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

Authors: HANCHARD, NEIL - Children'S Nutrition Research Center (CNRC); SWAMINATHAN, SHANKER - Children'S Nutrition Research Center (CNRC); BUCASAS, KRISTINE - Baylor College Of Medicine; FERNBACH, SUSAN - Baylor College Of Medicine; AZAMIAN, MAHSHID - Baylor College Of Medicine; WANG, XUEQING - Baylor College Of Medicine; LEWIN, MARK - Seattle Children'S Research Institute; BHATTACHARYA, SHOUMO - Oxford Radcliffe Hospitals; LALANI, SEEMA - Baylor College Of Medicine; LECERF, KELSEY - The Ohio State University; ZAPATA, GLADYS - Children'S Nutrition Research Center (CNRC); HERNANDEZ, PATRICIA - Children'S Nutrition Research Center (CNRC); GOODSHIP, JUDITH - Newcastle University; KEAVNEY, BERNARD - University Of Manchester; CORDELL, HEATHER - Newcastle University; BELMONT, JOHN - Children'S Nutrition Research Center (CNRC)

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2016
Publication Date: 6/1/2016
Citation: Hanchard, N.A., Swaminathan, S., Bucasas, K., Furthner, D., Fernbach, S., Azamian, M.S., Wang, X., Lewin, M., Towbin, J.A., D'Alessandro, L.C., Morris, S.A., Dreyer, W., Denfield, S., Ayres, N.A., Franklin, W.J., Justino, H., Lantin-Hermoso, M.R., Ocampo, E.C., Santos, A.B., Parekh, D., Moodie, D., Jeewa, A., Lawrence, E., Allen, H.D., Penny, D.J., Fraser, C.D., Lupski, J.R., Popoola, M., Wadhwa, L., Brook, J.D., Bu'Lock, F.A., Bhattacharya, S., Lalani, S.R., Zender, G.A., Fitzgerald-Butt, S.M., Bowman, J., Corsmeier, D., White, P., Lecerf, K., Zapata, G., Hernandez, P., Goodship, J.A., Garg, V., Keavney, B.D., Leal, S.M., Cordell, H.J., Belmont, J.W., McBride, K.L. 2016. A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20. Human Molecular Genetics. 25(11):2331-2341. https://doi.org/10.1093/hmg/ddw071.
DOI: https://doi.org/10.1093/hmg/ddw071

Interpretive Summary: The genes implicated in congenital heart disease (CHD) have typically been found by looking for changes in the DNA sequence or amount that are rare in the general population; however, more recent studies have indicated that even changes that are commonly seen can have a an impact on similar diseases. We looked at more than 750,000 DNA sequence changes and compared the frequencies of these changes in 800 cases with CHD against public datasets of >2500 individuals without CHD. We identified a single region of the genome on chromosome number 20 in which the DNA variants were more common in cases than controls. These variants were found over a gene that is expressed in the developing fetal heart. This studies confirms a role for commonly observed genetic variation in CHD and specifically highlights changes on chromosome 20.

Technical 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.