Journal article
Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts
American journal of medical genetics. Part A, Vol.179(3), pp.467-474
03/2019
DOI: 10.1002/ajmg.a.61002
PMCID: PMC6374160
PMID: 30582786
Abstract
Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the "missing" heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01-1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value = .001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.
Details
- Title: Subtitle
- Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts
- Creators
- John R Shaffer - Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PennsylvaniaJessica LeClair - Department of Biostatistics, School of Public Health, Boston University, Boston, MassachusettsJenna C Carlson - Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PennsylvaniaEleanor Feingold - Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PennsylvaniaCarmen J Buxó - Dental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto Rico, San Juan, Puerto RicoKaare Christensen - Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, DenmarkFrederic W B Deleyiannis - Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, ColoradoL Leigh Field - Department of Medical Genetics, University of British Columbia, Vancouver, CanadaJacqueline T Hecht - Department of Pediatrics, McGovern Medical School and School of Dentistry UT Health at Houston, Houston, TexasLina Moreno - Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IowaIeda M Orioli - ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, BrazilCarmencita Padilla - Philippine Genome Center, University of the Philippines System, Manila, The PhilippinesAlexandre R Vieira - Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PennsylvaniaGeorge L Wehby - Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IowaJeffrey C Murray - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IowaSeth M Weinberg - Department of Anthropology, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PennsylvaniaMary L Marazita - Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PennsylvaniaElizabeth J Leslie - Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia
- Resource Type
- Journal article
- Publication Details
- American journal of medical genetics. Part A, Vol.179(3), pp.467-474
- DOI
- 10.1002/ajmg.a.61002
- PMID
- 30582786
- PMCID
- PMC6374160
- NLM abbreviation
- Am J Med Genet A
- ISSN
- 1552-4825
- eISSN
- 1552-4833
- Publisher
- United States
- Grant note
- R25-MD007607 / NIH HHS R01-DE011931 / NIH HHS R01-DE016148 / NIH HHS R01-DE009886 / NIH HHS X01-HG007485 / NIH HHS R01-DE012472 / NIH HHS R01 DE016148 / NIDCR NIH HHS U01-DE024425 / NIH HHS R01 DE011948 / NIDCR NIH HHS R01-DE011948 / NIH HHS U54 MD007587 / NIMHD NIH HHS DBI-1263020 / National Science Foundation R01 DE014667 / NIDCR NIH HHS AMFDP Grant 72429 / Robert Wood Johnson Foundation HHSN268201200008I / NHLBI NIH HHS S21-MD001830 / NIH HHS E-26/20300/2017 / Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila R01-DE014667 / NIH HHS K99 DE024571 / NIDCR NIH HHS R00-DE025060 / NIH HHS R01 DE009886 / NIDCR NIH HHS U01-DD000295 / NIH HHS R21 DE016930 / NIDCR NIH HHS R01 DD000295 / NCBDD CDC HHS Department of Defense R00 DE024571 / NIDCR NIH HHS 310772/2017-6400427/2013-3 / Conselho Nacional de Desenvolvimento Científico e Tecnológico R37 DE008559 / NIDCR NIH HHS R00 DE025060 / NIDCR NIH HHS U54-MD007587 / NIH HHS Research Institute of the Children's Hospital of Colorado U01 DE024425 / NIDCR NIH HHS
- Language
- English
- Date published
- 03/2019
- Academic Unit
- Preventive and Community Dentistry; Orthodontics; Anatomy and Cell Biology; Health Management and Policy; Stead Family Department of Pediatrics; Epidemiology; Economics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Public Policy Center (Archive); Dental Research
- Record Identifier
- 9984065999702771
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