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Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus

Molecular Psychiatry volume 7, pages 579–593 (2002)Cite this article

Abstract

Identification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the voltage-dependent calcium channel were associated with bipolar disorder at the P<0.05 level. In view of the large number of hypotheses tested, the two nominally positive associations were then tested in independent populations of bipolar patients and only BDNF remains a potential risk gene. In the replication samples, excess transmission of the valine allele of amino acid 66 of BDNF was observed in the direction of the original result in an additional sample of 334 parent-proband trios (T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene identified 44 additional SNPs. Genotyping eight common SNPs identified three additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD was observed across this region and all adjacent pairwise haplotypes showed excess transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT revealed a global P value of 0.03. A single haplotype was identified that is shared by both the original dataset and the replication sample that is uniquely marked by both the rare A allele of the original SNP and a novel allele 11.5 kb 3′. Therefore, this study of 76 candidate genes has identified BDNF as a potential risk allele that will require additional study to confirm.

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Acknowledgements

We thank the patients and families for participation, Rose Kouyoumjian and Noel Burtt for technical assistance with genotyping, Michele Cargill and the high-throughput SNP detection team, David Altshuler and Leif Groop for DNAs. We thank the Stanley Foundation for brain RNA. For the NIMH samples, data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (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, MSW. Collection and typing of the UK sample was supported by grants from the Wellcome Trust.

This study was supported by a NARSAD Young Investigator Award (PS), a research grant from Bristol-Myers Squibb, Millennium Pharmaceuticals, and Affymetrix (ESL). GK is a Wellcome Trust Advanced Fellow, IJ is a Wellcome Trust Training Fellow in Mental Health, and NC is a Wellcome Trust Research Fellow in Clinical Sciences.

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  1. Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    P Sklar

  2. Harvard Medical School, Boston, MA, USA

    P Sklar

  3. Whitehead Institute/MIT Center for Genome Research, Cambridge, MA, USA

    P Sklar, S B Gabriel, Y-M Lim, G Tsan, S Schaffner & E S Lander

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

    M G McInnis & J R DePaulo

  5. Division of Neuroscience, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham, UK

    P Bennett, I Jones & N Craddock

  6. Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK

    G Kirov & M Owen

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Sklar, P., Gabriel, S., McInnis, M. et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol Psychiatry 7, 579–593 (2002). https://doi.org/10.1038/sj.mp.4001058

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