Genome-wide association analyses identify variants in developmental genes associated with hypospadias

Frank Geller; Bjarke Feenstra; Lisbeth Carstensen; Tune H. Pers; Iris A. L. M. van Rooij; Izabella Baranowska Korberg; Shweta Choudhry; Juha M. Karjalainen; Tine H. Schnack; Mads V. Hollegaard; Wout F. J. Feitz; Nel Roeleveld; David M. Hougaard; Joel N. Hirschhorn; Lude Franke; Laurence S. Baskin; Agneta Nordenskjold; Loes F. M. van der Zanden; Mads Melbye

doi:10.1038/ng.3063

Genome-wide association analyses identify variants in developmental genes associated with hypospadias

Frank Geller, Bjarke Feenstra, Lisbeth Carstensen, Tune H. Pers, Iris A. L. M. van Rooij, Izabella Baranowska Korberg, Shweta Choudhry, Juha M. Karjalainen, Tine H. Schnack, Mads V. Hollegaard, Wout F. J. Feitz, Nel Roeleveld, David M. Hougaard, Joel N. Hirschhorn, Lude Franke, Laurence S. Baskin, Agneta Nordenskjold, Loes F. M. van der Zanden, Mads Melbye

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P <5 x 10(-8). Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.

Original language	English
Journal	Nature Genetics
Volume	46
Issue number	9
Pages (from-to)	957-967
Number of pages	10
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3063
Publication status	Published - 2014

Keywords

Denmark Europe Palearctic region
Netherlands Europe Palearctic region
Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common female, male
human EYA1 gene [Hominidae] expression
human HOXA4 gene [Hominidae] expression
human IRX5 gene [Hominidae] expression
human IRX6 gene [Hominidae] expression
03502, Genetics - General
03508, Genetics - Human
15504, Urinary system - Physiology and biochemistry
15506, Urinary system - Pathology
16504, Reproductive system - Physiology and biochemistry
16506, Reproductive system - Pathology
25503, Development and Embryology - Pathology
Molecular Genetics
Reproductive System
Urinary System
hypospadias Hypospadias (MeSH) urologic disease, reproductive system disease/female, reproductive system disease/male, congenital disease
DEPICT
GRAIL
Biochemistry and Molecular Biophysics
Chemical Coordination and Homeostasis
Reproduction
penis reproductive system
urethra reproductive system, excretory system
genome-wide association analyses laboratory techniques, genetic techniques
surgery therapeutic and prophylactic techniques, clinical techniques
GENETICS
DISEASE
LOCI
METAANALYSIS
EXPRESSION
MUTATIONS
RISK
DIFFERENTIATION
SUSCEPTIBILITY
IDENTIFICATION
POPULATION
HYPOSPADIAS
Genetic aspects

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.3063

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Geller, F., Feenstra, B., Carstensen, L., Pers, T. H., van Rooij, I. A. L. M., Korberg, I. B., Choudhry, S., Karjalainen, J. M., Schnack, T. H., Hollegaard, M. V., Feitz, W. F. J., Roeleveld, N., Hougaard, D. M., Hirschhorn, J. N., Franke, L., Baskin, L. S., Nordenskjold, A., van der Zanden, L. F. M., & Melbye, M. (2014). Genome-wide association analyses identify variants in developmental genes associated with hypospadias. Nature Genetics, 46(9), 957-967. https://doi.org/10.1038/ng.3063

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title = "Genome-wide association analyses identify variants in developmental genes associated with hypospadias",

abstract = "Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P <5 x 10(-8). Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.",

keywords = "Denmark Europe Palearctic region, Netherlands Europe Palearctic region, Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common female, male, human EYA1 gene [Hominidae] expression, human HOXA4 gene [Hominidae] expression, human IRX5 gene [Hominidae] expression, human IRX6 gene [Hominidae] expression, 03502, Genetics - General, 03508, Genetics - Human, 15504, Urinary system - Physiology and biochemistry, 15506, Urinary system - Pathology, 16504, Reproductive system - Physiology and biochemistry, 16506, Reproductive system - Pathology, 25503, Development and Embryology - Pathology, Molecular Genetics, Reproductive System, Urinary System, hypospadias Hypospadias (MeSH) urologic disease, reproductive system disease/female, reproductive system disease/male, congenital disease, DEPICT, GRAIL, Biochemistry and Molecular Biophysics, Chemical Coordination and Homeostasis, Reproduction, penis reproductive system, urethra reproductive system, excretory system, genome-wide association analyses laboratory techniques, genetic techniques, surgery therapeutic and prophylactic techniques, clinical techniques, GENETICS, DISEASE, LOCI, METAANALYSIS, EXPRESSION, MUTATIONS, RISK, DIFFERENTIATION, SUSCEPTIBILITY, IDENTIFICATION, POPULATION, HYPOSPADIAS, Genetic aspects",

author = "Frank Geller and Bjarke Feenstra and Lisbeth Carstensen and Pers, {Tune H.} and {van Rooij}, {Iris A. L. M.} and Korberg, {Izabella Baranowska} and Shweta Choudhry and Karjalainen, {Juha M.} and Schnack, {Tine H.} and Hollegaard, {Mads V.} and Feitz, {Wout F. J.} and Nel Roeleveld and Hougaard, {David M.} and Hirschhorn, {Joel N.} and Lude Franke and Baskin, {Laurence S.} and Agneta Nordenskjold and {van der Zanden}, {Loes F. M.} and Mads Melbye",

year = "2014",

doi = "10.1038/ng.3063",

language = "English",

volume = "46",

pages = "957--967",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

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Geller, F, Feenstra, B, Carstensen, L, Pers, TH, van Rooij, IALM, Korberg, IB, Choudhry, S, Karjalainen, JM, Schnack, TH, Hollegaard, MV, Feitz, WFJ, Roeleveld, N, Hougaard, DM, Hirschhorn, JN, Franke, L, Baskin, LS, Nordenskjold, A, van der Zanden, LFM & Melbye, M 2014, 'Genome-wide association analyses identify variants in developmental genes associated with hypospadias', Nature Genetics, vol. 46, no. 9, pp. 957-967. https://doi.org/10.1038/ng.3063

TY - JOUR

T1 - Genome-wide association analyses identify variants in developmental genes associated with hypospadias

AU - Geller, Frank

AU - Feenstra, Bjarke

AU - Carstensen, Lisbeth

AU - Pers, Tune H.

AU - van Rooij, Iris A. L. M.

AU - Korberg, Izabella Baranowska

AU - Choudhry, Shweta

AU - Karjalainen, Juha M.

AU - Schnack, Tine H.

AU - Hollegaard, Mads V.

AU - Feitz, Wout F. J.

AU - Roeleveld, Nel

AU - Hougaard, David M.

AU - Hirschhorn, Joel N.

AU - Franke, Lude

AU - Baskin, Laurence S.

AU - Nordenskjold, Agneta

AU - van der Zanden, Loes F. M.

AU - Melbye, Mads

PY - 2014

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N2 - Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P <5 x 10(-8). Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.

AB - Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P <5 x 10(-8). Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.

KW - Denmark Europe Palearctic region

KW - Netherlands Europe Palearctic region

KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common female, male

KW - human EYA1 gene [Hominidae] expression

KW - human HOXA4 gene [Hominidae] expression

KW - human IRX5 gene [Hominidae] expression

KW - human IRX6 gene [Hominidae] expression

KW - 03502, Genetics - General

KW - 03508, Genetics - Human

KW - 15504, Urinary system - Physiology and biochemistry

KW - 15506, Urinary system - Pathology

KW - 16504, Reproductive system - Physiology and biochemistry

KW - 16506, Reproductive system - Pathology

KW - 25503, Development and Embryology - Pathology

KW - Molecular Genetics

KW - Reproductive System

KW - Urinary System

KW - hypospadias Hypospadias (MeSH) urologic disease, reproductive system disease/female, reproductive system disease/male, congenital disease

KW - DEPICT

KW - GRAIL

KW - Biochemistry and Molecular Biophysics

KW - Chemical Coordination and Homeostasis

KW - Reproduction

KW - penis reproductive system

KW - urethra reproductive system, excretory system

KW - genome-wide association analyses laboratory techniques, genetic techniques

KW - surgery therapeutic and prophylactic techniques, clinical techniques

KW - GENETICS

KW - DISEASE

KW - LOCI

KW - METAANALYSIS

KW - EXPRESSION

KW - MUTATIONS

KW - RISK

KW - DIFFERENTIATION

KW - SUSCEPTIBILITY

KW - IDENTIFICATION

KW - POPULATION

KW - HYPOSPADIAS

KW - Genetic aspects

U2 - 10.1038/ng.3063

DO - 10.1038/ng.3063

M3 - Journal article

C2 - 25108383

VL - 46

SP - 957

EP - 967

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

ER -

Genome-wide association analyses identify variants in developmental genes associated with hypospadias

Abstract

Keywords

UN SDGs

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