A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.

TitleA genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.
Publication TypeJournal Article
Year of Publication2016
AuthorsHanchard, NA, Swaminathan, S, Bucasas, K, Furthner, D, Fernbach, S, Azamian, MS, Wang, X, Lewin, M, Towbin, JA, D'Alessandro, LCA, Morris, SA, Dreyer, W, Denfield, S, Ayres, NA, Franklin, WJ, Justino, H, M Lantin-Hermoso, R, Ocampo, EC, Santos, AB, Parekh, D, Moodie, D, Jeewa, A, Lawrence, E, Allen, HD, Penny, DJ, Fraser, CD, Lupski, JR, Popoola, M, Wadhwa, L, J Brook, D, Bu'Lock, FA, Bhattacharya, S, Lalani, SR, Zender, GA, Fitzgerald-Butt, SM, Bowman, J, Corsmeier, D, White, P, Lecerf, K, Zapata, G, Hernandez, P, Goodship, JA, Garg, V, Keavney, BD, Leal, SM, Cordell, HJ, Belmont, JW, McBride, KL
JournalHum Mol Genet
Volume25
Issue11
Pagination2331-2341
Date Published2016 Jun 01
ISSN1460-2083
Abstract

Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 × 10(-8) for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 10(-9), odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 × 10(-5), OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 × 10(-9) for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 × 10(-7) for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.

DOI10.1093/hmg/ddw071
Alternate JournalHum. Mol. Genet.
PubMed ID26965164
PubMed Central IDPMC5081047
Grant ListRG/15/12/31616 / / British Heart Foundation / United Kingdom
UM1 HG006542 / HG / NHGRI NIH HHS / United States
RG/13/10/30376 / / British Heart Foundation / United Kingdom
RG/07/010/23676 / / British Heart Foundation / United Kingdom
R01 HL109758 / HL / NHLBI NIH HHS / United States