In this cohort of people in Norway who were born between 1967 and 1983, the risks of medical and social disabilities in adulthood increased with decreasing gestational age at birth.

Case-parent trios were used in a genome wide association study of cleft lip with/without cleft palate (CL/P). SNPs near two genes not previously associated with CL/P [MAFB: most significant SNP rs13041247, with odds ratio per minor allele OR=0.704; 95%CI=0.635,0.778; p=2.05*10 −11 ; and ABCA4: most significant SNP rs560426, with OR=1.432; 95%CI=1.292,1.587; p=5.70*10 −12 ] and two previously identified regions (chr. 8q24 and IRF6) attained genome wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes were similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24 while Asian families showed stronger evidence for MAFB and ABCA4. Expression studies support a role for MAFB in palate development.Corresponding author: THB (tbeaty@jhsph.edu). NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 September 17. Published in final edited form as:Nat Genet. 2010 June ; 42(6): 525-529. doi:10.1038/ng.580. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptCleft lip with or without cleft palate (CL/P) is a common human birth defect with documented genetic and environmental risk factors 1 . While CL/P can occur in many Mendelian malformation syndromes, the isolated, non-syndromic form constitutes 70% of all cases2. Evidence for genetic control of CL/P is compelling: recurrence risks are 20-30 times greater than population prevalences3 , 4 and both twin and family studies 5 suggest a major role for genes, Mutations in IRF6 cause VanderWoude syndrome, the most common Mendelian syndrome including CL/P, and markers in IRF6 have repeatedly shown evidence of association with isolated, non-syndromic CL/P 6-9 . An allele disrupting an AP2 binding site near IRF6 showed particularly strong evidence among European CL families, although multiple risk alleles are likely 10 .Birnbaum et al. 11 conducted a case-control genome wide association study (GWAS) in Germany and found significant evidence of association with markers in 8q24.21, and a US case-control GWAS confirmed this region 12 , with rs987525 being the most significant marker in both studies. Here we present a GWAS using a case-parent trio design in a consortium drawing cases from Europe, the US, China, Taiwan, Singapore, Korea and the Philippines. This design has the advantage of being robust to confounding due to population stratification, which is important when cases from diverse populations are combined. ResultsBecause these case-parent trios came from different populations (Table 1), we conducted a principal components analysis (PCA) on all parents to document genetic variation in our consortium (Supplementary Figure 1). Approximately 50% of parents could be classified as Asian and 45% as European, with remaining parents being of African or "other" ancestry (including mixed). Transmission disequilibrium tests...