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.
Key Words
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References
- Validating, augmenting and refining genome-wide association signals.Nat Rev Genet. 2009; 10: 318-329
- Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007; 447: 661-678
- Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.Nat Genet. 2008; 40: 1056-1058
- Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder.Am J Hum Genet. 2011; 88: 372-381
- Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry.Proc Natl Acad Sci U S A. 2009; 106: 7501-7506
- Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1.Nat Genet. 2010; 42: 128-131
- Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression.Nat Genet. 2011; 43: 3-5
- Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries.Hum Mol Genet. 2011; 20: 387-391
- Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.Nature Genet. 2011; 43: 977-983
- Common variants conferring risk of schizophrenia.Nature. 2009; 460: 744-747
- The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines.WHO, Geneva1992
- Diagnostic and Statistical Manual of Mental Disorders.4th ed. APA, Washington, DC2000 (Text Revision (DSM-IV).)
- Schedules for Clinical Assessment in Neuropsychiatry (Version 2.1).WHO Assessment, Classification and Epidemiology, Geneva1999
- Past and present state examination: The assessment of ‘lifetime ever’ psychopathology.Psychol Med. 1986; 16: 461-465
- A polydiagnostic application of operational criteria in studies of psychotic illness.Arch Gen Psychiatry. 1991; 48: 764-770
- Research diagnostic criteria: rationale and reliability.Arch Gen Psychiatry. 1978; 35: 773-782
- Schedule for Affective Disorders and Schizophrenia: Life-Time Version.3rd ed. State Psychiatric Institute, New York1979
- Procedural validity of the computerized version of the Composite International Diagnostic Interview (CIDI-Auto) in the anxiety disorders.Psychol Med. 1995; 25: 1269-1280
- Composite International Diagnostic Interview (CIDI): Interviewer's Manual.WHO, Geneva1993
- Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P).Biometrics Research, New York State Psychiatric Institute, New York2002
- Utility of a new procedure for diagnosing mental disorders in primary care.JAMA. 1994; 272: 1749-1756
- A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample.J Affect Disord. 2010; 126: 312-316
- Variation in P2RX7 candidate gene (rs2230912) is not associated with bipolar I disorder and unipolar major depression in four European samples.Am J Med Genet B Neuropsychiatr Genet. 2009; 150B: 1017-1021
- The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.Nat Genet. 2003; 35: 131-138
- Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560
- Stata Statistical Software: Release 10.StataCorp, College Station, Texas2007
- Common variants at VRK2 and TCF4 conferring risk of schizophrenia.Hum Mol Genet. 2011; 20: 4076-4081
- Genetic Power Calculator: Design of linkage and association genetic mapping studies of complex traits.Bioinformatics. 2003; 19: 149-150
- Quantifying and correcting for the winner's curse in genetic association studies.Genet Epidemiol. 2009; 33: 453-462
- Replication validity of genetic association studies.Nat Genet. 2001; 29: 306-309
- Polybromo-1: The chromatin targeting subunit of the PBAF complex.Biochimie. 2009; 91: 309-319
- Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.Nature. 2011; 469: 539-542
- A map of human genome variation from population-scale sequencing.Nature. 2010; 467: 1061-1073
- A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells.Genes Dev. 2002; 16: 2991-3003
- Psychiatric genetics: Progress amid controversy.Nat Rev Genet. 2008; 9: 527-540
- The Kraepelinian dichotomy—going, going… but still not gone.Br J Psychiatry. 2010; 196: 92-95
- Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: A population-based study.Lancet. 2009; 373: 234-239
- The heritability of bipolar affective disorder and the genetic relationship to unipolar depression.Arch Gen Psychiatry. 2003; 60: 497-502
- The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia.Mol Psychiatry. 2010; 15: 1016-1022
- Genome-wide association study identifies five new schizophrenia loci.Nature genetics. 2011; 43: 969-976
- Cognitive ontologies for neuropsychiatric phenomics research.Cogn Neuropsychiatry. 2009; 14: 419-450
Article info
Publication history
Published online: May 07, 2012
Accepted:
February 10,
2012
Received in revised form:
January 23,
2012
Received:
September 16,
2011
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
