Immediate Communication

Molecular Psychiatry (2008) 13, 558–569; doi:10.1038/sj.mp.4002151; published online 4 March 2008

Whole-genome association study of bipolar disorder

Authors and their contributions appear at the end of the paper.

P Sklar1,2,3,4, J W Smoller1,2,3,4, J Fan1,2,4, M A R Ferreira1,2,4,5, R H Perlis1,2,3,4, K Chambert4, V L Nimgaonkar6, M B McQueen7, S V Faraone8,9, A Kirby4,10, P I W de Bakker1,4,10, M N Ogdie1,2,4, M E Thase6, G S Sachs2,3, K Todd-Brown1,2,4, S B Gabriel4, C Sougnez4, C Gates4, B Blumenstiel4, M Defelice4, K G Ardlie4, J Franklin4, W J Muir11, K A McGhee11, D J MacIntyre11, A McLean11, M VanBeck11, A McQuillin12, N J Bass12, M Robinson12, J Lawrence12, A Anjorin12, D Curtis12, E M Scolnick4, M J Daly1,3,4,10, D H Blackwood11, H M Gurling12 and S M Purcell1,2,3,4

  1. 1Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
  2. 2Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
  3. 3Departments of Genetics, Psychiatry or Medicine, Harvard Medical School, Boston, MA, USA
  4. 4Broad Institute of Harvard and MIT, Cambridge, MA, USA
  5. 5Queensland Institute of Medical Research, QLD, Australia
  6. 6Departments of Psychiatry and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
  7. 7Department of Psychology, University of Colorado, Boulder, CO, USA
  8. 8Department of Psychiatry and Behavioral Sciences, Upstate Medical University, State University of New York, Syracuse, NY, USA
  9. 9Department of Neuroscience and Physiology, Upstate Medical University, State University of New York, Syracuse, NY, USA
  10. 10Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
  11. 11Divison of Psychiatry, University of Edinburgh, Edinburgh, UK
  12. 12Molecular Psychiatry Laboratory, Department of Mental Health Sciences, Windeyer Institute of Medical Sciences, University College London, London, UK

Correspondence: Dr P Sklar, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. E-mail: sklar@chgr.mgh.harvard.edu

Received 24 September 2007; Revised 13 December 2007; Accepted 14 December 2007; Published online 4 March 2008.

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Abstract

We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 × 10−7) and tetraspanin-8 (TSPAN8; P=6.11 × 10−7). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 × 10−8, TSPAN8; P=7.57 × 10−7 and EGFR; P=8.36 × 10−8). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case–control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case–Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

Keywords:

genetic, schizophrenia, CACNA1C, MYO5B, TSPAN8, EGFR