Original Article

Molecular Psychiatry (2008) 13, 197–207; doi:10.1038/sj.mp.4002012; published online 8 May 2007

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

A E Baum1, N Akula1, M Cabanero1, I Cardona1, W Corona1, B Klemens1,2, T G Schulze3, S Cichon4,5, M Rietschel3, M M Nöthen4,5, A Georgi3, J Schumacher4, M Schwarz6, R Abou Jamra4, S Höfels7, P Propping4, J Satagopan8, S D Detera-Wadleigh1, J Hardy19 and F J McMahon1 NIMH Genetics Initiative Bipolar Disorder Consortium1,9,10,11,12,13,14,15,16,17,18

  1. 1Unit on the Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, US Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
  2. 2Center on Social and Economic Dynamics, Brookings Institution, Washington, DC, USA
  3. 3Department of Genetic Epidemiology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
  4. 4Institute of Human Genetics, University of Bonn, Bonn, Germany
  5. 5Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
  6. 6Psychiatrisches Zentrum Nordbaden, Academic Teaching Hospital of the University of Heidelberg, Wiesloch, Germany
  7. 7Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
  8. 8Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  9. 9Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  10. 10Department of Psychiatry, University of California, Irvine, CA, USA
  11. 11Department of Psychiatry, University of California, San Diego, CA, USA
  12. 12Department of Psychiatry, University of Chicago, Chicago, IL, USA
  13. 13Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
  14. 14Laboratory of Clinical Science, US Department of Health and Human Services, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA
  15. 15Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA
  16. 16Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
  17. 17Department of Psychiatry, University of Iowa Medical School, Iowa City, IA, USA
  18. 18Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
  19. 19Laboratory of Neurogenetics, US Department of Health and Human Services, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr FJ McMahon, Unit on the Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, 35 Convent Drive, 1A-202, Bethesda, MD 20892, USA. E-mail: mcmahonf@mail.nih.gov

Received 19 February 2007; Revised 26 March 2007; Accepted 29 March 2007; Published online 8 May 2007.

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Abstract

The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P=1.5 × 10−8, experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.

Keywords:

mania, DFNB31, whirlin, Wnt, DAG, SORCS2