Genome-wide association study identifies five new schizophrenia loci

Stephan Ripke, Alan R Sanders, Kenneth S Kendler, Douglas F Levinson, Pamela Sklar, Peter A Holmans, Dan-Yu Lin, Jubao Duan, Roel A Ophoff, Ole A Andreassen, Edward Scolnick, Sven Cichon, David St Clair, Aiden Corvin, Hugh Gurling, Thomas Werge, Dan Rujescu, Douglas H R Blackwood, Carlos N Pato, Anil K MalhotraShaun Purcell, Frank Dudbridge, Benjamin M Neale, Lizzy Rossin, Peter M Visscher, Danielle Posthuma, Douglas M Ruderfer, Ayman Fanous, Hreinn Stefansson, Stacy Steinberg, Bryan J Mowry, Vera Golimbet, Marc De Hert, Erik G Jönsson, István Bitter, Olli P H Pietiläinen, David A Collier, Sarah Tosato, Ingrid Agartz, Margot Albus, Madeline Alexander, Richard L Amdur, Farooq Amin, Nicholas Bass, Sarah E Bergen, Donald W Black, Anders D Børglum, Matthew A Brown, Richard Bruggeman, Nancy G Buccola, Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium

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Abstract

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).
Original languageEnglish
Pages (from-to)969-976
Number of pages8
JournalNature Genetics
Volume43
Issue number10
Early online date18 Sep 2011
DOIs
Publication statusPublished - Oct 2011

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Keywords

  • alleles
  • bipolar disorder
  • case-control studies
  • European continental ancestry group
  • female
  • gene dosage
  • gene expression regulation
  • genetic loci
  • genetic predisposition to disease
  • genome, human
  • genome-wide association study
  • haplotypes
  • humans
  • linkage disequilibrium
  • logistic models
  • male
  • microRNAs
  • mutation
  • polymorphism, single nucleotide
  • schizophrenia

Cite this

Ripke, S., Sanders, A. R., Kendler, K. S., Levinson, D. F., Sklar, P., Holmans, P. A., ... Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011). Genome-wide association study identifies five new schizophrenia loci. Nature Genetics, 43(10), 969-976. https://doi.org/10.1038/ng.940