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PMID: 25108383 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 46 ·No. 9 ·2014-09-00 ·Pages 957-63

Geller F, Feenstra B, Carstensen L, Pers TH, van Rooij IA, Körberg IB, Choudhry S, Karjalainen JM, Schnack TH, Hollegaard MV, Feitz WF, Roeleveld N, Hougaard DM, Hirschhorn JN, Franke L, Baskin LS, Nordenskjöld A, van der Zanden LF, Melbye M

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 × 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.

MeSH Terms
Case-Control Studies Denmark Female Genes, Developmental Genetic Predisposition to Disease Genome-Wide Association Study/methods Genotype Humans Hypospadias/genetics Male Netherlands Polymorphism, Single Nucleotide Sweden
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Geller Frank
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Feenstra Bjarke
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Carstensen Lisbeth
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Pers Tune H
1] Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [4] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
van Rooij Iris A L M
Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
Körberg Izabella Baranowska
1] Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. [2] Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Choudhry Shweta
Department of Urology, University of California, San Francisco, San Francisco, California, USA.
Karjalainen Juha M
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
Schnack Tine H
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Hollegaard Mads V
Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
Feitz Wout F J
Department of Urology, Pediatric Urology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
Roeleveld Nel
1] Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands. [2] Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
Hougaard David M
Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
Hirschhorn Joel N
1] Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [4] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Franke Lude
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
Baskin Laurence S
Department of Urology, University of California, San Francisco, San Francisco, California, USA.
Nordenskjöld Agneta
1] Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. [2] Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
van der Zanden Loes F M
Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
Melbye Mads
1] Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. [2] Department of Medicine, Stanford School of Medicine, Stanford, California, USA.
References (55)
55 references, click to expand
  1. Identifying a high fraction of the human genome to be under selective constraint using GERP++.
    PLoS Comput Biol. 2010 Dec 02;6(12):e1001025 PMID: 21152010
  2. Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances.
    Hum Mol Genet. 2013 Sep 15;22(18):3807-17 PMID: 23704328
  3. Common variants in DGKK are strongly associated with risk of hypospadias.
    Nat Genet. 2011 Jan;43(1):48-50 PMID: 21113153
  4. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies.
    PLoS Genet. 2009 Jun;5(6):e1000529 PMID: 19543373
  5. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.
    Nucleic Acids Res. 2010 Sep;38(16):e164 PMID: 20601685
  6. The mouse genome database: genotypes, phenotypes, and models of human disease.
    Nucleic Acids Res. 2013 Jan;41(Database issue):D885-91 PMID: 23175610
  7. Comparative gene expression analysis of genital tubercle development reveals a putative appendicular Wnt7 network for the epidermal differentiation.
    Dev Biol. 2010 Aug 15;344(2):1071-87 PMID: 20510229
  8. METAL: fast and efficient meta-analysis of genomewide association scans.
    Bioinformatics. 2010 Sep 1;26(17):2190-1 PMID: 20616382
  9. Genotype imputation for genome-wide association studies.
    Nat Rev Genet. 2010 Jul;11(7):499-511 PMID: 20517342
  10. A method and server for predicting damaging missense mutations.
    Nat Methods. 2010 Apr;7(4):248-9 PMID: 20354512
  11. LocusZoom: regional visualization of genome-wide association scan results.
    Bioinformatics. 2010 Sep 15;26(18):2336-7 PMID: 20634204
  12. A travel guide to Cytoscape plugins.
    Nat Methods. 2012 Nov;9(11):1069-76 PMID: 23132118
  13. APCluster: an R package for affinity propagation clustering.
    Bioinformatics. 2011 Sep 1;27(17):2463-4 PMID: 21737437
  14. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.
    Nat Protoc. 2009;4(7):1073-81 PMID: 19561590
  15. Familial aggregation of hypospadias: a cohort study.
    Am J Epidemiol. 2008 Feb 1;167(3):251-6 PMID: 18042671
  16. Estimating missing heritability for disease from genome-wide association studies.
    Am J Hum Genet. 2011 Mar 11;88(3):294-305 PMID: 21376301
  17. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
    Nature. 2012 Nov 1;491(7422):119-24 PMID: 23128233
  18. Genome-wide association study identifies four loci associated with eruption of permanent teeth.
    PLoS Genet. 2011 Sep;7(9):e1002275 PMID: 21931568
  19. Quantifying heterogeneity in a meta-analysis.
    Stat Med. 2002 Jun 15;21(11):1539-58 PMID: 12111919
  20. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
    Nat Genet. 2012 Apr 15;44(5):491-501 PMID: 22504420
  21. SMIM1 underlies the Vel blood group and influences red blood cell traits.
    Nat Genet. 2013 May;45(5):542-545 PMID: 23563608
  22. Clustering by passing messages between data points.
    Science. 2007 Feb 16;315(5814):972-6 PMID: 17218491
  23. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility.
    Nat Genet. 2009 Oct;41(10):1122-6 PMID: 19767754
  24. Mutation screening of BMP4, BMP7, HOXA4 and HOXB6 genes in Chinese patients with hypospadias.
    Eur J Hum Genet. 2007 Jan;15(1):23-8 PMID: 17003840
  25. A map of human genome variation from population-scale sequencing.
    Nature. 2010 Oct 28;467(7319):1061-73 PMID: 20981092
  26. Systematic identification of trans eQTLs as putative drivers of known disease associations.
    Nat Genet. 2013 Oct;45(10):1238-1243 PMID: 24013639
  27. Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
    Nat Genet. 2013 Apr;45(4):353-61, 361e1-2 PMID: 23535729
  28. Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia.
    Development. 2003 Jul;130(14):3095-109 PMID: 12783783
  29. Identification of deleterious mutations within three human genomes.
    Genome Res. 2009 Sep;19(9):1553-61 PMID: 19602639
  30. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
    Nat Genet. 2011 Sep 11;43(10):1005-11 PMID: 21909110
  31. Is hypospadias a genetic, endocrine or environmental disease, or still an unexplained malformation?
    Int J Androl. 2009 Jun;32(3):187-97 PMID: 18637150
  32. Urethral seam formation and hypospadias.
    Cell Tissue Res. 2001 Sep;305(3):379-87 PMID: 11572091
  33. Six1 and Eya1 are critical regulators of peri-cloacal mesenchymal progenitors during genitourinary tract development.
    Dev Biol. 2011 Dec 1;360(1):186-94 PMID: 21968101
  34. KEGG for integration and interpretation of large-scale molecular data sets.
    Nucleic Acids Res. 2012 Jan;40(Database issue):D109-14 PMID: 22080510
  35. Diacylglycerol kinase K variants impact hypospadias in a California study population.
    J Urol. 2013 Jan;189(1):305-11 PMID: 23177175
  36. Hypospadias: anatomy, etiology, and technique.
    J Pediatr Surg. 2006 Mar;41(3):463-72 PMID: 16516617
  37. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  38. Genome-wide association study identifies five loci associated with lung function.
    Nat Genet. 2010 Jan;42(1):36-44 PMID: 20010834
  39. A Wilcoxon-type test for trend.
    Stat Med. 1985 Jan-Mar;4(1):87-90 PMID: 3992076
  40. Reactome: a database of reactions, pathways and biological processes.
    Nucleic Acids Res. 2011 Jan;39(Database issue):D691-7 PMID: 21067998
  41. MutationTaster evaluates disease-causing potential of sequence alterations.
    Nat Methods. 2010 Aug;7(8):575-6 PMID: 20676075
  42. GCTA: a tool for genome-wide complex trait analysis.
    Am J Hum Genet. 2011 Jan 7;88(1):76-82 PMID: 21167468
  43. Genome-wide meta-analysis identifies new susceptibility loci for migraine.
    Nat Genet. 2013 Aug;45(8):912-917 PMID: 23793025
  44. A human phenome-interactome network of protein complexes implicated in genetic disorders.
    Nat Biotechnol. 2007 Mar;25(3):309-16 PMID: 17344885
  45. HOX homeobox genes exhibit spatial and temporal changes in expression during human skin development.
    J Invest Dermatol. 1998 Feb;110(2):110-5 PMID: 9457903
  46. Aetiology of hypospadias: a systematic review of genes and environment.
    Hum Reprod Update. 2012 May-Jun;18(3):260-83 PMID: 22371315
  47. Genomic control for association studies.
    Biometrics. 1999 Dec;55(4):997-1004 PMID: 11315092
  48. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.
    Nat Genet. 2010 Dec;42(12):1077-85 PMID: 21102462
  49. Human HOX gene mutations.
    Clin Genet. 2001 Jan;59(1):1-11 PMID: 11206481
  50. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
    Methods. 2001 Dec;25(4):402-8 PMID: 11846609
  51. PLINK: a tool set for whole-genome association and population-based linkage analyses.
    Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
  52. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
    Nature. 2011 Sep 11;478(7367):103-9 PMID: 21909115
  53. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions.
    PLoS Genet. 2009 Jun;5(6):e1000534 PMID: 19557189
  54. The eyes absent gene: genetic control of cell survival and differentiation in the developing Drosophila eye.
    Cell. 1993 Feb 12;72(3):379-95 PMID: 8431945
  55. A linear complexity phasing method for thousands of genomes.
    Nat Methods. 2011 Dec 04;9(2):179-81 PMID: 22138821
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3063
Published
2014-09-00
Epub
2014-00-10
Pages
957-63
Language
English
Region
United States
NLM ID
9216904
Subset
IM
Grants
NIDDK NIH HHS · 5K12DK083021 · United States
Corrections
CommentIn
PMID: 25179497
External Links
PubMed source DOI: 10.1038/ng.3063 View journal details
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