Family-based association of FKBP5 in bipolar disorder

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