Genetic heterogeneity and homogeneity among orofacial cleft subtypes: genome-wide association studies in the cleft collective

Abstract Several genome wide association studies (GWASs) of orofacial cleft have been conducted. However only a few such studies to date have combined all cleft cases, focused on subtypes other than non-syndromic cleft lip with/without cleft palate, or investigated subtype heterogeneity. We conducted a GWAS of orofacial clefts within 2268 cases from the Cleft Collective and 7913 population-based controls; we performed analyses of all orofacial clefts, plus 7 subgroups. We replicated our findings in a meta-analysis of independent samples and investigated patterns of correlation across subgroups. We identified 27 regions at genome-wide significance, 8 of which were novel. We also conducted the first GWAS of Pierre Robin Sequence, despite the small sample size (n cases = 237), we found one genome wide significant SNP (P < 5 × 10−8), and another 21 suggestive associations (P < 10−5). Novel loci include those mapping to LHX8 and TSBP1 (combined clefts), ARHGEF18 and ARHGEF19 (cleft lip with/without palate), FBN2 (cleft lip only), SLC35B3 (cleft palate only), CASC20 (Pierre Robin Sequence) and CHRM2 (non-syndromic cleft palate only). Several novel hits were in regions previously associated with facial morphology in GWAS or were in regions involved in key developmental processes, including neural crest cell migration and craniofacial development. We identified genetic loci with similar effects across all subgroups and some loci which were subtype specific, we also identified 3 loci with opposing effects on cleft lip and Pierre Robin sequence. Our findings highlight the merit of including all orofacial cleft subtypes in GWAS studies and investigating heterogeneity of effects across subtypes.