significance (P < 1 ×10−7) (Table 2). In the 8p23.2 region, the CUB and Sushi Multiple Domains 1 (CSMD1) gene is contained; in 11q25 the beta-1,3-glucuronyltransferase 1 (B3GAT1) and beta-galactosidase-1-like protein 2 (GLB1L2) genes, and in 19p12, the Homo Sapiens Zinc Finger Protein 431 (ZNF431) and Homo Sapiens Zinc Finger Protein 714 (ZNF714) genes.

Table 2.

Results of gene-based association tests using VEGAS with 107 permutations.

Chromosome Gene N Start (bp) Stop (bp) Test statistic P-value
19 ZNF431 5 21,116,679 21,160,645 63.955 <10−7
19 ZNF714 2 21,056,810 21,099,723 34.681 <10−7
11 B3GAT1 6 133,753,607 133,787,022 62.712 <10−7
11 GLB1L2 5 133,707,018 133,751,428 57.138 <10−7
8 CSMD1 19 2,780,281 4,839,736 101.600 <10−7
16 CDH13 10 81,218,078 82,387,700 53.829 <10−6
11 CNTN5 19 98,397,080 99,732,683 119.099 <10−6
11 GLB1L3 5 133,651,484 133,694,668 57.138 <10−6
9 PTPRD 19 8,304,245 10,602,509 104.050 <10−6
2 CTNNA2 7 79,593,633 80,729,416 43.953 <10−6
20 CDH4 10 59,260,953 59,945,694 54.390 2 × 10−6
1 CSMD2 18 33,752,195 34,404,030 132.064 2 × 10−6
5 AP3B1 2 77,333,905 77,626,284 26.100 3 × 10−6
8 SULF1 10 70,541,412 70,735,701 71.135 4 × 10−6
7 DNAH11 9 21,549,357 21,907,982 59.205 4 × 10−6
5 ARHGAP26 6 142,130,475 142,588,765 57.388 4 × 10−6
12 TMEM132D 17 128,122,223 128,954,165 105.118 5 × 10−6
16 A2BP1 12 6,009,132 7,702,500 59.851 7 × 10−6
10 CAMK1D 11 12,431,588 12,911,739 57.470 7 × 10−6
1 FMN2 8 238,321,807 238,705,112 49.759 7 × 10−6
19 KANK2 10 11,135,945 11,167,496 73.331 9 × 10−6
11 OPCML 13 131,790,084 132,907,613 67.945 1.1 × 10−5
3 RBMS3 11 29,297,946 30,021,624 76.673 1.4 × 10−5
9 ASTN2 9 118,227,327 119,217,138 54.474 1.5 × 10−5
7 CNTNAP2 26 145,444,385 147,749,019 160.697 1.6 × 10−5
5 LHFPL2 8 77,816,793 77,980,404 102.079 1.6 × 10−5
9 ABCA1 3 106,583,104 106,730,257 30.986 1.7 × 10−5
8 SGCZ 26 13,991,743 15,140,163 147.671 1.7 × 10−5
20 PLCB1 9 8,061,295 8,813,547 48.709 1.9 × 10−5
6 FARS2 13 5,206,582 5,716,815 87.725 1.9 × 10−5
Open in a new tab

VEGAS: Versatile Gene-based Association Study. N: Total number of SNPs; bp: Base pair; SNP: Single Nucleotide Polymorphism.

4. Discussion

Most studies of non-syndromic clefts have focused on CL/P rather than isolated cleft palate. This has been biased perhaps by the larger number of cases, easier ascertainment and less confusion from confounding syndromes. To date, there are three published GWAS studies for CL/P using a case-control design[35–37] and one case-parent trio study from an international consortium that is part of GENEVA (the gene-environment association studies consortium) [29,38]. The data from these studies is summarized in Klotz et al.[39]. Although a number of important genes showing association to NS CL/P have been reported, disease-causing variants still remain unidentified. In our study, using extended and multigenerational pedigrees from the Paisa community, a genetic isolate in Colombia, South America, we have identified new loci harboring very interesting candidate genes for conferring a risk of susceptibility for NS CL/P.

CSMD1, a complement control-related gene with potential suppressive activity of squamous cell carcinomas, has been associated with the development of head and neck cancers[40,41]. It has been proposed that CSMD1 may be an important regulator of complement activation and inflammation in the developing central nervous system, and it may play a role in the context of growth cone function [42]. A recent report also associates CSMD1 with schizophrenia in three independent European populations [43], although the direct relevance of this finding to NS CL/P is unclear. This gene has an intermediate level of expression in the brain, including cerebellum, substantia nigra, hippocampus and fetal brain[44].

B3GAT1 encodes a member of the glucuronyltransferase gene family that functions as the key enzyme in a glucuronyl transfer reaction during the biosynthesis of the carbohydrate epitope HNK-1 (Human Natural Killer-1, also known as CD57 and LEU7) [45]. B3GAT1 has a prominent expression in the brain, and little or no expression in other tissues. Like CSMD1, B3GAT1 has been previously associated with schizophrenia [46].

ZNF431 is an uncharacterized Krüppel-associated box (KRAB)-containing C2H2 zinc finger protein. These transcription factors are involved in the regulation of cell differentiation, proliferation, apoptosis and neoplastic transformation[47–49]. A recent report implicates ZNF431 in controlling both Ptch1 basal expression and cellular response to Hedgehog signaling, which suggests a role for this transcription factor during developmental stages[50].

ZNF714 and GLB1L2 are of unknown function. Because ZNF714 is a zinc finger protein belonging to the same subfamily as ZNF431, there is a possibility of a developmental role for this gene. GLB1L2 is highly expressed in neural crest-derived tissues.

Supplementary Material

supp Table

Acknowledgments

The authors would like to extend their deepest gratitude to all the patients and families from Antioquia, Colombia, who took part in our ongoing CL/CP program. This research was supported by COLCIENCIAS (Grant 1115-408-20519), Programa Sostenibilidad Universidad de Antioquia, Colombia, and in part by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, USA.

Appendix A. Supplementary data

Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.ejmg.2012.06.005.

References

  • 1.Marazita ML, Lidral AC, Murray JC, Field LL, Maher BS, McHenry TG, et al. Genome scan, fine-mapping, and candidate gene analysis of non-syndromic cleft lip with or without cleft palate reveals phenotype-specific differences in linkage and association results. Hum Hered. 2009;68(3):151–170. doi: 10.1159/000224636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Moreno LM, Arcos-Burgos M, Marazita ML, Krahn K, Maher BS, Cooper ME, et al. Genetic analysis of candidate loci in non-syndromic cleft lip families from Antioquia-Colombia and Ohio. Am J Med Gen Part A. 2004 Mar 1;125A(2):135–144. doi: 10.1002/ajmg.a.20425. [DOI] [PubMed] [Google Scholar]
  • 3.Marazita ML, Mooney MP. Current concepts in the embryology and genetics of cleft lip and cleft palate. Clin Plast Surg. 2004 Apr;31(2):125–140. doi: 10.1016/S0094-1298(03)00138-X. [DOI] [PubMed] [Google Scholar]
  • 4.Marazita ML, Goldstein AM, Smalley SL, Spence MA. Cleft lip with or without cleft palate: reanalysis of a three-generation family study from England. Genet Epidemiol. 1986;3(5):335–342. doi: 10.1002/gepi.1370030506. [DOI] [PubMed] [Google Scholar]
  • 5.Schliekelman P, Slatkin M. Multiplex relative risk and estimation of the number of loci underlying an inherited disease. Am J Hum Genet. 2002 Dec;71(6):1369–1385. doi: 10.1086/344779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Jezewski PA, Vieira AR, Nishimura C, Ludwig B, Johnson M, O’Brien SE, et al. Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet. 2003 Jun;40(6):399–407. doi: 10.1136/jmg.40.6.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Watanabe A, Akita S, Tin NT, Natsume N, Nakano Y, Niikawa N, et al. A mutation in RYK is a genetic factor for nonsyndromic cleft lip and palate. Cleft Palate Craniofac J. 2006 May;43(3):310–316. doi: 10.1597/04-145.1. [DOI] [PubMed] [Google Scholar]
  • 8.Marazita ML, Field LL, Tuncbilek G, Cooper ME, Goldstein T, Gursu KG. Genome-scan for loci involved in cleft lip with or without cleft palate in consanguineous families from Turkey. Am J Med Gen Part A. 2004 Apr 15;126A(2):111–122. doi: 10.1002/ajmg.a.20564. [DOI] [PubMed] [Google Scholar]
  • 9.Vieira AR, McHenry TG, Daack-Hirsch S, Murray JC, Marazita ML. A genome wide linkage scan for cleft lip and palate and dental anomalies. Am J Med Gen Part A. 2008 Jun 1;146A(11):1406–1413. doi: 10.1002/ajmg.a.32295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002 Apr;61(4):233–247. doi: 10.1034/j.1399-0004.2002.610401.x. [DOI] [PubMed] [Google Scholar]
  • 11.Pineda DA, Palacio LG, Puerta IC, Merchan V, Arango CP, Galvis AY, et al. Environmental influences that affect attention deficit/hyperactivity disorder: study of a genetic isolate. Eur Child Adolesc Psychiatry. 2007 Aug;16(5):337–346. doi: 10.1007/s00787-007-0605-4. [DOI] [PubMed] [Google Scholar]
  • 12.Jain M, Velez JI, Acosta MT, Palacio LG, Balog J, Roessler E, et al. A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Mol Psychiatry. 2011 May 24; doi: 10.1038/mp.2011.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Palacio JD, Castellanos FX, Pineda DA, Lopera F, Arcos-Burgos M, Quiroz YT, et al. Attention-deficit/hyperactivity disorder and comorbidities in 18 Paisa Colombian multigenerational families. J Am Acad Child Adolesc Psychiatry. 2004 Dec;43(12):1506–1515. doi: 10.1097/01.chi.0000142279.79805.dc. [DOI] [PubMed] [Google Scholar]
  • 14.Jimenez I, Mora O, Jimenez M, Zuluaga L, Isaza R, Sanchez JL, et al. Complex segregation analysis of non-myoclonic idiopathic generalized epilepsy in families ascertained from probands affected with idiopathic epilepsy with tonic-clonic seizures in Antioquia, Colombia. Hum Genet. 1996 Aug;98(2):214–218. doi: 10.1007/s004390050194. [DOI] [PubMed] [Google Scholar]
  • 15.Jimenez I, Mora O, Lopez G, Jimenez ME, Zuluga L, Isaza R, et al. Idiopathic epilepsy with generalized tonic clonic seizures in Antioquia, Colombia: is the joint Amerindian and Negroid racial admixture the cause of its high prevalence? Biol Res. 1996;29(3):297–304. [PubMed] [Google Scholar]
  • 16.Palacio LG, Sanchez JL, Jimenez ME, Rivera-Valencia D, Jimenez-Ramirez I, Arcos-Burgos M. Linkage analysis of the 15q25-15q22 region in an extended multigenerational family segregating for idiopathic epilepsy. Rev Neurol. 2004 Dec 1–15; 39(11):1021–1025. [PubMed] [Google Scholar]
  • 17.Arboleda-Velasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla D, Gutierrez JE, et al. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology. 2002 Jul 23;59(2):277–279. doi: 10.1212/wnl.59.2.277. [DOI] [PubMed] [Google Scholar]
  • 18.Lopera F, Ardilla A, Martinez A, Madrigal L, Arango-Viana JC, Lemere CA, et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA: J Am Med Association. 1997 Mar 12;277(10):793–799. [PubMed] [Google Scholar]
  • 19.Arcos-Burgos M, Castellanos FX, Konecki D, Lopera F, Pineda D, Palacio JD, et al. Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate. Mol Psychiatry. 2004 Mar;9(3):252–259. doi: 10.1038/sj.mp.4001396. [DOI] [PubMed] [Google Scholar]
  • 20.Arcos-Burgos M, Jain M, Acosta MT, Shively S, Stanescu H, Wallis D, et al. A common variant of the latrophilin, 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry. 2010 Nov;15(11):1053–1066. doi: 10.1038/mp.2010.6. [DOI] [PubMed] [Google Scholar]
  • 21.Jain M, Palacio LG, Castellanos FX, Palacio JD, Pineda D, Restrepo MI, et al. Attention-deficit/hyperactivity disorder and comorbid disruptive behavior disorders: evidence of pleiotropy and new susceptibility loci. Biol Psychiatry. 2007 Jun 15;61(12):1329–1339. doi: 10.1016/j.biopsych.2006.06.026. [DOI] [PubMed] [Google Scholar]
  • 22.Domene S, Stanescu H, Wallis D, Tinloy B, Pineda DE, Kleta R, et al. Screening of human LPHN3 for variants with a potential impact on ADHD susceptibility. Am J Med Genet B Neuropsychiatr Genet. 2011 Jan;156(1):11–18. doi: 10.1002/ajmg.b.31141. [DOI] [PubMed] [Google Scholar]
  • 23.Anaya JM, Correa PA, Mantilla RD, Arcos-Burgos MTAP. HLA-DQB1, and HLA-DRB1 polymorphism in Colombian patients with primary Sjogren’s syndrome. Semin Arthritis Rheum. 2002 Jun;31(6):396–405. doi: 10.1053/sarh.2002.32557. [DOI] [PubMed] [Google Scholar]
  • 24.Anaya JM, Correa PA, Mantilla RD, Arcos-Burgos M. Rheumatoid arthritis association in Colombian population is restricted to HLA-DRB1*04 QRRAA alleles. Genes Immun. 2002 Feb;3(1):56–58. doi: 10.1038/sj.gene.6363833. [DOI] [PubMed] [Google Scholar]
  • 25.Anaya JM, Rivera D, Palacio LG, Arcos-Burgos M, Correa PA. D6S439 microsatellite identifies a new susceptibility region for primary Sjogren’s syndrome. J Rheumatol. 2003 Oct;30(10):2152–2156. [PubMed] [Google Scholar]
  • 26.Arcos-Burgos M, Parodi E, Salgar M, Bedoya E, Builes J, Jaramillo D, et al. Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA. Hum Genet. 2002 Apr;110(4):334–342. doi: 10.1007/s00439-002-0687-5. [DOI] [PubMed] [Google Scholar]
  • 27.Moreno LM, Mansilla MA, Bullard SA, Cooper ME, Busch TD, Machida J, et al. FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. Hum Mol Genet. 2009 Dec 15;18(24):4879–4896. doi: 10.1093/hmg/ddp444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, et al. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004 Aug 19;351(8):769–780. doi: 10.1056/NEJMoa032909. [DOI] [PubMed] [Google Scholar]
  • 29.Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, et al. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet. 2010 Jun;42(6):525–529. doi: 10.1038/ng.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Chiquet BT, Lidral AC, Stal S, Mulliken JB, Moreno LM, Arcos-Burgos M, et al. CRISPLD2: a novel NSCLP candidate gene. Hum Mol Genet. 2007 Sep 15;16(18):2241–2248. doi: 10.1093/hmg/ddm176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS. A genome-wide scalable SNP genotyping assay using microarray technology. Nat Genetics. 2005 May;37(5):549–554. doi: 10.1038/ng1547. [DOI] [PubMed] [Google Scholar]
  • 32.Lange C, Silverman EK, Xu X, Weiss ST, Laird NM. A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics. 2003 Apr;4(2):195–206. doi: 10.1093/biostatistics/4.2.195. [DOI] [PubMed] [Google Scholar]
  • 33.Bender PL. Genetics of cleft lip and palate. J Pediatr Nurs. 2000 Aug;15(4):242–249. doi: 10.1053/jpdn.2000.8148. [DOI] [PubMed] [Google Scholar]
  • 34.Liu JZ, McRae AF, Nyholt DR, Medland SE, Wray NR, Brown KM, et al. A versatile gene-based test for genome-wide association studies. Am J Hum Genet. 2010 Jul 9;87(1):139–145. doi: 10.1016/j.ajhg.2010.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Birnbaum S, Ludwig KU, Reutter H, Herms S, Steffens M, Rubini M, et al. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genetics. 2009 Apr;41(4):473–477. doi: 10.1038/ng.333. [DOI] [PubMed] [Google Scholar]
  • 36.Grant SF, Wang K, Zhang H, Glaberson W, Annaiah K, Kim CE, et al. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr. 2009 Dec;155(6):909–913. doi: 10.1016/j.jpeds.2009.06.020. [DOI] [PubMed] [Google Scholar]
  • 37.Mangold E, Ludwig KU, Birnbaum S, Baluardo C, Ferrian M, Herms S, et al. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genetics. 2010 Jan;42(1):24–26. doi: 10.1038/ng.506. [DOI] [PubMed] [Google Scholar]
  • 38.Cornelis MC, Agrawal A, Cole JW, Hansel NN, Barnes KC, Beaty TH, et al. The Gene, Environment Association Studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions. Genet Epidemiology. 2010 May;34(4):364–372. doi: 10.1002/gepi.20492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Klotz CM, Wang X, Desensi RS, Grubs RE, Costello BJ, Marazita ML. Revisiting the recurrence risk of nonsyndromic cleft lip with or without cleft palate. Am J Med Gen Part A. 2010 Nov;152A(11):2697–2702. doi: 10.1002/ajmg.a.33695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Scholnick SB, Richter TM. The role of CSMD1 in head and neck carcinogenesis. Genes Chromosomes Cancer. 2003 Nov;38(3):281–283. doi: 10.1002/gcc.10279. [DOI] [PubMed] [Google Scholar]
  • 41.Toomes C, Jackson A, Maguire K, Wood J, Gollin S, Ishwad C, et al. The presence of multiple regions of homozygous deletion at the CSMD1 locus in oral squamous cell carcinoma question the role of CSMD1 in head and neck carcinogenesis. Genes Chromosomes Cancer. 2003 Jun;37(2):132–140. doi: 10.1002/gcc.10191. [DOI] [PubMed] [Google Scholar]
  • 42.Kraus DM, Elliott GS, Chute H, Horan T, Pfenninger KH, Sanford SD, et al. CSMD1 is a novel multiple domain complement-regulatory protein highly expressed in the central nervous system and epithelial tissues. J Immunol. 2006 Apr 1;176(7):4419–4430. doi: 10.4049/jimmunol.176.7.4419. [DOI] [PubMed] [Google Scholar]
  • 43.Havik B, Le Hellard S, Rietschel M, Lybaek H, Djurovic S, Mattheisen M, et al. The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry. 2011 Jul 1;70(1):35–42. doi: 10.1016/j.biopsych.2011.01.030. [DOI] [PubMed] [Google Scholar]
  • 44.Nagase T, Kikuno R, Ohara O. Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins. DNA Res. 2001 Aug 31;8(4):179–187. doi: 10.1093/dnares/8.4.179. [DOI] [PubMed] [Google Scholar]
  • 45.Mitsumoto Y, Oka S, Sakuma H, Inazawa J, Kawasaki T. Cloning and chromosomal mapping of human glucuronyltransferase involved in biosynthesis of the HNK-1 carbohydrate epitope. Genomics. 2000 Apr 15;65(2):166–173. doi: 10.1006/geno.2000.6152. [DOI] [PubMed] [Google Scholar]
  • 46.Jeffries AR, Mungall AJ, Dawson E, Halls K, Langford CF, Murray RM, et al. Beta-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation. Mol Psychiatry. 2003 Jul;8(7):654–663. doi: 10.1038/sj.mp.4001382. [DOI] [PubMed] [Google Scholar]
  • 47.Jheon AH, Ganss B, Cheifetz S, Sodek J. Characterization of a novel KRAB/C2H2 zinc finger transcription factor involved in bone development. J Biol Chem. 2001 May 25;276(21):18282–18289. doi: 10.1074/jbc.M010885200. [DOI] [PubMed] [Google Scholar]
  • 48.Hennemann H, Vassen L, Geisen C, Eilers M, Moroy T. Identification of a novel Kruppel-associated box domain protein, Krim-1, that interacts with c-Myc and inhibits its oncogenic activity. J Biol Chem. 2003 Aug 1;278(31):28799–28811. doi: 10.1074/jbc.M207196200. [DOI] [PubMed] [Google Scholar]
  • 49.Hering TM, Kazmi NH, Huynh TD, Kollar J, Xu L, Hunyady AB, et al. Characterization and chondrocyte differentiation stage-specific expression of KRAB zinc-finger protein gene ZNF470. Exp Cell Res. 2004 Sep 10;299(1):137–147. doi: 10.1016/j.yexcr.2004.05.030. [DOI] [PubMed] [Google Scholar]
  • 50.He Z, Cai J, Lim JW, Kroll K, Ma L. A novel KRAB domain-containing zinc finger transcription factor ZNF431 directly represses Patched1 transcription. J Biol Chem. 2011 Mar 4;286(9):7279–7289. doi: 10.1074/jbc.M110.178780. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supp Table
NIHMS407263-supplement-supp_Table.docx (113.8KB, docx)

RESOURCES