TY - JOUR

T1 - The psychiatric vulnerability gene CACNA1C and its sex-specific relationship with personality traits, resilience factors and depressive symptoms in the general population

AU - Strohmaier, J.

AU - Amelang, M.

AU - Hothorn, L. A.

AU - Witt, S. H.

AU - Nieratschker, V.

AU - Gerhard, D.

AU - Meier, S.

AU - Wüst, S.

AU - Frank, J.

AU - Loerbroks, A.

AU - Rietschel, M.

AU - Stürmer, T.

AU - Schulze, T. G.

N1 - Funding Information: This work was supported by the National Genome Research Network 442 (NGFN) of the German Federal Ministry of Education and Research (BMBF) and the National Institute of Mental Health (NIMH). The HeiDE cohort study was supported by the German Research Foundation (DFG-STU 235/10-2 and HE-2443/8-1, DFG-AM-37/19-1). TGS received support from NARSAD (Young Investigator Award 2007). JS was supported by the German Research Foundation (GRK 793). TS receives investigator-initiated research funding and support from the National Institute on Aging at the National Institutes of Health in his roles as Principal Investigator (RO1 AG023178) and Co-Investigator (RO1 AG018833). He also receives research funding from the Agency for Healthcare Research and Quality as Principal Investigator of the UNC-DEcIDE center. TS accepts no kind of personal compensation from any pharmaceutical company. He receives salary support from the UNC Center of Excellence in Pharmacoepidemiology and Public Health and from unrestricted research grants to UNC from pharmaceutical companies.

PY - 2012/6/5

Y1 - 2012/6/5

N2 - Genome-wide association studies have reported an association between the A-allele of rs1006737 within CACNA1C and affective disorders and schizophrenia. The aim of the present study was to investigate the relationship between rs1006737 and established and potential endophenotypes for these disorders in a population-based cohort of 3793 subjects, using an analytical method designed to assess a previously reported sex-specific effect of CACNA1C. The investigated endophenotypes included personality traits and resilience factors. At 10-year follow-up, subjects were screened for depressive symptoms. All subjects were genotyped for rs1006737. The direction of the effect and mode of inheritance of rs1006737 differed between the sexes. In men, the A-allele was associated with higher emotional lability and lower resilience, that is, lower sense of coherence (P=0.021), lower perceived social support (P=0.018), lower dispositional optimism (P=0.032) and more depressive symptoms at follow-up (P=0.007). In women, the A-allele was associated with lower emotional lability and stronger resilience, that is, higher sense of coherence (P=0.00028), higher perceived social support (P=0.010), lower neuroticism (P=0.022) and fewer depressive symptoms at follow-up (P=0.035). After conservative Bonferroni correction for 32 tests, results only remained significant for sense of coherence in women (P=0.009). These results suggest that CACNA1C is involved in the genetic architecture of endophenotypes for affective disorders and schizophrenia, and that it shows a distinct sex-specific effect. Comprehensive phenotype characterization in case-control samples and the general population, as well as an adequate modeling of sex-specific genetic effects, may be warranted to elucidate the pathogenetic mechanisms conferred by robustly identified susceptibility genes.

AB - Genome-wide association studies have reported an association between the A-allele of rs1006737 within CACNA1C and affective disorders and schizophrenia. The aim of the present study was to investigate the relationship between rs1006737 and established and potential endophenotypes for these disorders in a population-based cohort of 3793 subjects, using an analytical method designed to assess a previously reported sex-specific effect of CACNA1C. The investigated endophenotypes included personality traits and resilience factors. At 10-year follow-up, subjects were screened for depressive symptoms. All subjects were genotyped for rs1006737. The direction of the effect and mode of inheritance of rs1006737 differed between the sexes. In men, the A-allele was associated with higher emotional lability and lower resilience, that is, lower sense of coherence (P=0.021), lower perceived social support (P=0.018), lower dispositional optimism (P=0.032) and more depressive symptoms at follow-up (P=0.007). In women, the A-allele was associated with lower emotional lability and stronger resilience, that is, higher sense of coherence (P=0.00028), higher perceived social support (P=0.010), lower neuroticism (P=0.022) and fewer depressive symptoms at follow-up (P=0.035). After conservative Bonferroni correction for 32 tests, results only remained significant for sense of coherence in women (P=0.009). These results suggest that CACNA1C is involved in the genetic architecture of endophenotypes for affective disorders and schizophrenia, and that it shows a distinct sex-specific effect. Comprehensive phenotype characterization in case-control samples and the general population, as well as an adequate modeling of sex-specific genetic effects, may be warranted to elucidate the pathogenetic mechanisms conferred by robustly identified susceptibility genes.

KW - CACNA1C

KW - depression

KW - neuroticism

KW - personality

KW - resilience

KW - sex-specific

UR - http://www.scopus.com/inward/record.url?scp=84876673658&partnerID=8YFLogxK

U2 - 10.1038/mp.2012.53

DO - 10.1038/mp.2012.53

M3 - Article

C2 - 22665259

AN - SCOPUS:84876673658

VL - 18

SP - 607

EP - 613

JO - Molecular psychiatry

JF - Molecular psychiatry

SN - 1359-4184

IS - 5

ER -