Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.
Alleles
Brain
/ abnormalities
Cleft Lip
/ diagnosis
Cleft Palate
/ diagnosis
Enhancer Elements, Genetic
Genetic Association Studies
/ methods
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Phenotype
Polymorphism, Single Nucleotide
Regulatory Sequences, Nucleic Acid
cleft lip
cleft palate
genetic association
orofacial cleft
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
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
467-474Subventions
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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