A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals

• Type of Material: Article
• Authors: Jenna C. Carlson, University of Pittsburgh; Deepti Anand, University of Delaware; Azeez Butali, University of Iowa; Carmen J. Buxo, University of Puerto Rico; Kaare Christensen, University of Southern Denmark; Frederic Deleyiannis, UCHealth Plastic & Reconstructive Surgery; Jacqueline T. Hecht, McGovern Medical School and School of Dentistry UT Health at Houston; Lina M. Moreno, University of Iowa; Ieda M. Orioli, INAGEMP (National Institute of Population Medical Genetics); Carmencita Padilla, University of the Philippines Manila; John R. Shaffer, University of Pittsburgh; Alexandre R. Vieira, University of Pittsburgh; George L. Wehby, University of Iowa; Seth M. Weinberg, University of Pittsburgh; Jeffrey C. Murray, University of Iowa; Terri H. Beaty, Johns Hopkins University; Irfan Saadi, University of Kansas; Salil A. Lachke, University of Delaware; Mary L. Marazita, University of Pittsburgh; Eleanor Feingold, University of Pittsburgh; Elizabeth Leslie, Emory University
• Language: English
• Date: 2019-09-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 John Wiley & Sons, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1002/gepi.22214
• Title of Journal or Parent Work: Genetic Epidemiology
• Volume: 43
• Issue: 6
• Start Page: 704
• End Page: 716
• Grant/Funding Information: Genotyping and data cleaning were provided via an NIH contract to the Johns Hopkins Center for Inherited Disease Research: HHSN268201200008I.; This work was funded by grants from the National Institutes of Health: R00-DE025060 [EJL], R03-DE024776 [SAL, IS], X01-HG007485 [MLM, EF], R01-DE016148 [MLM., SMW], R01-DE009886 [MLM], R21-DE016930 [MLM], R01-DE014667 [LMM], R01-DE012472 [MLM], R01-DE011931 [JTH], R01-DE011948 [KC], R37-DE008559 [JCM, MLM], U01-DD000295 [GLW], R00-DE024571 [CJB], S21-MD001830 [CJB], U54-MD007587 [CJB], R00-DE022378 [AB], R01-DE014581 [TB], U01-DE018993 [TB], and Robert Wood Johnson Foundation Grant #72429 [AB].
• Keywords: orofacial clefts; Metaanalysis; Risk; Facebase consortium; genome-wide association studies; birth defects; Genome-wide association studies; IRF6; Identify; Lip; Palate; Variant; Mutations; Life Sciences & Biomedicine; subtypes; Mathematical & Computational Biology; Genetics & Heredity; Science & Technology
• Research Categories: Health Sciences, Pathology; Health Sciences, Public Health; Biology, Genetics; Biology, Cell; Health Sciences, Dentistry

Abstract

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes—cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a “cleft map” of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.