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

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 550 000 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.

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Acknowledgements

We thank the study participants who made this research possible. Jo Steele provided technical assistance; Michael O'Donovan and Paul Boyce gave advice on the pooling methods; Husseini Manji provided helpful comments on the manuscript; and the Rutgers University Cell and DNA Repository managed DNA samples.

Data and biomaterials for the NIMH sample were collected as part of 10 projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991–98, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01 MH46282 – John Nurnberger, MD, PhD, Marvin Miller, MD and Elizabeth Bowman, MD; Washington University, St Louis, MO, U01 MH46280 – Theodore Reich, MD, Allison Goate, PhD and John Rice, PhD; Johns Hopkins University, Baltimore, MD U01 MH46274 – J. Raymond DePaulo Jr, MD Sylvia Simpson, MD, MPH and Colin Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD – Elliot Gershon, MD, Diane Kazuba, BA and Elizabeth Maxwell, M.S.W. From 1999–03, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545 – John Nurnberger, MD, PhD, Marvin J Miller, MD, Elizabeth S Bowman, MD, N Leela Rau, MD, P Ryan Moe, MD, Nalini Samavedy, MD, Rif El-Mallakh, MD (at University of Louisville), Husseini Manji, MD (at Wayne State University), Debra A Glitz, MD (at Wayne State University), Eric T Meyer, MS, Carrie Smiley, RN, Tatiana Foroud, PhD, Leah Flury, MS, Danielle M Dick, PhD and Howard Edenberg, PhD; Washington University, St Louis, MO, R01 MH059534, John Rice, PhD, Theodore Reich, MD, Allison Goate, PhD and Laura Bierut, MD; Johns Hopkins University, Baltimore, MD, R01 MH59533 – Melvin McInnis, MD, J Raymond DePaulo Jr, MD, Dean F MacKinnon, MD, Francis M Mondimore, MD, James B Potash, MD, Peter P Zandi, PhD, Dimitrios Avramopoulos and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553 – Wade Berrettini, MD, PhD; University of California at Irvine, CA, R01 MH60068 – William Byerley, MD and Mark Vawter, MD; University of Iowa, IA, R01 MH059548 – William Coryell, MD and Raymond Crowe, MD; University of Chicago, IL, R01 MH59535 – Elliot Gershon, MD, Judith Badner, PhD, Francis McMahon, MD, Chunyu Liu, PhD, Alan Sanders, MD, Maria Caserta, Steven Dinwiddie, MD, Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567 – John Kelsoe, MD, Rebecca McKinney, BA; Rush University, IL, R01 MH059556 – William Scheftner, MD, Howard M Kravitz, DO, MPH, Diana Marta, BA, Annette Vaughn-Brown, MSN, RN and Laurie Bederow, MA; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J. McMahon, MD, Layla Kassem, PsyD, Sevilla Detera-Wadleigh, PhD, Lisa Austin, PhD, Dennis L Murphy, MD.

The NIMH control subjects were collected by the NIMH Schizophrenia Genetics Initiative ‘Molecular Genetics of Schizophrenia II’ (MGS-2) collaboration. The investigators and coinvestigators are: ENH/Northwestern University, Evanston, IL, MH059571 – Pablo V. Gejman, MD (Collaboration Coordinator; PI), Alan R. Sanders, MD; Emory University School of Medicine, Atlanta, GA, MH59587 – Farooq Amin, MD (PI); Louisiana State University Health Sciences Center; New Orleans, LA, MH067257 – Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870 – William Byerley, MD (PI); Washington University, St Louis, MO, U01, MH060879 – C. Robert Cloninger, MD (PI); University of Iowa, Iowa, IA, MH59566 – Raymond Crowe, MD (PI), Donald Black, MD; University of Colorado, Denver, CO, MH059565 – Robert Freedman, MD (PI); University of Pennsylvania, Philadelphia, PA, MH061675 – Douglas Levinson, MD (PI); University of Queensland, QLD, Australia, MH059588 – Bryan Mowry, MD (PI); Mt Sinai School of Medicine, New York, NY, MH59586 – Jeremy Silverman, PhD (PI).

We thank the following clinician colleagues for help in collecting German patients: Margot Albus, Margitta Borrmann-Hassenbach, Ernst Franzek, Jürgen Fritze, Magdalena Gross, Thilo Held, Roland Kreiner, Mario Lanczik, Dirk Lichtermann, Wolfgang Maier, Jürgen Minges, Stephanie Ohlraun, Ulrike Reuner, Monja Tullius, Bettina Weigelt.

Supported by the NIMH Intramural Research Program, Deutsche Forschungsgemeinschaft, the National German Genome Research Network of the Federal Ministry of Education and Research, the National Alliance for Research on Schizophrenia and Depression (FJM, TGS), the Alfried Krupp von Bohlen und Halbach-Stiftung, and the National Institute on Aging. J Satagopan is supported by NIH grants R01GM60457 and R01CA098438.

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Baum, A., Akula, N., Cabanero, M. et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13, 197–207 (2008). https://doi.org/10.1038/sj.mp.4002012

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Keywords

  • mania
  • DFNB31
  • whirlin
  • Wnt
  • DAG
  • SORCS2

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