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Genome-wide association study of bipolar disorder in European American and African American individuals

Molecular Psychiatry volume 14, pages 755–763 (2009)Cite this article

Abstract

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 × 10−6) and rs10193871 in NAP5 at 2q21.2 (P=9.8 × 10−6). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 × 10−6) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 × 10−5). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 × 10−6), rs4657247 in RGS5 at 1q23.3 (P=4.1 × 10−6), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 × 10−6). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.

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Acknowledgements

We thank the participants in the study, as without them this work would not have been possible. For best estimate diagnostic work, we thank Vegas Coleman, Robert Schweitzer, N Leela Rau and Kelly Rhoadarmer. For data management, we thank Mariano Erpe and for study coordination Carre Fisher RN. This work was supported by grants from the NIMH and NHGRI to JRK (MH078151, MH081804, MH059567 supplement), and by the Genetic Association Information Network (GAIN). This work was additionally supported by the NIMH Intramural Research Program (FJM and TGS). WHB was supported by a grant from the Tzedakah Foundation, a grant from NIH (R01 MH59553) and a grant from Philip and Marcia Cohen. Falk Lohoff was supported by the Daland Fellowship Award from the American Philosophical Society and by NIH grant K08 MH080372. David Craig and Corrie Panganiban acknowledge the Stardust foundation. Follow-up genotyping was performed in the laboratory of HE at Indiana University School of Medicine. This research was also supported, in part, by the Intramural Research Program of the NIH, National Library of Medicine. Dr Smith, Dr Bloss, Dr Murray and Dr Schork are supported in part by National Institutes of Health grant NIH 1U54RR025204-01. Data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1991 to 1998, the principal investigators and coinvestigators were: Indiana University, Indianapolis, IN, U01 MH46282, John Nurnberger, Marvin Miller and Elizabeth Bowman; Washington University, St Louis, MO, U01 MH46280, Theodore Reich, Allison Goate and John Rice; Johns Hopkins University, Baltimore, MD U01 MH46274, J Raymond DePaulo, Jr, Sylvia Simpson and Colin Stine; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, Diane Kazuba and Elizabeth Maxwell. Data and biomaterials were collected as part of 10 projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1999 to 2007, the principal investigators and coinvestigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, Marvin J Miller, Elizabeth S Bowman, N Leela Rau, P Ryan Moe, Nalini Samavedy, Rif El-Mallakh (at University of Louisville), Husseini Manji (at Wayne State University), Debra A Glitz (at Wayne State University), Eric T Meyer, Carrie Smiley, Tatiana Foroud, Leah Flury, Danielle M Dick, Howard Edenberg; Washington University, St Louis, MO, R01 MH059534, John Rice, Theodore Reich, Allison Goate, Laura Bierut; Johns Hopkins University, Baltimore, MD, R01 MH59533, Melvin McInnis, J Raymond DePaulo, Jr, Dean F MacKinnon, Francis M Mondimore, James B Potash, Peter P Zandi, Dimitrios Avramopoulos and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini; University of California at Irvine, CA, R01 MH60068, William Byerley and Mark Vawter; University of Iowa, IA, R01 MH059548, William Coryell and Raymond Crowe; University of Chicago, IL, R01 MH59535, Elliot Gershon, Judith Badner, Francis McMahon, Chunyu Liu, Alan Sanders, Maria Caserta, Steven Dinwiddie, Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, Rebecca McKinney; Rush University, IL, R01 MH059556, William Scheftner, Howard M Kravitz, Diana Marta, Annette Vaughn-Brown and Laurie Bederow; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J McMahon, Layla Kassem, Sevilla Detera-Wadleigh, Lisa Austin, Dennis L Murphy.

Author information

Author notes

  1. E N Smith and C S Bloss: These authors contributed equally to this work.

Authors and Affiliations

  1. Scripps Genomic Medicine, Scripps Translational Science Institute, La Jolla, CA, USA

    E N Smith, C S Bloss, S S Murray & N J Schork

  2. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA

    E N Smith, S S Murray & N J Schork

  3. Scripps Health, La Jolla, CA, USA

    C S Bloss, S S Murray & N J Schork

  4. Department of Psychiatry, University of Chicago, Chicago, IL, USA

    J A Badner, E Gershon & C Liu

  5. Department of Psychiatry, Portland VA Medical Center, Portland, OR, USA

    T Barrett

  6. Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA

    P L Belmonte, J B Potash & P P Zandi

  7. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    W Berrettini & F Lohoff

  8. Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA

    W Byerley

  9. Department of Psychiatry, University of Iowa, Iowa City, IA, USA

    W Coryell

  10. Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA

    D Craig & C Panganiban

  11. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    H J Edenberg

  12. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    H J Edenberg & T Foroud

  13. Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA

    E Eskin & N Zaitlen

  14. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    T A Greenwood, C Nievergelt & J R Kelsoe

  15. Department of Psychiatry, Howard University, Washington, DC, USA

    M Hipolito, W B Lawson & E A Nwulia

  16. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

    D L Koller & J Nurnberger

  17. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    M G McInnis & S Zöllner

  18. US Department of Health and Human Services, Genetic Basis of Mood and Anxiety Disorders Unit, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    F J McMahon & T G Schulze

  19. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA

    D B Mirel

  20. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA

    J Paschall

  21. Division of Biostatistics, Washington University, St Louis, MO, USA

    J Rice

  22. Department of Psychiatry, Rush University, Chicago, IL, USA

    W Scheftner

  23. Department of Psychiatry, VA San Diego Healthcare System, La Jolla, CA, USA

    J R Kelsoe

Authors
  1. E N Smith
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  2. C S Bloss
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  3. J A Badner
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  36. N J Schork
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  37. J R Kelsoe
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Corresponding author

Correspondence to N J Schork.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Smith, E., Bloss, C., Badner, J. et al. Genome-wide association study of bipolar disorder in European American and African American individuals. Mol Psychiatry 14, 755–763 (2009). https://doi.org/10.1038/mp.2009.43

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