Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.


Journal

American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741

Informations de publication

Date de publication:
03 2019
Historique:
received: 18 06 2018
revised: 06 08 2018
accepted: 01 11 2018
pubmed: 26 12 2018
medline: 17 4 2020
entrez: 25 12 2018
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 30582786
doi: 10.1002/ajmg.a.61002
pmc: PMC6374160
mid: NIHMS998829
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

467-474

Subventions

Organisme : NIDCR NIH HHS
ID : R37 DE008559
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE014667
Pays : United States
Organisme : NIH HHS
ID : R25-MD007607
Pays : United States
Organisme : Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila
Pays : International
Organisme : NIH HHS
ID : R01-DE011931
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007587
Pays : United States
Organisme : Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
ID : E-26/20300/2017
Pays : International
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico
ID : 310772/2017-6400427/2013-3
Pays : International
Organisme : NIH HHS
ID : X01-HG007485
Pays : United States
Organisme : NIDCR NIH HHS
ID : R00 DE025060
Pays : United States
Organisme : NIDCR NIH HHS
ID : R21 DE016930
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE009886
Pays : United States
Organisme : NIDCR NIH HHS
ID : K99 DE024571
Pays : United States
Organisme : National Science Foundation
ID : DBI-1263020
Pays : International
Organisme : Research Institute of the Children's Hospital of Colorado
Pays : International
Organisme : NIH HHS
ID : R01-DE016148
Pays : United States
Organisme : Robert Wood Johnson Foundation
ID : AMFDP Grant 72429
Pays : International
Organisme : NIH HHS
ID : R01-DE014667
Pays : United States
Organisme : NIDCR NIH HHS
ID : R00 DE024571
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE016148
Pays : United States
Organisme : NIH HHS
ID : R00-DE025060
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE011948
Pays : United States
Organisme : NIDCR NIH HHS
ID : U01 DE024425
Pays : United States
Organisme : NIH HHS
ID : R01-DE009886
Pays : United States
Organisme : NIH HHS
ID : R01-DE012472
Pays : United States
Organisme : Department of Defense
Pays : International
Organisme : NIH HHS
ID : R01-DE011948
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008I
Pays : United States
Organisme : NIH HHS
ID : U01-DD000295
Pays : United States
Organisme : NIH HHS
ID : U01-DE024425
Pays : United States
Organisme : NIH HHS
ID : S21-MD001830
Pays : United States
Organisme : NIH HHS
ID : U54-MD007587
Pays : United States
Organisme : NCBDD CDC HHS
ID : R01 DD000295
Pays : United States

Informations de copyright

© 2018 Wiley Periodicals, Inc.

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Auteurs

John R Shaffer (JR)

Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Jessica LeClair (J)

Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts.

Jenna C Carlson (JC)

Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Eleanor Feingold (E)

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Carmen J Buxó (CJ)

Dental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico.

Kaare Christensen (K)

Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

Frederic W B Deleyiannis (FWB)

Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, Colorado.

L Leigh Field (LL)

Department of Medical Genetics, University of British Columbia, Vancouver, Canada.

Jacqueline T Hecht (JT)

Department of Pediatrics, McGovern Medical School and School of Dentistry UT Health at Houston, Houston, Texas.

Lina Moreno (L)

Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa.

Ieda M Orioli (IM)

Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.

Carmencita Padilla (C)

Department of Pediatrics, College of Medicine; and Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, The Philippines.
Philippine Genome Center, University of the Philippines System, Manila, The Philippines.

Alexandre R Vieira (AR)

Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

George L Wehby (GL)

Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, Iowa.

Jeffrey C Murray (JC)

Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa.

Seth M Weinberg (SM)

Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Anthropology, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.

Mary L Marazita (ML)

Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Elizabeth J Leslie (EJ)

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia.

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