Variations in FKBP5 and BDNF genes are suggestively associated with depression in a Swedish population-based cohort

Abstract

Background

Genetic variations in FKBP5, BDNF, P2RX7 and CACNA1 are current candidates for involvement in depression.

Methods

The single nucleotide polymorphisms FKBP5:rs1360780, BDNF:rs6265 (Val66Met), P2RX7:2230912 (Gln460Arg) and CACNA1C:rs1006737 were genotyped in DNA from 457 depression cases (major depression, dysthymia, and mixed anxiety depression) and 2286 healthy controls with no symptom of psychopathology. Cases and controls were derived from a large well-characterized longitudinal population-based sample of adult Swedes with data on life situation and life history. Association to depression was analyzed with and without consideration to problems during childhood and negative life events last year.

Results

FKBP5:rs1360780 allele T and genotype TT were overrepresented in depression for men. Childhood problems and negative life events (two or more) conferred a risk for depression (OR = 2.8, 95% CI: 2.2–3.5 and OR = 2.9, 95% CI: 2.4–3.7, respectively). The BDNF:rs6265 Met-allele was overrepresented in depression for women with problems during their childhood. No indication for association to depression was found for P2RX7:2230912 and CACNA1C:rs1006737 without or with consideration of childhood problems or negative life events.

Limitations

The sample size did not allow exclusion of true association to depression at low odds ratios. There was possibly some recall bias of childhood problems.

Conclusions

These data support previous reports on FKBP5:rs1360780 and show a gender difference. Likewise, they support previous reports on BDNF:rs6265 and show involvement of environmental stress. P2RX7:2230912 and CACNA1C:rs1006737 did not have a large or moderate-size effect on depression risk. Further studies are required to estimate the significance of these findings.

Introduction

Vulnerability to the development of unipolar depression lies in both genetic factors and environmental exposure. The genetic component is estimated to explain ∼ 40% of the risk to develop major depression (Sullivan et al., 2000). Life event stressors are associated with development of depressive disorders (Brugha, 1995, Kessler, 1997, Risch et al., 2009). Previously, we and others proposed etiological pathways for depression in adulthood where environmental stressors in childhood predispose risk factors later in life, such as stressful life events (Kendler et al., 2002, Kendler et al., 2006, Sjöholm et al., 2009b).

We have in a population-based material of adult Swedes investigated for association between depression and genetic variation in four genes (FKBP5, BDNF, P2RX7 and CACNA1C) that are, from results in previous studies, a selection of the current candidates for involvement in major depression. This selection was based on their classification as possible candidate genes by congruent evidence for involvement in major depression (Burmeister et al., 2008, Green et al., 2009) and not being within the serotonin pathway. In the analysis we considered exposure to childhood problems and stressful life events during the last year. To our knowledge, these stressors have not been considered in previous genetic association studies of these polymorphisms.

The hsp90 co-chaperone FK506 binding protein 51 (FKBP5) is an important regulator of the glucocorticoid receptor complex (GR) activity (Grad and Picard, 2007). GR activity terminates physiological stress responses promoted by glucocorticoid hormones. FKBP5 has been shown to inhibit GR activity (Wochnik et al., 2005, Zhang et al., 2008), hence increased FKBP5 activity would imply reduced GR activity and less efficient termination of stress. An impaired signaling via cortisol-activated GR, leading to a weakened negative feedback regulation, appears to be one significant biological abnormality observed in mood disorders (Holsboer, 2000). FKBP5 expression is regulated by the androgen receptor through AR binding site in intron 5, and FKBP5 interacts functionally with progesterone receptor complexes (Davies et al., 2002, Magee et al., 2006). Homozygosity for the minor allele T of SNP rs1360780, located < 200 bp from a functional response element for progesterins and glucocorticoids in intron 2 (Hubler and Scammell, 2004), was associated with increased FKBP5 mRNA and protein expression (Binder et al., 2004) and with incomplete normalization of stress-elicited cortisol secretion in healthy individuals (Ising et al., 2008). Previously, significant overrepresentation of the TC versus CC genotype has been found in major depression (Lekman et al., 2008) and transmission of the TT genotype has been associated with bipolar disorder (Willour et al., 2009) which is in line with Binder and colleagues who reported that the number of depressive episodes was increased among those depression patients with the TT genotype (Binder et al., 2004) (for review see Binder, 2009).

Brain-derived neurotrophic factor (BDNF) is involved in neuronal and synaptic plasticity, neuronal excitability and neurogenesis especially in the hippocampus (Schmidt-Kastner et al., 1996, Koyama and Ikegaya, 2005). Depression in humans and animal models has been associated with reduced BDNF levels, whereas the use of antidepressants has been associated with an upregulation of BDNF in line with the ‘neurotrophic hypothesis’ of depression. However, negative and contradicting results falsify a simple causal relationship between brain BDNF levels and mood (see review by Groves, 2007). The SNP (rs6265) encoding Val66Met in the prodomain of BDNF has been extensively studied in mood disorders. The Met-allele has been associated with poorer episodic memory performance, reduced hippocampal volume and activity and less activity-dependent proBDNF secretion (Egan et al., 2003, Chen et al., 2004, Hariri et al., 2003, Pezawas et al., 2004). One recent meta analysis showed that the Met-allele was associated with depression among men (Verhagen et al., 2010) whereas another meta analysis showed no Val66Met association with depression (Chen et al., 2008).

P2RX7 forms homomeric ATP-gated ion channels with high permeability for calcium influx. It activates microglial cells, and facilitates presynaptic neurotransmitter release from neurons, and cultured astrocytes, raising the possibility for involvement in the glia-neuron cross-talk where astrocytes can produce trophic factors promoting neurogenesis or neuronal survival (Sperlagh et al., 2006, Skaper et al., 2010), in line with the hypothesis of deficient neuroprotection/neurotrophy in depression. The C-terminal domain, known to be important for the P2RX7 function, harbors a Gln460Arg SNP (rs2230912) (Sperlagh et al., 2006). The Arg-allele G has been associated with both bipolar affective disorder (BPD) and recurrent major depression (Barden et al., 2006, Lucae et al., 2006, McQuillin et al., 2008).

CACNA1C encodes an L-typed voltage-dependent calcium channel subunit contributing to channels that influence neuronal excitability. Its candidacy was discovered in large genome-wide SNP association studies of BPD that showed SNPs in CACNA1C to be among the few significant associations, with strongest signal at the non-coding SNP rs1006737 with risk allele A (Wellcome Trust Case Control Consortium, 2007, Ferreira et al., 2008, Sklar et al., 2008). Association to allele A of rs1006737 was recently found also for recurrent major depression and schizophrenia in patients from the British Isles (Green et al., 2009).