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Eur J Hum Genet. 2018 Apr;26(4):561-569. doi: 10.1038/s41431-017-0053-7. Epub 2018 Jan 29.

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

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Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Paediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Pediatric Surgery, Children's Hospital, University of Helsinki, Helsinki, Finland.
Department of Congenital Disorders, Danish Centre for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark.
Center of Molecular Medicine, Karolinska institutet, Stockholm, Sweden.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.


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 × 10-10; 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.

[Available on 2019-04-01]

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