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However, some evidence of shared genetic risk in\n                    <jats:italic>IRF6<\/jats:italic>\n                    ,\n                    <jats:italic>GRHL3<\/jats:italic>\n                    and\n                    <jats:italic>ARHGAP29<\/jats:italic>\n                    regions exists; only\n                    <jats:italic>FOXE1<\/jats:italic>\n                    has been recognized as significantly associated with both CL\/P and CP in genome-wide association studies (GWAS). We used a new statistical approach, PLACO (pleiotropic analysis under composite null), on a combined multi-ethnic GWAS of 2,771 CL\/P and 611 CP case-parent trios. At the genome-wide significance threshold of 5 \u00d7 10\n                    <jats:sup>\u22128<\/jats:sup>\n                    , PLACO identified 1 locus in 1q32.2 (\n                    <jats:italic>IRF6<\/jats:italic>\n                    ) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10\n                    <jats:sup>\u22126<\/jats:sup>\n                    , we found 5 more loci with compelling candidate genes having opposite effects on CL\/P and CP: 1p36.13 (\n                    <jats:italic>PAX7<\/jats:italic>\n                    ), 3q29 (\n                    <jats:italic>DLG1<\/jats:italic>\n                    ), 4p13 (\n                    <jats:italic>LIMCH1<\/jats:italic>\n                    ), 4q21.1 (\n                    <jats:italic>SHROOM3<\/jats:italic>\n                    ) and 17q22 (\n                    <jats:italic>NOG<\/jats:italic>\n                    ). Additionally, we replicated the recognized shared locus 9q22.33 (\n                    <jats:italic>FOXE1<\/jats:italic>\n                    ), and identified 2 loci in 19p13.12 (\n                    <jats:italic>RAB8A<\/jats:italic>\n                    ) and 20q12 (\n                    <jats:italic>MAFB<\/jats:italic>\n                    ) that appear to influence risk of both CL\/P and CP in the same direction. We found locus-specific effects may vary by racial\/ethnic group at these regions of genetic overlap, and failed to find evidence of sex-specific differences. We confirmed shared etiology of the two OFC subtypes comprising CL\/P, and additionally found suggestive evidence of differences in their pathogenesis at 2 loci of genetic overlap. Our novel findings include 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. Our\n                    <jats:italic>in-silico<\/jats:italic>\n                    validation showed PLACO is robust to subtype-specific effects, and can achieve massive power gains over existing approaches for identifying genetic overlap between disease subtypes. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1009584","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T13:36:38Z","timestamp":1625837798000},"page":"e1009584","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":56,"title":["Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0979-2935","authenticated-orcid":true,"given":"Debashree","family":"Ray","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6479-5215","authenticated-orcid":true,"given":"Sowmya","family":"Venkataraghavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8035-4700","authenticated-orcid":true,"given":"Wanying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5735-1712","authenticated-orcid":true,"given":"Elizabeth J.","family":"Leslie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3876-0518","authenticated-orcid":true,"given":"Jacqueline B.","family":"Hetmanski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9467-4556","authenticated-orcid":true,"given":"Seth M.","family":"Weinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-6551","authenticated-orcid":true,"given":"Jeffrey C.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-2832","authenticated-orcid":true,"given":"Mary L.","family":"Marazita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Ruczinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret 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