Association between the European GWAS-Identified Susceptibility Locus at Chromosome 4p16 and the Risk of Atrial Septal Defect: A Case-Control Study in Southwest China and a Meta-Analysis

Abstract

Atrial septal defect (ASD) is the third most frequent type of congenital heart anomaly, featuring shunting of blood between the two atria. Gene-environment interaction remains to be an acknowledged cause for ASD occurrence. A recent European genome-wide association study (GWAS) of congenital heart disease (CHD) identified 3 susceptibility SNPs at chromosome 4p16 associated with ASD: rs870142, rs16835979 and rs6824295. A Chinese-GWAS of CHD conducted in the corresponding period did not reveal the 3 susceptibility SNPs, but reported 2 different risk SNPs: rs2474937 and rs1531070. Therefore, we aimed to investigate the associations between the 3 European GWAS-identified susceptibility SNPs and ASD risk in the Han population in southwest China. Additionally, to increase the robustness of our current analysis, we conducted a meta-analysis combining published studies and our current case-control study. We performed association, linkage disequilibrium, and haplotype analysis among the 3 SNPs in 190 ASD cases and 225 age-, sex-, and ethnicity-matched healthy controls. Genotype and allele frequencies among the 3 SNPs showed statistically significant differences between the cases and controls. Our study found that individuals carrying the allele T of rs870142, the allele A of rs16835979, and the allele T of rs6824295 had a respective 50.1% (odds ratio (OR) = 1.501, 95% confidence interval (CI) = 1.122-2.009, PFDR-BH = 0.018), 48.5% (OR = 1.485, 95%CI = 1.109-1.987, PFDR-BH = 0.012), and 38.6% (OR = 1.386, 95%CI = 1.042-1.844, PFDR-BH = 0.025) increased risk to develop ASD than wild-type allele carriers in our study cohort. In the haplotype analysis, we identified a disease-risk haplotype (TAT) (OR = 1.540, 95%CI = 1.030-2.380, PFDR-BH = 0.016). Our meta-analysis also showed that the investigated SNP was associated with ASD risk (combined OR (95%CI) = 1.35 (1.24-1.46), P < 0.00001). Our study provides compelling evidence to motivate better understanding of the etiology of ASD.

Association between the 4p16 genomic locus and different types of congenital heart disease: results from adult survivors in the UK Biobank

“…estimates around 60% in their discovery sample (OR of 1.24, given MAF of 0.333 and disease prevalence of 1%), and 53% in their replication cohort (at OR of 1.2). Power was higher in the study by Zhao et al 8 (~69%); however, they reported an unusual MAF of 28.7% in their controls as opposed to the 33% values reported by the other Chinese groups, which may indicate strong differences in ancestry of the participants. The design by Pei et al 9 was well powered to detect the effect they found (OR of 1.431, power close to 90%).…”

“…European-ancestry samples: a discovery cohort of 340 individuals with ostium secundum ASD and 5,159 controls, and a further 417 secundum ASD cases with 2,520 controls. Independent studies in Chinese cohorts have provided additional support to that finding: Zhao et al 7 replicated the results in Han Chinese subjects (two cohorts, totaling 701 ASD cases and 3,208 controls); next, a similar outcome was observed in a sample from Southwest China (190 ASD cases and 225 controls) 8 ; and more recently, Pei et al 9 reported analogous findings in a Fujian Chinese population (354 non-syndromic ASD cases and 557 controls). Demographic data on sex and age distributions across diagnoses is summarized in Supplementary Table S1, organized as "controls" (subjects with no evidence of CHD), "LVOTO" (including both LVOTO and bicuspid aortic valve, BAV), "any ASD" (comprising participants with either a pure ASD diagnose, or an ASD and another CHD condition), or "pure ASD" (a subset of "any ASD": people with evidence of ASD, but no other CHD).…”

Genome-wide association study in European patients with congenital heart disease identifies risk loci for transposition of the great arteries and anomalies of the thoracic arteries and veins and expression of discovered candidate genes in the developing heart

“…[13][14][15][16][17] For atrial septal defects (ASDs) 4p16 was identified as a risk locus. 17,18 For tetralogy of Fallot (TOF), regions of interest have been reported on chromosomes 1, 12 and 13. 19,20 Agopian and colleagues have shown an association of a single intra-genetic single nucleotide polymorphism (SNP) with left ventricular obstructive defects.…”

STX18-AS1 is a Long Noncoding RNA predisposing to Atrial Septal Defect via downregulation of NKX2-5 in differentiating cardiomyocytes

“…Among all disease-associated SNPs, 45% map to lncRNAs, suggesting an important role for these genes in complex disease susceptibility 30 . Relatively few annotated lncRNAs containing GWAS associated 11 SNPs for cardiovascular diseases have been investigated 31 . Recently, the human homolog of the mouse lncRNA Upperhand was found to be a control on expression of the cardiac transcription factor Hand2 and essential for mouse heart development 32 .…”