Family-based association of FKBP5 in bipolar disorder

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.

Figure 1

The FKBP5 chromosomal location, gene structure, single-nucleotide polymorphism (SNP) locations and linkage disequilibrium (LD) structure are depicted in the figure. The chromosomal location and gene structure were taken from the UCSC genome browser (March 2006 Build; NCBI Build 36.1). The RefSeq transcript has 11 exons and spans 115kb from 35 649 346–35 764 692 on chromosome 6. The locations of the study's nine FKBP5 SNPs are indicated by arrows. The LD structure for the nine FKBP5 SNPs was determined using our own genotype data in the family sample. The LD diagram demonstrates that the nine markers belong to two haplotype blocks as determined by the ‘confidence intervals’ method. High pairwise LD (D′) between markers is illustrated with dark shading. The r² scores for the marker pairs are listed in the corresponding blocks.