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Author Notes:

Debashree Ray. dray@jhu.edu

Terri H. Beaty, tbeaty1@jhu.edu

Debashree Ray, Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing, Sowmya Venkataraghavan, Data curation, Formal analysis, Software, Validation, Visualization, Writing – review & editing, Wanying Zhang, Data curation, Formal analysis, Software, Writing – review & editing,Elizabeth J. Leslie, Investigation, Validation, Writing – review & editing,Jacqueline B. Hetmanski, Data curation, Writing – review & editing, Seth M. Weinberg, Resources, Writing – review & editing,Jeffrey C. Murray, Resources, Mary L. Marazita, Resources, Writing – review & editing, Ingo Ruczinski, Investigation, Methodology, Writing – review & editing, Margaret A. Taub, Investigation, Validation, Writing – review & editing, and Terri H. Beaty, Conceptualization, Investigation, Project administration, Resources, Supervision, Writing – review & editing

This research was carried out using computing cluster—the Joint High Performance Computing Exchange—at the Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health.


Research Funding:

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 (S.M.W., M.L.M.) and U24OD023382 (D.R.). The funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • LIP
  • FOXE1
  • RISK
  • SCAN

Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios

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Journal Title:



Volume 17, Number 7


, Pages e1009584-e1009584

Type of Work:

Article | Final Publisher PDF


Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts– the most common craniofacial birth defects in humans– are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions exists; only FOXE1 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 × 10−8, PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10−6, we found 5 more loci with compelling candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7), 3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). Additionally, we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2 loci in 19p13.12 (RAB8A) and 20q12 (MAFB) 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 in-silico 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.

Copyright information:

© 2021 Ray et al

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
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