Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder

Evangelos Vassos, Stacy Steinberg, Sven Cichon, Gerome Breen, Engilbert Sigurdsson, Ole A Andreassen, Srdjan Djurovic, Gunnar Morken, Maria Grigoroiu-Serbanescu, Carmen C Diaconu, Piotr M Czerski, Joanna Hauser, Gulja Babadjanova, Lilia I Abramova, Thomas W Mühleisen, Markus M Nöthen, Marcella Rietschel, Peter McGuffin, David St Clair, Omar GustafssonIngrid Melle, Olli P H Pietiläinen, Mirella Ruggeri, Sarah Tosato, Thomas Werge, Roel A Ophoff, Dan Rujescu, Anders D Børglum, Ole Mors, Preben B Mortensen, Ditte Demontis, Mads V Hollegaard, Ruud van Winkel, Gunter Kenis, Marc De Hert, János M Réthelyi, István Bitter, I Alex Rubino, Vera Golimbet, Lambertus A Kiemeney, Leonard H van den Berg, Barbara Franke, Erik G Jönsson, Anne Farmer, Hreinn Stefansson, Kari Stefansson, David A Collier, GROUP Consortium

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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.
Original languageEnglish
Pages (from-to)645-650
Number of pages6
JournalBiological Psychiatry
Volume72
Issue number8
Early online date4 May 2012
DOIs
Publication statusPublished - 15 Oct 2012

Keywords

  • 3p21.1
  • bipolar disorder
  • genetics
  • polybromo 1
  • genome-wide association
  • schizophrenia

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    Vassos, E., Steinberg, S., Cichon, S., Breen, G., Sigurdsson, E., Andreassen, O. A., Djurovic, S., Morken, G., Grigoroiu-Serbanescu, M., Diaconu, C. C., Czerski, P. M., Hauser, J., Babadjanova, G., Abramova, L. I., Mühleisen, T. W., Nöthen, M. M., Rietschel, M., McGuffin, P., Clair, D. S., ... GROUP Consortium (2012). Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder. Biological Psychiatry, 72(8), 645-650. https://doi.org/10.1016/j.biopsych.2012.02.040