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SNPs in FKBP5 determine a novel subtype of depression characterized by rapid response to antidepressant treatment
Clinical Neuropsychopharmacology MRI and repetitive behaviors in autism. Biol Psychiatr 58, 226-32. [2] Anagnostou E, Shevell M, Miller S, Karpati G, Dilenge ME, 2005. Type 1 spinal muscular atrophy may mimic sensory-motor axonal neuropathy. J Child Neurol 20, 147-50. [3] Anagnostou E, Hollander E, 2005. Autism spectrum disorders. In: Neurological and Psychiatric Disorders. Humana Press.
F P _ ~ SNPs in FKBP5 determine a novel subtype of depression characterized by rapid response to antidepressant treatment E.B. Binder 1, S. Lucae 1 *, D. Salyakina 1, P. Lichtner2, T. Meitinger 2, B. Bondya, G. Wochnik 1, T. Rein 1, E Holsboer 1, B. Mtfller-Myhsok1. 1Max-Planck-Institute
of Psychiatry, Genetics of affective disorders, Munich, Germany; 2Technical University and GSE Institute for Human Genetics, Munich, Germany; 3Ludwig-Maximilians-University, Department of Psychiatry, Munich, Germany The stress hormone regulating hypothalamic pituitar~ adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. It is hypothesized that antidepressants might all target a common final signaling pathway. Due to consistent dysregulations of stress hormones in the brain and peripheral circulation of depressed patients, the HPA system is considered a strong candidate. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single nucleotide polymorphisms (SNPs) in eight of these genes in depressed patients and matched controls. Candidate genes such as the glucocorticoid receptor (GR) itself, the target genes CRH and AVP and five co-chaperones of the GR, BAG1, STUB1, TEBP, FKBP4 and FKBP5 were selected for the analysis. We found a strong association of three SNPs in FKBP5 (rs1360780, rs1334894 and rs755658), a glucorticoid receptor-regulating co-chaperone of hsp90 with response to antidepressant drugs after 2 and 5 weeks of hospitalization and to remission at discharge (N=233). By fine-mapping about 300 kb around this gene, including the neighboring genes TULP1, FLJ25390 and CLPS, we could show that only SNPs located within the major LD block containing FKBP5 were highly associated with response to antidepressant treatment (p=0.00003). We genotyped the three SNPs with the strongest association in our sample in a replication sample (N = 85). Two of
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the three SNPs showed a significant association with response to antidepressant treatment in the replication sample. In both samples, the association of response reflects an overrepresentation of homozygotes of the minor allele of the associated SNPs among the responders. Homozygocity for the minor alleles was also correlated with a higher protein expression of FKBP5 in lymphocytes and with a lower ACTH response in a neuroendocrine test assessing HPA-axis activity. The association of FKBP5 polymorphisms with response to antidepressant drugs appears to be independent of the primary pharmacological profile of antidepressants, as similar associations were obtained when dividing patients into three groups treated with different classes of antidepressants. We investigated whether the rs1360780 genotype was associated with additional disease-related variables. No genotype-dependent differences in sex, age, age of onset or the diagnostic subgroup (unipolar, bipolar, psychotic, presence of melancholic features) of depressed patients were observed. Correcting for multiple testing, we could not detect any significant differences in frequencies of single SNPs or haplotypes between our patient and our control sample. There was, however, a significant difference in the number of previously experienced depressive episodes (p=0.005). Patients with the TT genotype of rs1360780 experienced over twice as many depressive episodes before the index episode suggesting that these patients have more lifetime depressive episodes in addition to their faster response to antidepressant drugs. These results support that FKBP5 and by extension the HPA system may be involved in the common final signaling pathway of antidepressant drugs.
References [1] Holsboer, E, 2000. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 472501.
F P _ ~ SNPs in FKBP5 determine a novel subtype of depression characterized by rapid response to antidepressant treatment E.B. Binder 1, S. Lucae 1 *, D. Salyakina 1, P. Lichtner2, T. Meitinger 2, B. Bondya, G. Wochnik 1, T. Rein 1, E Holsboer 1, B. Mtfller-Myhsok1. 1Max-Planck-Institute
of Psychiatry, Genetics of affective disorders, Munich, Germany; 2Technical University and GSE Institute for Human Genetics, Munich, Germany; 3Ludwig-Maximilians-University, Department of Psychiatry, Munich, Germany The stress hormone regulating hypothalamic pituitar~ adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. It is hypothesized that antidepressants might all target a common final signaling pathway. Due to consistent dysregulations of stress hormones in the brain and peripheral circulation of depressed patients, the HPA system is considered a strong candidate. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single nucleotide polymorphisms (SNPs) in eight of these genes in depressed patients and matched controls. Candidate genes such as the glucocorticoid receptor (GR) itself, the target genes CRH and AVP and five co-chaperones of the GR, BAG1, STUB1, TEBP, FKBP4 and FKBP5 were selected for the analysis. We found a strong association of three SNPs in FKBP5 (rs1360780, rs1334894 and rs755658), a glucorticoid receptor-regulating co-chaperone of hsp90 with response to antidepressant drugs after 2 and 5 weeks of hospitalization and to remission at discharge (N=233). By fine-mapping about 300 kb around this gene, including the neighboring genes TULP1, FLJ25390 and CLPS, we could show that only SNPs located within the major LD block containing FKBP5 were highly associated with response to antidepressant treatment (p=0.00003). We genotyped the three SNPs with the strongest association in our sample in a replication sample (N = 85). Two of
$75
the three SNPs showed a significant association with response to antidepressant treatment in the replication sample. In both samples, the association of response reflects an overrepresentation of homozygotes of the minor allele of the associated SNPs among the responders. Homozygocity for the minor alleles was also correlated with a higher protein expression of FKBP5 in lymphocytes and with a lower ACTH response in a neuroendocrine test assessing HPA-axis activity. The association of FKBP5 polymorphisms with response to antidepressant drugs appears to be independent of the primary pharmacological profile of antidepressants, as similar associations were obtained when dividing patients into three groups treated with different classes of antidepressants. We investigated whether the rs1360780 genotype was associated with additional disease-related variables. No genotype-dependent differences in sex, age, age of onset or the diagnostic subgroup (unipolar, bipolar, psychotic, presence of melancholic features) of depressed patients were observed. Correcting for multiple testing, we could not detect any significant differences in frequencies of single SNPs or haplotypes between our patient and our control sample. There was, however, a significant difference in the number of previously experienced depressive episodes (p=0.005). Patients with the TT genotype of rs1360780 experienced over twice as many depressive episodes before the index episode suggesting that these patients have more lifetime depressive episodes in addition to their faster response to antidepressant drugs. These results support that FKBP5 and by extension the HPA system may be involved in the common final signaling pathway of antidepressant drugs.
References [1] Holsboer, E, 2000. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 472501.