Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease

Abstract

Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 [odds ratio (OR) = 5.2, P = 4.7 × 10-10]. Conditional analyses on the lead SNPs revealed a secondary association signal, corresponding to an Asian-specific, low-frequency missense variant encoding RET p.Asp489Asn (rs9282834, conditional OR = 20.3, conditional P = 4.1 × 10-14). When in trans with the RET intron 1 enhancer risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7. Overall, our study provides further insights into the genetic architecture of HSCR and has profound implications for future study designs.

Figure 1.

Regional plots of association for the Asian-specific and trans-ethnic meta-analyses at the three known HSCR-associated loci. Significance of association is reported in P-values for the fixed-effects Asian-specific meta-analysis (upper panel) and in Bayes factors for the trans-ethnic meta-analyses (lower panel). Genomic regions covered by the 99% credible set are highlighted by the purple boxes. The lead SNP of each locus is highlighted by purple diamond. Color indicates the LD (r²) with the lead SNP.

Figure 2.

Epistatic effect of the two RET SNPs independently associated with HSCR (rs9282834 and rs2435357) in (A) Korean and (B) Chinese GWAS. Information [proportion and odds ratio (OR)] regarding each genotype combination [rs9282834 (row) × rs2435357 (column)] is represented by cells. In each cell, left bar denotes the proportion of cases with the specified genotype combination among all cases while right bar denotes the same for controls. OR is defined as the odds of being HSCR with the combination relative to the baseline double homozygote carrying neither risk allele (i.e. GG for rs9282834 and CC for rs2435357).