title: Genetic risk factors for orofacial clefts in Central Africans and Southeast Asians.
abstract: Genome-wide association studies (GWAS) for orofacial clefts have identified several susceptibility regions, but have largely focused on non-Hispanic White populations in developed countries. We performed a targeted genome-wide study of single nucleotide polymorphisms (SNPs) in exons using the Illumina HumanExome+ array with custom fine mapping of 16 cleft susceptibility regions in three underserved populations: Congolese (87 case-mother, 210 control-mother pairs), Vietnamese (131 case-parent trios), and Filipinos (42 case-mother, 99 control-mother pairs). All cases were children with cleft lip with or without cleft palate. Families were recruited from local hospitals and parental exposures were collected using interviewer-administered questionnaires. We used logistic regression models for case-control analyses, family-based association tests for trios, and fixed-effect meta-analyses to determine individual SNP effects corrected for multiple testing. Of the 16 known susceptibility regions tested, SNPs in four regions reached statistical significance in one or more of these populations: 1q32.2 (IRF6), 10q25.3 (VAX1), and 17q22 (NOG). Due to different linkage disequilibrium patterns, significant SNPs in these regions differed between the Vietnamese and Filipino populations from the index SNP selected from previous GWAS studies. Among Africans, there were no significant associations identified for any of the susceptibility regions. rs10787738 near VAX1 (P = 4.98E-3) and rs7987165 (P = 6.1E-6) were significant in the meta-analysis of all three populations combined. These results confirm several known susceptibility regions and identify novel risk alleles in understudied populations.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Figueiredo
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ly
authors.forename: Haley
authors.initials: H
authors.lastname: Raimondi
authors.forename: Kathy
authors.initials: K
authors.lastname: Magee
authors.forename: James W
authors.initials: JW
authors.lastname: Baurley
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Sanchez-Lara
authors.forename: Ugonna
authors.initials: U
authors.lastname: Ihenacho
authors.forename: Caroline
authors.initials: C
authors.lastname: Yao
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.forename: David
authors.initials: D
authors.lastname: van den Berg
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Yves A
authors.initials: YA
authors.lastname: DeClerk
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Samet
authors.forename: William
authors.initials: W
authors.lastname: Magee
mesh_terms: D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
keywords: CL(P); GREM1; GWAS; IRF6; NOG; VAX1