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

Content Provider	Scilit
Author	Shaffer, John R. LeClair, Jessica Carlson, Jenna Feingold, Eleanor Buxó, Carmen J. Christensen, Kaare Deleyiannis, Frederic W. B. Field, L. Leigh Hecht, Jacqueline T. Moreno, Lina Orioli, Ieda M. Padilla, Carmencita Vieira, Alexandre R. Wehby, George L. Murray, Jeffrey C. Weinberg, Seth M. Marazita, Mary L. Leslie, Elizabeth J.
Copyright Year	2018
Description	Journal: American Journal of Medical Genetics Part A 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.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374160/pdf
Ending Page	474
Page Count	8
Starting Page	467
e-ISSN	15524833
DOI	10.1002/ajmg.a.61002
Journal	American Journal of Medical Genetics Part A
Issue Number	3
Volume Number	179
Language	English
Publisher	Wiley-Blackwell
Publisher Date	2019-03-01
Access Restriction	Open
Subject Keyword	Journal: American Journal of Medical Genetics Part A Dentistry and Oral Surgery Cleft Lip Cleft Palate Genetic Association Orofacial Cleft
Content Type	Text
Resource Type	Article