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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported in part by the NIH grants R03DE029254 (D.R., S.V., J.B.H., T.H.B.), R03DE027121 (S.V., W.Z., M.A.T., T.H.B.), R00DE025060 (E.J.L.), R01DE016148 (M.L.M.) and U24OD023382 (D.R.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This manuscript involves data analysis of only existing de-identified genetic studies that are publicly available on dbGaP. There is no new data collection or patient contact. So, there is no IRB associated with this work. The research protocols of the original studies were approved by IRB at Johns Hopkins Bloomberg School of Public Health, at the University of Pittsburgh, and at each participating recruitment site. The details are provided in the Methods section of this manuscript. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes This work is entirely on existing genetic data from the POFC and the GENEVA studies, which are publicly available on dbGaP (, study accession numbers phs000774.v1.p1 and phs000094.v1.p1).