Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus

Abstract

Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.

The advances of genetics research on Hirschsprung's disease

“…More recently, another HSCR GWAS of Caucasians was published. It confirmed RET and SMEA3 as being associated with HSCR in a Danish cohort, and additionally reported a novel low‐frequency variant (rs144432435) of RET …”

Association of Variants in PLD1, 3p24.1, and 10q11.21 Regions With Hirschsprung’s Disease in Han Chinese Population

“…It is well known that genetic factors play an essential role in the development of HSCR, with RET as the major risk gene, as genome-wide association studies (GWASs) using single nucleotide polymorphism (SNP) chip revealed that RET, SEMA3, and NRG1 were associated with HSCR, which was also confirmed in subsequent independent studies (Garcia- Barcelo et al, 2009;Kim et al, 2014;Jiang et al, 2015;Fadista et al, 2018). Earlier studies adapting whole genome or exome sequencing strategies also revealed new risk variants with high penetrance.…”

What is new about the genetic background of Hirschsprung disease?

“…In the past few years, the identification of novel susceptibility genes and variants for HSCR was based on the use of GWAS,GWES 20,25,[38][39][40][154][155][156][157][158][159][160][161] and next-generation sequencing (NGS) approaches. [162][163][164][165][166][167][168][169][170] All of them have fairly improved our knowledge about the genetic background of the disease.…”