Pleiotropy method identifies genetic overlap between orofacial clefts at multiple loci from GWAS of multi-ethnictrios

Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). While nearly forty risk genes have been identified for CL/P, few risk genes are known for CP. We used a new statistical method, PLACO, to identify genetic variants influencing risk of both CL/P and CP. In a combined multi-ethnic genome-wide study of 2,771 CL/P and 611 CP case-parent trios, we discovered 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. We replicated the shared genetic etiology of subtypes underlying CL/P, and further discovered loci of genetic overlap exhibiting etiologic differences. In summary, we found evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.