Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder

T. G. Schulze, S. D. Detera-Wadleigh, N. Akula, A. Gupta, L. Kassem, J. Steele, J. Pearl, J. Strohmaier, R. Breuer, M. Schwarz, P. Propping, M. M. Nöthen, S. Cichon, J. Schumacher, M. Rietschel, F. J. McMahon

Research output: Contribution to journalArticlepeer-review

Abstract

Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1-4 (P0.05; odds ratio (OR)1.24) and German (P0.0006; OR1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P0.017; OR1.38). A random-effects meta-analysis of all three samples was significant (P3 × 106; OR1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P0.0001; OR1.70), and similar ORs in the NIMH 1-4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P1.7 × 10 5; OR1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.

Original languageEnglish (US)
Pages (from-to)487-491
Number of pages5
JournalMolecular psychiatry
Volume14
Issue number5
DOIs
StatePublished - May 2009

Keywords

  • Allelic heterogeneity
  • Ankyrins
  • Genome-wide association study
  • Interaction
  • Linkage disequilibrium
  • Manic depressive illness

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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