A genome-wide association study identifies two risk loci for congenital heart malformations in Han Chinese populations

Abstract

Congenital heart malformation (CHM) is the most common form of congenital human birth anomaly and is the leading cause of infant mortality. Although some causative genes have been identified, little progress has been made in identifying genes in which low-penetrance susceptibility variants occur in the majority of sporadic CHM cases. To identify common genetic variants associated with sporadic non-syndromic CHM in Han Chinese populations, we performed a multistage genome-wide association study (GWAS) in a total of 4,225 CHM cases and 5,112 non-CHM controls. The GWAS stage included 945 cases and 1,246 controls and was followed by 2-stage validation with 2,160 cases and 3,866 controls. The combined analyses identified significant associations (P < 5.0 × 10⁻⁸) at 1p12 (rs2474937 near TBX15; odds ratio (OR) = 1.40; P = 8.44 × 10⁻¹⁰) and 4q31.1 (rs1531070 in MAML3; OR = 1.40; P = 4.99 × 10⁻¹²). These results extend current knowledge of genetic contributions to CHM in Han Chinese populations.

Association analysis identifies new risk loci for congenital heart disease in Chinese populations

“…summarized all subjects in Supplementary Tables 1 and 4. All of the samples used in the validations in the previous study 10 were included in the current study.…”

“…The SNPs for Validation I were selected based on the following criteria: (i) the SNPs had 1.0 Â 10 À 5 oPr1.0 Â 10 À 4 in the GWAS stage; (ii) the SNPs were not located in the same chromosomal region/gene of SNPs reported in our previous study 10 ; (iii) the SNPs had clear genotyping clusters; (iv) if more than one SNPs were located in the same chromosomal region/gene, only one SNP with the lowest P value was selected; and (v) only the SNP with the lowest P value was selected when multiple SNPs were observed in strong LD (r 2 Z0.8). A total of 45 SNPs met these criteria (Supplementary Data 1).…”

“…One study on European Caucasians reported that single nucleotide polymorphisms (SNPs) at chromosome 4p16 were associated with the risk of atrial septal defect (ASD), but not other subtypes 11 . Simultaneously, we reported a multistage GWAS of CHD in Han Chinese and identified two CHD susceptibility loci (rs2474937 at 1p12 for TBX15 and rs1531070 at 4q31.1 for MAML3) 10 . Additional genetic factors, particularly those with relatively moderate P values in the GWA scan, still remain to be discovered.…”

“…To date, several genome-wide association studies (GWASs) have achieved success in deciphering the genetic basis of CHD [10][11][12] . One study on European Caucasians reported that single nucleotide polymorphisms (SNPs) at chromosome 4p16 were associated with the risk of atrial septal defect (ASD), but not other subtypes 11 .…”

Elucidating the mechanisms of transcription regulation during heart development by next-generation sequencing

“…One group analyzed 5112 controls and 4225 CHDs, including ASD, ventricular septal defect and ASD/ventricular septal defect to avoid heterogeneity. 85 Although they found two SNPs, these SNPs may not have a significant function in CHDs. Another group analyzed 1995 CHDs, including septal, obstructive and cyanotic defects and 5159 controls.…”