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Am J Med Genet A. 2017 Jun;173(6):1531-1538. doi: 10.1002/ajmg.a.38210. Epub 2017 Apr 19.

Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate.

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 Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
4
School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico.
5
CEMIC: Center for Medical Education and Clinical Research, Buenos Aires, Argentina.
6
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.
7
Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
8
Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
9
Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, Colorado.
10
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
11
Department of Pediatrics, McGovern Medical School and School of Dentistry UT Health at Houston, Houston, Texas.
12
Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa.
13
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, 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
Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Abstract

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome-wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The "missing" heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low-frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P.

KEYWORDS:

association; burden test; orofacial cleft; rare variant

PMID:
28425186
PMCID:
PMC5444956
DOI:
10.1002/ajmg.a.38210
[Indexed for MEDLINE]
Free PMC Article

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