A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

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Authors: Terri H Beaty ; Jeffrey C Murray ; Mary L Marazita ; Ronald G Munger ; Ingo Ruczinski ; Jacqueline B Hetmanski ; Kung Yee Liang ; Tao Wu ; Tanda Murray ; M Daniele Fallin ; Richard A Redett ; Gerald Raymond ; Holger Schwender ; Shin C Jin ; Margaret E Cooper ; Martine Dunnwald ; Maria A Mansilla ; Elizabeth Leslie ; Stephen Bullard ; Andrew C Lidral ; Lina M Moreno ; Renato Menezes ; Alexandre R Vieira ; Aline Petrin ; Allen J Wilcox ; Rolv T Lie ; Ethylin W Jabs ; Yah Huei Wu-Chou ; Philip K Chen ; Hong Wang ; Xiaoqian Ye ; Shangzhi Huang ; Vincent Yeow ; Samuel S Chong ; Sun Ha Jee ; Bing Shi ; Kaare Christensen ; Doheny Kimberly ; W Pugh Elizabeth ; Ling Hua ; E Castilla Eduardo ; Andrew E Czeizel ; Lian Ma ; L Leigh Field ; Lawrence Brody ; Faith Pangilinan ; James L Mills ; Anne M Molloy ; Peadar N Kirke ; John M Scott ; Mauricio Arcos-Burgos ; Alan F Scott

MeSH: ATP-Binding Cassette Transporters/genetics* ; Animals ; Asian Continental Ancestry Group/genetics ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; European Continental Ancestry Group/genetics ; Female ; Genetic Predisposition to Disease* ; Genome-Wide Association Study ; Genotype ; Humans ; MafB Transcription Factor/genetics* ; Mice ; Polymorphism, Single Nucleotide*

Abstract: Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.