Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2015 May 20.
Published in final edited form as: Eur J Oral Sci. 2012 Oct 15;120(6):553–557. doi: 10.1111/eos.12001

Further evidence of association of ABCA4 gene with cleft lip/palate

Clarissa Fontoura 1, Renato M Silva 2, Jose M Granjeiro 1, Ariadne Letra 2
PMCID: PMC4438764  NIHMSID: NIHMS407451  PMID: 23167473

Abstract

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with complex etiology. Numerous genes and environmental factors and their interactions are thought to play a role in the susceptibility to CL/P. A recent genome-wide association study with several populations revealed markers in/near MAFB and ABCA4 genes as new susceptibility loci for CL/P. We hypothesized that these genes could also contribute to CL/P in a Brazilian population, hence we evaluated if the associated SNPs in MAFB [rs13041247 and rs11696257] and ABCA4 [rs560426 and rs481931] were associated with CL/P in our case-control dataset. We genotyped 812 Caucasian individuals (400 cases and 412 controls) from Brazil,. Allele frequencies were compared for cases and controls as well as for cleft subgroups and controls. ABCA4 rs540426 showed strong association with CL/P, unilateral and right CL/P, and bilateral CL/P, whereas SNP rs481931 showed borderline association with CL/P, and bilateral CL/P. No association was found for MAFB . Our results support a potential role for ABCA4 in the etiology of CL/P in individuals from Brazil.

Keywords: cleft lip/cleft palate, association, ABCA4 gene, SNP

Craniofacial anomalies, and in particular oral-facial clefts, are major human birth defects with a worldwide frequency of 1 in 700 live births and substantial clinical impact. The possible etiologies are many, including single-gene disorders, chromosome aberrations, exposure to teratogens, and sporadic conditions of unknown cause (1). Oral-facial clefts can be further classified as nonsyndromic (isolated) or syndromic based on the presence of other structural anomalies. Approximately 30% of all clefts are associated with one of more than 400 described syndromes (2) while the remaining 70% are isolated defects. It is generally accepted that cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are genetically distinct phenotypes. CL/P is more common, affecting 1–2/1000 births and presenting considerable differences in prevalence, with Native Americans and Asians showing the highest rate and Africans the lowest. On the other hand, CPO is less common, with a prevalence of approximately 1/1500–2000 births in Caucasians, less variable among different ethnic backgrounds (3). These observations suggest that the relative contribution of individual susceptibility genes may vary across different populations, thus reinforcing the need of replication of association studies in different populations. Further, numerous lines of evidence now suggest that the phenotypic spectrum of nonsyndromic CL/P is more complex than previously realized and therefore genetic studies should include a more accurate description of the cleft phenotype, such as cleft type and laterality, as well as presence of subclinical phenotypes, such as defects in the orbicularis oris muscle and dental anomalies (4,5).

Several loci and genes - including, but not limited to, MSX1, IRF6, CRISPLD2, FOXE1, AXIN2 , and members of the WNT, FGF, and MMP gene families - have been associated with oral clefts (6–17). Additionally, recent advances in research methodologies have accelerated the discovery of loci conferring susceptibility to isolated CL/P through the use of genome-wide association studies (GWAS). The first three GWAS found strong evidence for association of an intergenic marker (rs987525) in the 8q24 chromosomal region with CL/P (18–20), and this association has been independently validated in additional populations, including a population from Brazil (21). Recently, a third GWAS identified associations with markers in/nearby ABCA4 and MAFB genes, located on chromosomes 1p22.1 and 20q11.1-q13.1, respectively, with CL/P in multiple populations (22). In two subsequent studies, the originally associated SNP in ABCA4 (rs540026) was associated with increased risk of CL/P in US and South American populations (23, 24) whereas a SNP in MAFB (rs13041247) was associated with increased risk of CL/P in Chinese (25). Intriguingly, a study with a Nigerian population did not find evidence of association for either ABCA4 or MAFB genes with CL/P (26).

Due to allelic heterogeneity among populations, in order to validate the findings of genetic association studies, it is necessary to independently attempt to replicate these findings in multiple populations. Hence, to further investigate a possible role for ABCA4 and MAFB in the susceptibility to CL/P in a population from Brazil, we tested the previously associated SNPs in ABC4 (rs560426 and rs481931), and MAFB (rs13041247 and rs11696257) genes (Table 1) for association with CL/P in our case-control dataset.

Table 1.

Details of the SNPs investigated in this study.

Gene Chromosome SNP SNP Function Allelesa
ABC4 1p22 rs560426 intron c/T
rs481931 intron G/t
MAFB 20q11.2-q13.1 rs13041247 intergenic c/T
rs11696257 intergenic C/t
Open in a new tab
a

Minor allele indicated as lower case, according to NCBI dbSNP.

MATERIALS AND METHODS

Subjects

A convenience sample consisting of 812 unrelated Caucasian individuals was included in this study. Of these, cases comprised 400 individuals (average age 17.3 yr, 252 males, 148 females) with isolated CL/P: 246 with unilateral CL/P and 154 cases with bilateral CL/P whereas 412 individuals without CL/P or family history of CL/P (average age 24.8 yearas, 165 males, 247 females) served as controls. Individuals were recruited at the Hospital of Rehabilitation and Craniofacial Anomalies and Bauru Dental School at the University of São Paulo, Brazil, after signing an informed consent. All individuals were from the Southeast region of Brazil, who are mostly European descendants from Portugal and Spain and have been suggested as bearing ~99% Caucasian ethnicity (27). Only cases with CL/P were recruited for the study, regardless of cleft side. Cases with cleft palate alone were not included. This study was approved by the University of Sao Paulo and University of Texas Health Science Center Institutional Review Boards.

Sample collection and genotyping

Saliva samples were collected from each individual as source of genomic DNA using Oragene kits (DNA Genotek, Ontario, CA). Genotyping was performed using Taqman chemistry (28) in 5uL reactions and detected on a 7900HT Sequence Detection Instrument (Applied Biosystems, Foster City, CA, USA). Assays and reagents were supplied by Applied Biosystems (Applied Biosystems). For quality control purposes, negative control reactions were performed using no nucleic acid template; positive control reactions included samples of known genotypes. Genotyping was performed blind to sample status.

Statistical Analyses

Power calculations were performed using the Genetic Power Calculator (29) and indicate that the sample size would provide approximately 80% statistical power to detect an associaton with an alpha of 0.05, if the markers selected are in linkage disequilibrium with the causal factor (D’=0.8) and their frequencies are around 20%.

Statistical analyses were performed using PLINK software (v.1.06) (30). For each SNP, We tested for deviation from Hardy-Weinberg equilibrium in cases and controls using a Pearson’s chi-square test. Association analyses were performed comparing differences in genotype and allele frequencies for each SNP between CL/P cases and controls, and between unilateral and bilateral CL/P cases and controls. We applied Bonferroni correction for multiple testing considering the number of tests and variables (0.05/7) and P≤0.007 was considered statistically significant.

RESULTS and DISCUSSION

There was no evidence of deviation from Hardy-Weinberg equilibrium for any of the SNPs investigated (data not shown). The results of the association analyses are summarized in Tables 2 and 3. We found evidence of genotypic and allelic association for the SNPs in ABCA4 and CL/P. SNP rs560426 showed association with CL/P (P=0.0002 for genotype, P=0.00007 for allele), particularly bilateral (P=0.0006 for genotype, P=0.001 for allele) and also unilateral (P=0.004 for genotype, P=0.001 for allele) CL/P. Additional associations were also found for ABCA4 SNP rs481931 alleles and bilateral (P=0.006) and unilateral (P=0.009) CL/P. We did not find association of MAFB SNPs and CL/P in our population (Tables 2 and 3).

Table 2.

Results of genotypic association analysis between single nucleotide polymorphisms (SNPs) in ABCA4 and MAFB genes and nonsyndromic cleft lip/palate (CL/P).

Gene SNP CL/P (n=400) P-
valueb 		CL/P Unilateral (n=246) P-
valueb 		CL/P Bilateral (n=154) P-
valueb
Genotypea Genotypea Genotypea
AA Aa aa AA Aa aa AA Aa aa
ABC4 rs560426 Case/control 116/74 118/203 86/123 0.0002 70/74 118/203 55/123 0.004 45/74 54/203 31/123 0.0006
rs481931 Case/control 184/154 155/192 44/57 0.02 113/154 104/192 29/57 0.15 71/154 49/192 14/57 0.05
MAFB rs13041247 Case/control 182/166 165/180 38/42 0.45 110/166 108/180 25/42 0.83 13/42 55/180 71/166 0.24
rs11696257 Case/control 185/181 163/185 32/41 0.44 115/181 107/185 22/41 0.78 69/181 54/185 10/41 0.29
Open in a new tab
a

Order of genotypes, AA/Aa/aa where a is the minor allele

b

Fisher exact test, significant if P≤0.05. Undetermined genotypes not included in analysis.

Table 3.

Results of allelic association analysis between single nucleotide polymorphisms (SNPs) in ABCA4 and MAFB genes and nonsyndromic cleft lip/palate (CL/P).

Gene SNP CL/P P-
valueb 		CL/P Unilateral P-
valueb 		CL/P Bilateral P-
valueb
Allelea Allelea Allelea
A a A a A a
ABC4 rs560426 Case/control 406/351 346/449 0.00007 258/351 228/449 0.001 144/351 116/449 0.001
rs481931 Case/control 523/500 243/306 0.06 330/500 162/306 0.009 191/500 77/306 0.006
MAFB rs13041247 Case/control 529/512 241/264 0.25 328/512 158/264 0.58 197/512 81//264 0.14
rs11696257 Case/control 533/547 227/267 0.21 337/547 151/267 0.48 192/547 74/267 0.13
Open in a new tab
a

Order of alleles, a where a is the minor allele

b

Fisher exact test, significant if P≤0.05.

Much progress has been made in the identification of putative candidate genes for CL/P. Recent genome-wide association studies (GWAS) have identified several novel loci associated with CL/P (18–20, 22). Nonetheless, to validate the findings of these studies and understand the overall impact of these results in the general population, it is necessary to independently replicate these findings in multiple populations. Our replication study suggests a role for ABCA4 and not MAFB in this Brazilian population of Caucasian ethnicity. Similarly, YUAN et al. (23) found evidence of association of ABCA4 with CL/P, whereas MAFB presented only nominal association values in their study with non-Hispanic white and Hispanic CL/P families. Moreover, both ABCA4 SNPs rs560426 and rs481931 showed association in the Hispanics, although the association in the non-hispanic whites was stronger for SNP rs481931.

The ABCA4 gene is located on chromosome 1p22.1 and belongs to a superfamily of transmembrane proteins expressed exclusively in retinal photoreceptors (31, 32). So far, there is little biological evidence to support a role for ABCA4 in craniofacial morphogenesis, particularly since Abca4 null mice do not exhibit cleft palate (22, 33). It is possible that the associated variants in ABCA4 are in linkage disequilibrium with a causal variant located in another gene, and act as indirect surrogates for a true etiologic variant in CL/P cases. Nevertheless, the previous associations of ABCA4 with CL/P in both GWAS (22, 33) and association studies in different populations (23, 24), including the population of the present study, warrants additional investigations on the possible role for this gene in the etiology of CL/P.

In summary, our results provide additional evidence for the association of ABCA4 with CL/P in a population from Brazil. Given the genetic heterogeneity across populations, it is important to investigate the association of previously reported genes with CL/P in multiple populations.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the individuals and families who participated in this study. This work was supported by NIH grants R00DE018954 (to AL) and R00DE018913 (to RM). Thanks to Ryan Rylands for technical assistance.

Footnotes

CONFLICTS OF INTEREST

The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

REFERENCES

  • 1.Murray JC. Gene/environment causes of cleft lip and/or palate. Clin Genet. 2002;61:248–256. doi: 10.1034/j.1399-0004.2002.610402.x. [DOI] [PubMed] [Google Scholar]
  • 2.Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the head and neck. New York: Oxford University Press; 2001. [Google Scholar]
  • 3.Mossey PA, Little J. Epidemiology of oral clefts: an international perspective. In: Wyszynski DF, editor. Cleft lip and palate: from origin to treatment. New York, NY: Oxford University Press; 2002. pp. 127–158. [Google Scholar]
  • 4.Weinberg SM, Neiswanger K, Martin RA, Mooney MP, Kane AA, Wenger SL, Losee J, Deleyiannis F, Ma L, De Salamanca JE, Czeizel AE, Marazita ML. The Pittsburgh Oral-Facial Cleft study: expanding the cleft phenotype. Background and justification. Cleft Palate Craniofac J. 2006;43:7–20. doi: 10.1597/04-122r1.1. [DOI] [PubMed] [Google Scholar]
  • 5.Letra A, Menezes R, Granjeiro JM, Vieira AR. Defining subphenotypes for oral clefts based on dental development. J Dent Res. 2007;86:986–991. doi: 10.1177/154405910708601013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Jezewski PA, Vieira AR, Nishimura C, Ludwig B, Johnson M, O’Brien SE, Daack-Hirsch S, Schultz RE, Weber A, Nepomucena B, Romitti PA, Christensen K, Orioli IM, Castilla EE, Machida J, Natsume N, Murray JC. Complete sequencing shows a role for MSX1 in nonsyndromic cleft lip and palate. J Med Genet. 2003;40:399–407. doi: 10.1136/jmg.40.6.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004;351:769–780. doi: 10.1056/NEJMoa032909. [DOI] [PubMed] [Google Scholar]
  • 8.Chiquet BT, Lidral AC, Stal S, Mulliken JB, Moreno LM, Arcos-Burgos M, Valencia-Ramirez C, Blanton SH, Hecht JT. CRISPLD2: a novel NSCLP candidate gene. Hum Mol Genet. 2007;16:2241–2248. doi: 10.1093/hmg/ddm176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Chiquet BT, Blanton SH, Burt A, Ma D, Stal S, Mulliken JB, Hecht JT. Variation in WNT genes is associated with non-syndromic cleft lip with or without cleft palate. Hum Mol Genet. 2008;17:2212–2218. doi: 10.1093/hmg/ddn121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Riley BM, Mansilla MA, Ma J, Daack-Hirsch S, Maher BS, Raffensperger LM, Russo ET, Vieira AR, DodÉ C, Mohammadi M, Marazita ML, Murray JC. Impaired FGF signaling contributes to cleft lip and palate. Proc Natl Acad Sci USA. 2007;104:4512–4517. doi: 10.1073/pnas.0607956104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Menezes R, Marazita ML, Goldstein Mchenry T, Cooper ME, Bardi K, Brandon C, Letra A, Martin RA, Vieira AR. AXIS inhibition protein 2 orofacial clefts and a family history of cancer. J Am Dent Assoc. 2009;140:80–84. doi: 10.14219/jada.archive.2009.0022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Menezes R, Letra A, Kim AH, KÜCHLER EC, Day A, Tannure PN, Gomes DA, Motta L, Paiva KB, Granjeiro JM, Vieira AR. Studies with Wnt genes and nonsyndromic cleft lip and palate. Birth Defects Res A Clin Mol Teratol. 2010;88:995–1000. doi: 10.1002/bdra.20720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Moreno LM, Mansilla MA, Bullard SA, Cooper ME, Busch TD, Machida J, Johnson MK, Brauer D, Krahn K, Daack-Hirsch S, L'Heureux J, Valencia-Ramirez C, Rivera D, LÓPez AM, Moreno MA, Hing A, Lammer EJ, Jones M, Christensen K, Lie RT, Jugessur A, Wilcox AJ, Chines P, Pugh E, Doheny K, Arcos-Burgos M, Marazita ML, Murray JC, Lidral AC. FOXE1 association with both isolated cleft lip with or without cleft palate and isolated cleft palate. Hum Mol Genet. 2009;18:4879–4896. doi: 10.1093/hmg/ddp444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Letra A, Menezes R, Govil M, Fonseca RF, Mchenry T, Granjeiro JM, Castilla EE, Orioli IM, Marazita ML, Vieira AR. Follow-up association studies of chromosome region 9q and nonsyndromic cleft lip/palate. Am J Med Genet A. 2010;152A:1701–1710. doi: 10.1002/ajmg.a.33482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Letra A, Menezes R, Fonseca RF, Govil M, Mchenry T, Murphy MJ, Hennebold JD, Granjeiro JM, Castilla EE, Orioli IM, Martin R, Marazita ML, Bjork BC, Vieira AR. Novel cleft susceptibility genes in chromosome 6q. J Dent Res. 2010;89:927–932. doi: 10.1177/0022034510370004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Letra A, Bjork B, Cooper ME, Szabo-Rogers H, Deleyiannis FW, Field LL, Czeizel AE, Ma L, Garlet GP, Poletta FA, Mereb JC, Lopez-Camelo JS, Castilla EE, Orioli IM, Wendell S, Blanton SH, Liu K, Hecht JT, Marazita ML, Vieira AR, Silva RM. Association of AXIN2 with non-syndromic oral clefts in multiple populations. J Dent Res. 2012;91:473–478. doi: 10.1177/0022034512440578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Letra A, Silva RM, Motta LG, Blanton SH, Hecht JT, Granjeiro JM, Vieira AR. Association of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts. Birth Defects Res A Clin Mol Teratol. 2012;94:540–548. doi: 10.1002/bdra.23026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Birnbaum S, Ludwig KU, Reutter H, Herms S, Steffens M, Rubini M, Baluardo C, Ferrian M, Almeida DE, Assis N, Alblas MA, Barth S, Freudenberg J, Lauster C, Schmidt G, Scheer M, Braumann B, BergÉ SJ, Reich RH, Schiefke F, Hemprich A, PÖTzsch S, Steegers-Theunissen RP, PÖTzsch B, Moebus S, Horsthemke B, Kramer FJ, Wienker TF, Mossey PA, Propping P, Cichon S, Hoffmann P, Knapp M, NÖThen MM, Mangold E. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet. 2009;41:473–477. doi: 10.1038/ng.333. [DOI] [PubMed] [Google Scholar]
  • 19.Grant SF, Wang K, Zhang H, Glaberson W, Annaiah K, Kim CE, Bradfield JP, Glessner JT, Thomas KA, Garris M, Frackelton EC, Otieno FG, Chiavacci RM, Nah HD, Kirschner RE, Hakonarson H. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr. 2009;155:909–913. doi: 10.1016/j.jpeds.2009.06.020. [DOI] [PubMed] [Google Scholar]
  • 20.Mangold E, Ludwig KU, Birnbaum S, Baluardo C, Ferrian M, Herms S, Reutter H, De Assis NA, Chawa TA, Mattheisen M, Steffens M, Barth S, Kluck N, Paul A, Becker J, Lauster C, Schmidt G, Braumann B, Scheer M, Reich RH, Hemprich A, PÖTzsch S, Blaumeiser B, Moebus S, Krawczak M, Schreiber S, Meitinger T, Wichmann HE, Steegers-Theunissen RP, Kramer FJ, Cichon S, Propping P, Wienker TF, Knapp M, Rubini M, Mossey PA, Hoffmann P, NÖThen MM. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet. 2010;42:24–26. doi: 10.1038/ng.506. [DOI] [PubMed] [Google Scholar]
  • 21.Brito LA, Paranaiba LM, Bassi CF, Masotti C, Malcher C, Schlesinger D, Rocha KM, Cruz LA, BÁRbara LK, Alonso N, Franco D, Bagordakis E, Martelli H, Jr, Meyer D, Coletta RD, Passos-Bueno MR. Region 8q24 is a susceptibility locus for nonsyndromic oral clefting in Brazil. Birth Defects Res A Clin Mol Teratol. 2012;94:464–468. doi: 10.1002/bdra.23011. [DOI] [PubMed] [Google Scholar]
  • 22.Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral AC, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox AJ, Lie RT, Jabs EW, Wu-Chou YH, Chen PK, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Melbye M, Doheny KF, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, Scott AF. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet. 2010;42:525–529. doi: 10.1038/ng.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Yuan Q, Blanton SH, Hecht JT. Association of ABCA4 and MAFB with non-syndromic cleft lip with or without cleft palate. Am J Med Genet A. 2011;155A:1469–1471. doi: 10.1002/ajmg.a.33940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Lennon CJ, Birkeland AC, NuÑEz JA, Su GH, Lanzano P, Guzman E, Celis K, Eisig SB, Hoffman D, Rendon MT, Ostos H, Chung WK, Haddad J., Jr Association of candidate genes with nonsyndromic clefts in Honduran and Colombian populations. Laryngoscope. 2012 Jul 2; doi: 10.1002/lary.23394. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
  • 25.Pan Y, Zhang W, Du Y, Tong N, Han Y, Zhang H, Wang M, Ma J, Wan L, Wang L. Different roles of two novel susceptibility loci for nonsyndromic orofacial clefts in a Chinese Han population. Am J Med Genet A. 2011;155A:2180–2185. doi: 10.1002/ajmg.a.34170. [DOI] [PubMed] [Google Scholar]
  • 26.Butali A, Mossey PA, Adeyemo WL, Jezewski PA, Onwuamah CK, Ogunlewe MO, Ugboko VI, Adejuyigbe O, Adigun AI, Abdur-Rahman LO, Onah II, Audu RA, Idigbe EO, Mansilla MA, Dragan EA, Petrin AL, Bullard SA, Uduezue AO, Akpata O, Osaguona AO, Olasoji HO, Ligali TO, Kejeh BM, Iseh KR, Olaitan PB, Adebola AR, Efunkoya E, Adesina OA, Oluwatosin OM, Murray JC. Genetic studies in the nigerian population implicate an MSX1 mutation in complex oral facial clefting disorders. Cleft Palate Craniofac J. 2011;48:646–653. doi: 10.1597/10-133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Pena SD, Di Pietro G, Fuchshuber-Moraes M, Genro JP, Hutz MH, Kehdy FDES, Kohlrausch F, Magno LA, Montenegro RC, Moraes MO, De Moraes ME, De Moraes MR, Ojopi EB, Perini JA, Racciopi C, Ribeiro-Dos-Santos AK, Rios-Santos F, Romano-Silva MA, Sortica VA, Suarez-Kurtz G. The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One. 2011;6:e17063. doi: 10.1371/journal.pone.0017063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Ranade K, Chang MS, Ting CT, Pei D, Hsiao CF, Olivier M, Pesich R, Hebert J, Chen YD, Dzau VJ, Curb D, Olshen R, Risch N, Cox DR, Botstein D. High-throughput genotyping with single nucleotide polymorphisms. Genome Res. 2001;11:1262–1268. doi: 10.1101/gr.157801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Purcell S, Cherny SS, Sham PC. Genetic power calculator: design of linkage and association genetic mapping of complex traits. Bioinformatics. 19:149–150. doi: 10.1093/bioinformatics/19.1.149. [DOI] [PubMed] [Google Scholar]
  • 30.Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Bender D, Maller J, Sklar P, De Bakker PI, Daly MJ, Sham PC. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet. 2007;81:559–575. doi: 10.1086/519795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Sun H, Molday RS, Nathans J. Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J Biol Chem. 1999;274:8269–8281. doi: 10.1074/jbc.274.12.8269. [DOI] [PubMed] [Google Scholar]
  • 32.Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EAM, Roman AJ, Sumaroka A, Steinberg JD, Jacobson SG, Stone EM, Palczewski K. ABCA4 disease progression and a proposed strategy for gene therapy. Hum Molec Genet. 2009;18:931–941. doi: 10.1093/hmg/ddn421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in Abcr knockout mice. Cell. 1999;98:13–23. doi: 10.1016/S0092-8674(00)80602-9. [DOI] [PubMed] [Google Scholar]

RESOURCES