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

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 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 10, 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, 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 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 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.

Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns

“…In some cases, particularly among medically unstable neonates, a comprehensive physical examination was not possible, and cases were included as long as there was not a strong clinical suspicion of a syndromic diagnosis. All cases were genotyped by chromosome microarray as part of a genome-wide association study of the LSL phenotype [ 14 ]. Cases found to have large (> 1 megabase) genomic defects were excluded from further analysis [ 15 ].…”

Assessment of large copy number variants in patients with apparently isolated congenital left‐sided cardiac lesions reveals clinically relevant genomic events

“…In addition, 49 parent-proband trios with HLHS were recruited at Children’s Hospital in Linz, Austria (CHL) and processed alongside the TCH cohort. Families enrolled through TCH, NCH, CHL are extensions of previously reported cohorts [Hanchard et al 2016; Lewin et al 2004; McBride et al 2009]. Patients were eligible for the study if they were willing to have DNA taken and banked, and had a characteristic LSL lesion without overt extra-cardiac involvement; i.e.…”

Genetic Basis of Human Congenital Heart Disease

“…Another study in the Han Chinese using a compound heterozygous model identified four additional loci that explained 7.8% of the CHD variance in the population, suggesting that multiple modes of inheritance are contributing (Jiang et al 2018). Several studies have examined specific groups of CHD including left-sided lesions and TOF and have identified susceptibility loci that account for a small proportion of the genetic variation in each case (Cordell et al 2013b;Mitchell et al 2015;Hanchard et al 2016). Although common variants likely have a role in CHD susceptibility, these account for only a small proportion of the genetic risk, and large studies of individuals with similar CHD lesions are needed to identify additional susceptibility loci.…”