Family-based association of FKBP5 in bipolar disorder

V. L. Willour, H. Chen, J. Toolan, P. Belmonte, D. J. Cutler, F. S. Goes, Peter P. Zandi, R. S. Lee, Dean F. MacKinnon, F. M. Mondimore, B. Schweizer, J. Raymond DePaulo, Elliot Gershon, F. J. McMahon, James B. Potash, Erin Miller, Justin Pearl, Layla Kassem, Victor Lopez, John NurnbergerMarvin J. Miller, Elizabeth S. Bowman, Theodore Reich, Allison Goate, John Rice, Colin Stine, Diane Kazuba, Elizabeth Maxwell, N. Leela Rau, P. Ryan Moe, Nalini Samavedy, Rif El-Mallakh, Husseini Manji, Debra A. Glitz, Eric T. Meyer, Carrie Smiley, Tatiana Foroud, Leah Flury, Danielle M. Dick, Howard Edenberg, Laura Bierut, Melvin McInnis, Dimitrios Avramopoulos, Jennifer Payne, Wade Berrettini, William Byerley, Mark Vawter, William Coryell, Raymond Crowe, Judith Badner, Chunyu Liu, Alan Sanders, Maria Caserta, Steven Dinwiddie, Tu Nguyen, Donna Harakal, John Kelsoe, Rebecca McKinney, William Scheftner, Howard M. Kravitz, Diana Marta, Annette Vaughn-Brown, Laurie Bederow, Sevilla Detera-Wadleigh, Lisa Austin, Dennis L. Murphy

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.

Original languageEnglish (US)
Pages (from-to)261-268
Number of pages8
JournalMolecular Psychiatry
Volume14
Issue number3
DOIs
StatePublished - Jan 1 2009

Keywords

  • HPA axis
  • Linkage disequilibrium
  • Mood disorder

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Willour, V. L., Chen, H., Toolan, J., Belmonte, P., Cutler, D. J., Goes, F. S., Zandi, P. P., Lee, R. S., MacKinnon, D. F., Mondimore, F. M., Schweizer, B., DePaulo, J. R., Gershon, E., McMahon, F. J., Potash, J. B., Miller, E., Pearl, J., Kassem, L., Lopez, V., ... Murphy, D. L. (2009). Family-based association of FKBP5 in bipolar disorder. Molecular Psychiatry, 14(3), 261-268. https://doi.org/10.1038/sj.mp.4002141