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

João Fadista; Marie Lund; Line Skotte; Frank Geller; Priyanka Nandakumar; Sumantra Chatterjee; Hans Matsson; Anna Löf Granström; Tomas Wester; Perttu Salo; Valtter Virtanen; Lisbeth Carstensen; Jonas Bybjerg-Grauholm; David Michael Hougaard; Mikko Pakarinen; Markus Perola; Agneta Nordenskjöld; Aravinda Chakravarti; Mads Melbye; Bjarke Feenstra

doi:10.1038/s41431-017-0053-7

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

João Fadista^*, Marie Lund, Line Skotte, Frank Geller, Priyanka Nandakumar, Sumantra Chatterjee, Hans Matsson, Anna Löf Granström, Tomas Wester, Perttu Salo, Valtter Virtanen, Lisbeth Carstensen, Jonas Bybjerg-Grauholm, David Michael Hougaard, Mikko Pakarinen, Markus Perola, Agneta Nordenskjöld, Aravinda Chakravarti, Mads Melbye, Bjarke Feenstra

^*Corresponding author for this work

Department of Clinical Medicine

9 Citations (Scopus)

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^-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.

Original language	English
Journal	European Journal of Human Genetics
Volume	26
Issue number	4
Pages (from-to)	561-569
Number of pages	9
ISSN	1018-4813
DOIs	https://doi.org/10.1038/s41431-017-0053-7
Publication status	Published - 2018

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Fadista, J., Lund, M., Skotte, L., Geller, F., Nandakumar, P., Chatterjee, S., Matsson, H., Granström, A. L., Wester, T., Salo, P., Virtanen, V., Carstensen, L., Bybjerg-Grauholm, J., Hougaard, D. M., Pakarinen, M., Perola, M., Nordenskjöld, A., Chakravarti, A., Melbye, M., & Feenstra, B. (2018). Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus. European Journal of Human Genetics, 26(4), 561-569. https://doi.org/10.1038/s41431-017-0053-7

Fadista, J, Lund, M, Skotte, L, Geller, F, Nandakumar, P, Chatterjee, S, Matsson, H, Granström, AL, Wester, T, Salo, P, Virtanen, V, Carstensen, L, Bybjerg-Grauholm, J, Hougaard, DM, Pakarinen, M, Perola, M, Nordenskjöld, A, Chakravarti, A, Melbye, M & Feenstra, B 2018, 'Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus', European Journal of Human Genetics, vol. 26, no. 4, pp. 561-569. https://doi.org/10.1038/s41431-017-0053-7

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title = "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 × 10-10; 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.",

author = "Jo{\~a}o Fadista and Marie Lund and Line Skotte and Frank Geller and Priyanka Nandakumar and Sumantra Chatterjee and Hans Matsson and Granstr{\"o}m, {Anna L{\"o}f} and Tomas Wester and Perttu Salo and Valtter Virtanen and Lisbeth Carstensen and Jonas Bybjerg-Grauholm and Hougaard, {David Michael} and Mikko Pakarinen and Markus Perola and Agneta Nordenskj{\"o}ld and Aravinda Chakravarti and Mads Melbye and Bjarke Feenstra",

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doi = "10.1038/s41431-017-0053-7",

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T1 - Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus

AU - Fadista, João

AU - Lund, Marie

AU - Skotte, Line

AU - Geller, Frank

AU - Nandakumar, Priyanka

AU - Chatterjee, Sumantra

AU - Matsson, Hans

AU - Granström, Anna Löf

AU - Wester, Tomas

AU - Salo, Perttu

AU - Virtanen, Valtter

AU - Carstensen, Lisbeth

AU - Bybjerg-Grauholm, Jonas

AU - Hougaard, David Michael

AU - Pakarinen, Mikko

AU - Perola, Markus

AU - Nordenskjöld, Agneta

AU - Chakravarti, Aravinda

AU - Melbye, Mads

AU - Feenstra, Bjarke

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1038/s41431-017-0053-7

DO - 10.1038/s41431-017-0053-7

M3 - Journal article

C2 - 29379196

AN - SCOPUS:85041106818

SN - 1018-4813

VL - 26

SP - 561

EP - 569

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 4

ER -

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

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