Abstract
Current understanding and treatment of depression is limited to the monoaminergic theory with little knowledge of the involvement of other cellular processes. Genome-wide association studies, however, implicate several novel single-nucleotide polymorphisms with weak but replicable effects and unclarified mechanisms. We investigated the effect of rs1106634 of the ATPV1B2 gene encoding the vacuolar H+ATPase on lifetime and current depression and the possible mediating role of neuroticism by logistic and linear regression in a white European general sample of 2226 subjects. Association of rs1106634 with performance on frontal (Stockings of Cambridge (SOC)) and hippocampal-dependent (paired associates learning (PAL)) cognitive tasks was investigated in multivariate general linear models in a smaller subsample. The ATP6V1B2 rs1106634 A allele had a significant effect on lifetime but not on current depression. The effect of the A allele on lifetime depression was not mediated by neuroticism. The A allele influenced performance on the PAL but not on the SOC test. We conclude that the effects of variation in the vacuolar ATPase may point to a new molecular mechanism that influences the long-term development of depression. This mechanism may involve dysfunction specifically in hippocampal circuitry and cognitive impairment that characterizes recurrent and chronic depression.
Highlights
Major depression has a great burden both in terms of suffering and costs for the society.[1,2,3,4,5] its pathology is still unclear
We investigated whether the effect of ATP6V1B2 rs1106634 A allele on lifetime depression is due to the association of the A allele with higher neuroticism scores
In our study in a large general sample ATP6V1B2 rs1106634 A allele was a significant risk factor for lifetime major depression but was not associated with current depressive symptom manifestation. This risk effect of the A allele on depression was only partially mediated by neuroticism, a well-known risk factor for depression, which was associated with both depression and the A allele in our study indicating overlapping genetic risk but different mechanisms
Summary
Major depression has a great burden both in terms of suffering and costs for the society.[1,2,3,4,5] its pathology is still unclear. A recent meta-analysis of three GWAS-s in major depressive disorder observed the strongest associations for three intronic single-nucleotide polymorphisms (SNPs), including one (rs1106634) in the ATP6V1B2 gene (Figure 1) encoding the B subunit of the vacuolar H+ pump-ATPase with a suggestive significance (P = 6.78 × 107) for the A allele.[11] In another large meta-analysis in schizophrenia and bipolar disorder, rs1106634 exhibited a suggestive P-value (3.97 × 10 − 6) for the opposite, T allele.[12] The cytosolic domain where this subunit is located is part of a transmembrane complex playing a role in the generation of H+ gradients across synaptic vesicle membranes and is a key player in receptor-mediated endocytosis.[11]. The information is based on the CEU population of version 2 and release 24 of the HapMap project (http://hapmap.ncbi.nlm. nih.gov/)
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