1. ¹Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA
2. ²Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI, USA
3. ³McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
4. ⁴Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
5. ⁵Department of Psychiatry, University of Chicago, Chicago, IL, USA
6. ⁶Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA

Correspondence: Dr VL Willour, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Meyer 4-143, 600 N Wolfe Street, Baltimore, MD 21287, USA. E-mail: willour@jhmi.edu

⁷These authors contributed equally to this work.

Received 25 June 2007; Revised 29 August 2007; Accepted 18 September 2007; Published online 8 January 2008.

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.