title: Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder.
abstract: BACKGROUND
  Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia.
  
  
  METHODS
  To replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method.
  
  
  RESULTS
  In our dataset, rs2251219 was associated with BP (odds ratio [OR] = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 × 10(-9)). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21).
  
  
  CONCLUSIONS
  There is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder.
authors.affiliation: MRC SGDP Centre, Institute of Psychiatry, King's College London, London, United Kingdom. vassos@iop.kcl.ac.uk
authors.forename: Evangelos
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authors.lastname: Vassos
authors.forename: Stacy
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authors.lastname: Steinberg
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authors.lastname: Cichon
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authors.lastname: Rietschel
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authors.lastname: McGuffin
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authors.forename: Olli P H
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authors.lastname: Pietiläinen
authors.forename: Mirella
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authors.lastname: Ruggeri
authors.forename: Sarah
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authors.lastname: Tosato
authors.forename: Thomas
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authors.lastname: Werge
authors.forename: Roel A
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authors.lastname: Ophoff
authors.forename: Dan
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authors.lastname: Rujescu
authors.forename: Anders D
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authors.lastname: Børglum
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authors.lastname: Mors
authors.forename: Preben B
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authors.lastname: Mortensen
authors.forename: Ditte
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authors.lastname: Demontis
authors.forename: Mads V
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authors.lastname: Hollegaard
authors.forename: Ruud
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authors.lastname: van Winkel
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authors.lastname: Kenis
authors.forename: Marc
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authors.lastname: De Hert
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authors.lastname: Réthelyi
authors.forename: István
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authors.lastname: Bitter
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authors.forename: Vera
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authors.lastname: Golimbet
authors.forename: Lambertus A
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authors.lastname: Kiemeney
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Barbara
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authors.lastname: Franke
authors.forename: Erik G
authors.initials: EG
authors.lastname: Jönsson
authors.forename: Anne
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authors.lastname: Farmer
authors.forename: Hreinn
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authors.lastname: Stefansson
authors.forename: Kari
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mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D030541:Databases, Genetic / Q000706:statistics & numerical data; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics; D044465:White People / Q000235:genetics