Format

Send to

Choose Destination
Am J Med Genet A. 2019 Mar;179(3):467-474. doi: 10.1002/ajmg.a.61002. Epub 2018 Dec 24.

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

Author information

1
Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
2
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
4
Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts.
5
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
6
Dental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico.
7
Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
8
Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, Colorado.
9
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
10
Department of Pediatrics, McGovern Medical School and School of Dentistry UT Health at Houston, Houston, Texas.
11
Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa.
12
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
13
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.
14
Department of Pediatrics, College of Medicine; and Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, The Philippines.
15
Philippine Genome Center, University of the Philippines System, Manila, The Philippines.
16
Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, Iowa.
17
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
18
Department of Anthropology, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
19
Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
20
Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia.

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.

KEYWORDS:

cleft lip; cleft palate; genetic association; orofacial cleft

PMID:
30582786
PMCID:
PMC6374160
[Available on 2020-03-01]
DOI:
10.1002/ajmg.a.61002

Grant support

Grant support

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center