Genome‐wide compound heterozygosity analysis highlighted 4 novel susceptibility loci for congenital heart disease in Chinese population

Abstract

Genome-wide association studies (GWASs) have achieved great success in deciphering the genetic cause of congenital heart disease (CHD). However, the heritability of CHD remains to be clarified, and numerous genetic factors responsible for occurrence of CHD are yet unclear. In this study, we performed a genome-wide search for relaxed forms of compound heterozygosity (CH) in association with CHD using our existing GWAS data including 2265 individuals (957 CHD cases and 1308 controls). CollapsABEL was used to iteratively test the association between the CH genotype and the CHD phenotype in a sliding window manner. We highlighted 17 genetic loci showing suggestive CH-like associations with CHD (P < 5 × 10 ), among which 4 genetic loci had expression quantitative trait loci (eQTL) effects in blood (P < 0.01). After conditional association analysis, each loci had only 1 independently effective signal reaching the significance threshold (rs2071477/rs3129299 at 6p21.32, P = 2.47 × 10 ; rs10773097/rs2880921 at 12q24.31, P = 3.30 × 10 ; rs73032040/rs7259476 at 19q13.11, P = 1.14 × 10 ; rs10416386/rs4239517 at 19q13.31, P = 1.15 × 10 ), together explained 7.83% of the CHD variance. Among these 4 associated loci, outstanding candidates for CHD-associated genes included UBC, CFM2, ZNF302, LYPD3 and CADM4. Although replication studies with larger sample size are warranted, the first CH GWAS of CHD may extend our current knowledge of the genetic contributions to CHD in the Han Chinese population.

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

“…Genomic wide association studies (GWAS) involve the comparison of genetic variants of different affected individuals within the society and whether the variants are associated with a certain trait. GWAS, therefore, can be used to detect multiple genetic risk factors which contribute to congenital heart diseases [59]. CHDs being heterogeneous group of diseases, the use GWAS may give us an insight to the etiology of CHDs [60].…”

Genetic Basis of Human Congenital Heart Disease

“…A GWAS in the Han Chinese population identified two loci, 1p12 and 4q13.1, associated with CHD. 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).…”

Genome‐wide association studies of structural birth defects: A review and commentary

“…In addition to the traditional GWAS of inherited variants (summarized above and in Table ), several additional GWAS of CHDs have been conducted. These include a study of inherited compound heterozygous genotypes (Jiang et al, ), and a study of inherited genotypes and neurodevelopmental outcomes following cardiac surgery in infancy (Kim et al, ). In addition, three GWAS have focused on the maternal genotype (Agopian et al, ; Agopian et al, ; Mitchell et al, ).…”