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ORIGINAL ARTICLE
The psychiatric vulnerability gene CACNA1C and its
sex-specific relationship with personality traits, resilience
factors and depressive symptoms in the general population
J Strohmaier
1
, M Amelang
2
, LA Hothorn
3
, SH Witt
1
, V Nieratschker
1
, D Gerhard
3
, S Meier
1
,SWu¨st
1,4
, J Frank
1
, A Loerbroks
5
,
M Rietschel
1
, T Stu¨rmer
6,7,9
and TG Schulze
1,8,9
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
(P¼0.021), lower perceived social support (P¼0.018), lower dispositional optimism (P¼0.032) and more depressive symptoms
at follow-up (P¼0.007). In women, the A-allele was associated with lower emotional lability and stronger resilience, that is,
higher sense of coherence (P¼0.00028), higher perceived social support (P¼0.010), lower neuroticism (P¼0.022) and fewer
depressive symptoms at follow-up (P¼0.035). After conservative Bonferroni correction for 32 tests, results only remained
significant for sense of coherence in women (P¼0.009). 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.
Molecular Psychiatry (2013) 18, 607--613; doi:10.1038/mp.2012.53; published online 5 June 2012
Keywords: CACNA1C; depression; neuroticism; personality; resilience; sex-specific
INTRODUCTION
CACNA1C on chromosome 12p13 is one of the best-replicated
vulnerability genes for affective disorders and schizophrenia (see,
for example, ref. 1--10). CACNA1C encodes an a-1 subunit of the
voltage-dependent L-type gated calcium channel CAv1.2, which
mediates the influx of calcium ions into the cell upon membrane
polarization. To improve understanding of the mechanisms under-
lying the association with bipolar disorder and schizophrenia, the
role of this gene in the pathogenesis of these disorders must be
elucidated. One approach is to appraise the relationship between
CACNA1C and potential endophenotypes for these disorders.
11
Genetic imaging studies have reported strong evidence for an
association between the A-allele of the CACNA1C single-nucleotide
polymorphism (SNP) rs1006737 and structural and functional
brain alterations (see, for example, ref. 12--14). Recent studies have
explored the relationship between rs1006737 and neuroticism---a
well-known endophenotype for affective disorders and schizo-
phrenia---and related traits.
12,15,16
Erk et al.
12
reported an
association between the A-allele of rs1006737 and higher levels
of neuroticism depression, anxiety, obsessive compulsive thoughts
and interpersonal sensitivity in 110 healthy individuals. A study of
530 healthy male army conscripts found higher levels of harm
avoidance, trait anxiety and paranoid ideation as well as lower
extraversion in carriers of the A-allele.
15
However, these findings
were not supported by a study involving the STAR*D sample,
which focused on a possible association between rs1006737 and
baseline depression.
16
Further adequately powered studies of
endophenotypic and related measures are therefore warranted.
Very recently, a sex-specific association between 15 SNPs in
CACNA1C (including rs1006737) and both bipolar disorder and
depression was detected in a large data set of 2021 affective
disorder cases and 1840 unrelated control subjects.
10
Although,
Received 26 January 2012; revised 2 April 2012; accepted 3 April 2012; published online 5 June 2012
1
Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany;
2
Institute of
Psychology, University of Heidelberg, Heidelberg, Germany;
3
Institute of Biostatistics, Leibniz University of Hannover, Hannover, Germany;
4
Institute of Experimental Psychology,
University of Regensburg, Regensburg, Germany;
5
Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, University of Heidelberg,
Heidelberg, Germany;
6
University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA;
7
Department of Internal Medicine VI, University of Heidelberg,
Heidelberg, Germany;
8
Section of Psychiatric Genetics, Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Go
¨ttingen, Germany
Correspondence: Professor T Stu¨ rmer, MD, MPH, PhD, UNC Gillings School of Global Public Health, McGavran Greenberg Campus, Box 7435, Chapel Hill, NC 27599-7435, USA or
Professor TG Schulze, MD, Section of Psychiatric Genetics, Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-University, Von-Siebold-Street 5,
37075 Go
¨ttingen, Germany.
E-mail: til.sturmer@post.harvard.edu or thomas.schulze@med.uni-goettingen.de
9
These authors contributed equally to this work.
Molecular Psychiatry (2013) 18, 607 -- 613
&
2013 Macmillan Publishers Limited All rights reserved 1359-4184/13
www.nature.com/mp
this sex-specific association was not supported by a previous
study in a larger data set of 4387 bipolar cases and 6209 control
subjects,
8
sex differences in disease prevalence, age at onset,
disease course and clinical features of affective disorders and
schizophrenia
17--22
add weight to the results of Dao et al.
10
Sex-specific differences in genetic architecture may account for
these observations, as highlighted by Ober et al.
23
The authors
concluded of their review of sex-specific gene regulation and
gene expression patterns in common human diseases and
disease-associated traits that these sex-specific patterns arise
from interactions between sex and genotype. These genotype-by-
sex interactions may manifest in a genotypic effect that is: (i)
apparent only in women; (ii) apparent only in men; or (iii) apparent
in both sexes but with differences in terms of the magnitude or
the direction of the effect. The genotype effects may be additive,
dominant or recessive. Important genotype-by-sex interaction
effects---particularly those showing opposite associations in men
and women---can only be detected if the study design and
statistical methods adequately address sex-specific effects.
23
On the basis of this reasoning and evidence from previous
studies, the aim of the present study was to investigate a potential
sex-specific association between rs1006737 and several person-
ality measures, resilience factors and depressive symptoms in a
large population-based cohort. Some of these traits have
repeatedly been proposed as endophenotypes for psychiatric
disorders, including neuroticism,extraversion,depressivity and
psychoticism (see, for example, ref. 12,15,24--26).
We also investigated the traits anger suppression,sense of
coherence,dispositional optimism and perceived social support as
potential endophenotypes. A previous factor analysis in the
present cohort revealed high-positive loadings of depressivity,
anger suppression and neuroticism, and high-negative loadings of
sense of coherence, dispositional optimism, perceived social
support and extraversion on a factor-labeled emotional lability.
27
Sense of coherence, perceived social support and dispositional
optimism are resilience factors.
28--31
Based on these results from previous studies, we hypothesized
a sex-specific association between the A-allele and high levels of
emotional lability, depressive symptoms and psychoticism. We
applied a two-factor interaction model that is specifically designed
to dissect genotype-by-sex interaction effects. We also contrasted
our sex-specific analysis with a simple non-sex-specific analysis.
METHODS
Study design and sample
The recruitment and follow-up of the cohort are described previously.
27,32,33
Between 1992 and 1995 a representative sample of 5114 adults (mostly
aged between 40 and 65 years) living in Heidelberg, Germany, completed
an extensive baseline self-report questionnaire concerning psychological
traits, lifestyle factors and co-morbidity. All participants provided written
informed consent to the re-assessment of their health status at 10-year-
follow-up. This included assessment of the cause of death where
appropriate and the study of the influence of psychological traits, lifestyle
factors and baseline diseases on the incidence of chronic diseases during
the 10-year-follow-up period (in particular cardiovascular disease and
cancer). In addition to the self-report questionnaire (sent out between
2002 and 2003), participants were asked to provide a mouthwash sample
for the genetic analyses.
34
Participants who did not reply and could not be
reached by telephone were followed up through population registries.
At follow-up, 4010 participants from the original cohort completed the
follow-up questionnaire, 847 declined further participation and 257 had
died. Of those participants who returned the follow-up questionnaire, 95%
provided written informed consent for genetic analyses and a mouthwash
sample for DNA extraction.
Only those participants with genotype data for rs1006737 were included
in the present sample, which comprised 1804 men (47.6%; mean age
53.5±7.1 years) and 1989 women (52.4%; mean age 52.8±7.0 years).
Measures
At baseline, all participants were assessed using the following personality
questionnaires: (i) the Eysenck-Personality-Inventory
35
for neuroticism and
extraversion; (ii) the State-Trait Anger Expression Inventory
36
for anger
suppression; (iii) the Sense of Coherence Scale
37
for perceived comprehen-
sibility (structured, predictable, explicable), manageability and mean-
ingfulness (challenges, worthy of investment and engagement) of
internal and external demands; (iv) the German-language Fragebogen zur
Sozialen Unterstu¨tzung
38
for perceived and anticipated support from the
social environment; (v) the Life Orientation Test
39
for dispositional
optimism; (vi) the depressivity scale of Zerssen;
40
and (vii) the psychoticism
scale of Baumann and Dittrich.
41
The criteria used to select these scales
and their reliability are described elsewhere.
27,32
Personality assessment was not repeated at 10-year follow-up. However,
to allow testing of the association between rs1006737 and symptoms of
major depression, three items were used to measure depressive symptoms
at follow-up (‘how often within the past 4 weeks did you feel (1) full of
energy, (2) calm and even-tempered, (3) sad and discouraged’?). Each of
these items was rated on a six-point scale.
Genotyping and quality control
DNA was extracted from epithelial cells obtained from mouthwash
samples.
42
Genotyping was performed on Applied Biosystems 7900HT
Fast Real-Time PCR (PCR; Applied Biosystems, Darmstadt, Germany) System
using the TaqMansSNP Genotyping Assay ID C_2584015_10 (Applied
Biosystems). Genotyping accuracy was assessed by running 15% of the
sample in duplicates. Reproducibility was 100%.
Statistical analyses
Analyses of descriptive data analyses were performed using IBM SPSS
statistics 19.0 (SPSS, 2010, Chicago, IL, USA, http://www.spss.com). All other
analyses were performed using R.
43
Most of the investigated phenotypes
represent sums of counts and are thus skewed. Therefore, a non-parametric
approach was used to allow analysis of categorical data with any type of
distribution and level of variance heterogeneity.
44
For almost all relevant
phenotypes, a global genotype-by-sex interaction exists (Po0.10). Thus, the
test for association was performed separately for men and women. The
association between phenotype and the three genotypes of SNP rs1006737
was analyzed using a maximum test, which includes the additive, recessive
and dominant modes of inheritance. A related approach has been
described for case--control data.
44
Two-tailed tests were used, and the
resulting P-values were adjusted for the number of inheritance modes.
These P-values were estimated using the R package nparcomp.
45
These sex-
specific analyses were contrasted with a simple non-sex-specific association
testing using PLINK-similar linear regression analysis.
Power calculations were performed using Quanto 1.2 (http://hydra.us-
c.edu/gxe/). For these, we assumed an additive model and various risk
allele frequencies ranging from 0.3 to 0.36. Effect sizes (r
2
) for the genetic
variant and sex were based on effect sizes of rs1006737 on neuroticism
reported in the literature, and were 0.0491 (ref. 12) and 0.0231 (ref. 46),
respectively. Effect size (r
2
) of the genotype-by-sex interaction was based on
the interaction effect between rs1006737 and sex for bipolar disorder and
depression reported by Dao et al.,
10
as estimates for neuroticism are not
available. This was 0.0076.
RESULTS
Genotyping
A total of 389 subjects were A homozygotes (0.1); 1543 were AG
heterozygotes (0.41); and 1861 were G homozygotes (0.49). The
genotype frequencies did not deviate from Hardy--Weinberg
equilibrium (P¼0.62).
Power analyses
The power analysis generated power estimates of 40.99. for the
genetic variant, sex and genotype-by-sex interaction. These power
estimates are not corrected for multiple testing, as Bonferroni
CACNA1C and personality traits, resilience factors and depressive symptoms
J Strohmaier et al
608
Molecular Psychiatry (2013), 607 -- 613 &2013 Macmillan Publishers Limited
correction for multiple testing would have resulted in an
underestimation of power, given the inter-correlation between
personality measures and depressive symptoms (Table 1).
Descriptive analyses
Table 1 shows the Pearson correlation coefficients for the
personality scales. Table 2 shows the demographic and personality
characteristics of the participants according to genotype status.
Association testing for personality measures
The simple non-sex-specific genotype--phenotype association
analysis did not reveal any significant results (Table 2) in contrast
to the sex-specific analyses shown in Table 3: (i) P-values of the
genotype-by-sex interactions; (ii) modes of inheritance multi-
plicity-adjusted P-values; and (iii) likely modes of inheritance. Clear
sex-specific associations were observed for neuroticism,sense of
coherence,dispositional optimism,perceived social support and
depressive symptoms at follow-up. Mode of inheritance, assuming
an additive, dominant or recessive mode, is reported for the
respective risk alleles in the present data set, that is, the A-allele in
men and the G-allele in women. The interaction plots according to
Ober et al.
23
for sense of coherence, perceived social support and
depressive symptoms at follow-up are shown in Figures 1--3.
Neuroticism. A significant dominant mode of inheritance was
observed in women only, with carriers of the AA-genotype scoring
lower on neuroticism than G-allele carriers.
Sense of coherence. A significant additive mode of inheritance was
observed in men, with the lowest scores being observed in carriers
of the AA-genotype and the highest scores in GG-homozygotes. A
dominant mode of inheritance was observed in women, with
carriers of the AA-genotype scoring higher on sense of coherence
than G-allele carriers.
Dispositional optimism. A significant additive mode of inheritance
was observed in men only, with the lowest scores being observed
in carriers of the AA-genotype and the highest scores in GG-
homozygotes.
Perceived social support. A significant recessive mode of inheri-
tance was observed in men, with carriers of the AA-genotype
scoring lower on perceived social support than G-allele carriers. A
dominant mode of inheritance was observed in women, with
carriers of the AA-genotype scoring higher on perceived social
support than G-allele carriers.
Depressive symptoms at follow-up. A significant additive mode of
inheritance was observed in men, with the highest scores being
observed in carriers of the AA-genotype and the lowest scores in
GG-homozygotes. A dominant mode of inheritance was observed
in women, with carriers of the AA-genotype scoring lower on
depressive symptoms at follow-up than G-allele carriers.
DISCUSSION
The aim of the present study was to investigate a possible sex-
specific association between the widely studied CACNA1C risk
variant rs1006737 and personality traits, resilience factors and
depressive symptoms in the general population. These may be
Table 1. Pearson correlation matrix for personality measures at baseline
D AI N SOC LOT SozU E P DS at follow-up
D 1 0.444** 0.659** 0.623** 0.442** 0.399** 0.178** 0.173** 0.442**
AI 1 0.452** 0.416** 0.316** 0.330** 0.209** 0.086** 0.256**
N10.606** 0.407** 0.295** 0.065** 0.123** 0.432**
SOC 1 0.525** 0.531** 0.202** 0.178** 0.431**
LOT 1 0.392** 0.221** 0.148** 0.309**
SozU 1 0.252** 0.209** 0.262**
E 1 0.116** 0.116**
P 1 0.106**
DS at follow-up 1
Abbreviations: AI, anger suppression; D, depression (Zerssen); DS at follow-up, depressive symptoms at follow-up; E, extraversion; LOT, dispositional optimism;
N, neuroticism; P, psychoticism; SOC, sense of coherence; SozU, perceived social support.
**P-value of correlation r0.01.
Table 2. Demographic, personality characteristics and depressive symptoms at follow-up according to genotype status; and F and P-values of the
linear regression analyses for the genotype effect
AA AG GG F P
Baseline
N 389 1543 1861
Age (years) 52.42 (7.23) 52.48 (7.0) 52.81 (7.11)
Personality M (s.d.) M (s.d.) M (s.d.)
Depression (Zerssen) 7.03 (5.70) 7.00 (5.77) 6.96 (5.67) 0.0546 0.8153
Anger suppression 16.27 (3.84) 16.73 (4.16) 16.79 (4.18) 3.3022 0.0693
Neuroticism 8.27 (5.27) 8.30 (5.2) 8.30 (5.01) 0.0061 0.9378
Sense of coherence 49.15 (6.18) 48.58 (7.06) 48.88 (6.95) 0.0148 0.9033
Dispositional optimism 28.56 (4.10) 28.41 (4.53) 28.55 (4.50) 0.1668 0.6830
Perceived social support 94.70 (12.52) 93.83 (12.48) 94.40 (11.96) 0.1245 0.7243
Extraversion 11.21 (3.80) 11.07 (3.74) 10.97 (3.77) 1.3463 0.2460
Psychoticism 1.78 (2.25) 1.75 (1.78) 1.79 (1.89) 0.1220 0.7269
Depressive symptoms at follow-up 7.64 (2.61) 7.63 (2.65) 7.59 (2.66) 0.2483 0.6183
CACNA1C and personality traits, resilience factors and depressive symptoms
J Strohmaier et al
609
Molecular Psychiatry (2013), 607 -- 613&2013 Macmillan Publishers Limited
considered endophenotypes for affective disorders and schizo-
phrenia. Based on evidence from the literature, we hypothesized a
sex-specific association between the A-allele and (i) high levels of
emotional lability, as reflected in depressivity, anger suppression,
neuroticism, sense of coherence, dispositional optimism, per-
ceived social support and extraversion scores; (ii) high levels of
depressive symptoms; or (iii) high levels of psychoticism. We
studied a total of nine measures, some of which had never been
studied in a genetic association study of the general population.
Simple non-sex-specific genotype--phenotype association ana-
lysis did not reveal any significant result. In contrast, for five of
these nine measures, significant sex-specific associations with
rs1006737 were observed. Neuroticism,sense of coherence,
dispositional optimism,perceived social support and depressive
symptoms at follow-up showed significant genotype-by-sex inter-
active effects and opposite associations with rs1006737 in men
and women.
Our findings are consistent with those of a previous report,
which indicated a sex-specific influence of 15 SNPs within the
CACNA1C gene on the risk for bipolar disorder and depression.
10
In
a large combined bipolar disorder and major depression data set,
the A-allele of rs1006737 was associated with an increased risk for
bipolar disorder and major depression in women (odds
ratio ¼1.17; P¼0.025), but not in men (odds ratio ¼0.94;
P¼0.36). The sex-specific influence of rs1006737 showed only
nominal significance. However, statistical significance was ob-
served for rs2370419 and rs2470411, which are in partial linkage
disequilibrium with rs1006737.
10
The only other large study of
20
30
40
50
60
AA
n = 378
AG
n = 1511
GG
n = 1817
Genotype
Sense of Coherence
sex
1
2
Figure 1. Interaction plots according to Ober et al.
23
for sense of
coherence (1 ¼men, 2 ¼women).
Table 3. P-values of the univariate ANOVA in a 2-factor interaction model (genotype-by-sex interactions) and adjusted P-values of the mode-of-
inheritance max-test
Phenotype
Genotype-by-sex
interaction Pooled over sex analysis
Males only
risk allele: A
Females only
risk allele: G
Depressivity (Zerssen) 0.072 Sex-specific analysis required NS NS
Anger suppression 0.30 Sex-specific analysis not required
Neuroticism 0.0202 Sex-specific analysis required NS 0.022 Dominant for
G-allele
Sense of coherence 0.00012 Sex-specific analysis required 0.021 Additive 0.00028 Dominant for
G-allele
Dispositional optimism 0.084 Sex-specific analysis required 0.032 Additive NS
Perceived social support 0.0028 Sex-specific analysis required 0.018 Recessive for
A-allele
0.010 Dominant for
G-allele
Extraversion 0.166 Sex-specific analysis not required
Psychoticism 0.0441 Sex-specific analysis required NS NS
Depressive symptoms at follow-up 0.0018 Sex-specific analysis required 0.007 Additive 0.035 Dominant for
G-allele
Abbreviation: NS, not significant.
40
60
80
100
AA
n = 374
AG
n = 1478
GG
n = 1791
Genotype
Perceived Social Support
sex
1
2
Figure 2. Interaction plots according to Ober et al.
23
for perceived
social suppor t (1 ¼men, 2 ¼women).
5
10
15
AA
n = 374
AG
n = 1492
GG
n = 1812
Genotype
Depressive Symptoms at Follow−Up
sex
1
2
Figure 3. Interaction plots according to Ober et al.
23
for depressive
symptoms at follow-up (1 ¼men, 2 ¼women).
CACNA1C and personality traits, resilience factors and depressive symptoms
J Strohmaier et al
610
Molecular Psychiatry (2013), 607 -- 613 &2013 Macmillan Publishers Limited
potential sex-specific effects for CACNA1C is the genome-wide
association study by Ferreira et al.,
8
who reported no such effects.
Whereas in the study of Dao et al.,
10
the A-allele was associated
with an increased risk of affective disorder in women, in the
present cohort the A-allele was associated with increased
emotional lability and depressive symptoms at follow-up in men.
Although emotional lability and depressive symptoms at follow-up
are not necessarily a proxy for affective disorder, they may be
considered a potential endophenotype. Thus, the finding of
opposite effects in our cohort compared with that of Dao et al.
10
warrants further discussion. A likely explanation is the difference in
sample design and ascertainment. Dao et al.
10
performed a case--
control study and combined samples from different sources.
Furthermore, they excluded around 35% of control subjects due to
a history of affective disorder. The use of ‘super-normals’ in case--
control studies has drawn repeated criticism from the field of
epidemiology on the grounds that it may introduce major
biases.
47--49
In the case of alleles that confer sex-specific disease
vulnerability, this approach---as applied by Dao et al.
10
---could
result in an underrepresentation of risk alleles in the control
group. The potential bias introduced by the use of super-normals
however does not explain why we did observe an association
with opposite alleles. Nevertheless it is important to emphasize
that the present study was based on a uniformly ascertained
epidemiological cohort from the general population of a well-
defined catchment area. In comparison to studies based on
super-normals, population-based samples may alter the asso-
ciation findings. Support for our results is provided by a study
reporting an association between the A-allele of rs1006737 and
decreased baseline depression and the likelihood of insomnia
in the STAR*D sample. This sample was comprised of individuals
treated for major depression, and the proportion of females was
64%.
16
The sex-specific associations observed in the present cohort are
consistent with the genotype-by-sex interaction models proposed
by Ober et al.
23
For example, for sense of coherence, the genotypic
effect was additive in men and dominant in women, although
with opposite directions of effect. These effects would have been
overlooked in a pooled-only analysis inadequately modeling and
thus masking genotype-by-sex interactions.
23
It is important to
emphasize the consistency of the direction of the sex-specific
associations observed in the present cohort. For the measures
sense of coherence,dispositional optimism,perceived social support
and depressive symptoms at follow-up, the A-allele conferred
vulnerability to emotional lability and decreased resilience in men.
In contrast, for the measures neuroticism,sense of coherence,
perceived social support and depressive symptoms at follow-up
vulnerability to these effects was conferred by the G-allele in
women.
The results of formal genetic and association studies support
the hypothesis of sex-specific effects for affective disorders and
schizophrenia. Formal genetic studies suggest sex-specific genetic
effects for depression and neuroticism.
50
Sex-specific genetic
associations with affective disorders and schizophrenia have been
reported, for example, for CREB1,COMT and RELN.
51--54
Further, sex
differences have been observed in terms of prevalence, risk, co-
morbidity, course, clinical features and/or age at onset (see
Introduction).
Three of the newly studied potential endophenotypes---sense of
coherence, perceived social support and dispositional optimism---
are resilience factors.
28--31
Although, they are negatively correlated
with neuroticism,
55--57
they explain additional variation in disease
outcome: after adjustment for neuroticism, sense of coherence is
still associated with all-cause mortality,
58
perceived social support
with outcome in depression
59,60
and dispositional optimism with
depression.
57
A substantial proportion of both the genetic
vulnerability to major depression and of genetic covariance
between major depression and generalized anxiety disorder
derives from factors that are not shared with neuroticism.
61,62
This may be explained by a lack of overlap between neuroticism
and facets of these resilience factors and other personality factors.
Although neuroticism,sense of coherence,dispositional optimism
and perceived social support are correlated (see Table 1), each
factor may explain a unique proportion of the genetic vulnerability
to affective disorder and schizophrenia. In the present data, clear
genetic associations exist for sense of coherence, perceived social
support and dispositional optimism. rs1006737 may therefore be
associated with vulnerability to affective disorders and schizo-
phrenia. Besides neuroticism, this vulnerability may be also
reflected in the resilience factors sense of coherence, social
support and dispositional optimism, that is, in decreased resilience
and competent functioning.
The most robust association was observed for sense of
coherence in women. Sense of coherence reflects an individual’s
resources to successfully cope with demanding external and
internal events and is based on the concept of salutogenesis.
37
Salutogenesis equally focuses on factors that support health as
well as on factors that cause disease and defines a continuum
between health-ease and dis-ease. The concept reflects well the
interplay of genetic and environmental protective and risk factors
in the development of psychiatric diseases. Instead of classifying
individuals into cases and controls, the concept suggests
positioning each individual on a continuum according to his/her
resilience and vulnerability. The present finding illustrates that
genetic association studies basing their analyses on vulnerability
and risk factors---that is, on quantitative endophenotypes asso-
ciated with the disease---rather than on dichotomous disease
status have the potential to elucidate the pathogenic mechanisms
underlying the association between vulnerability genes and
psychiatric disorders.
The present study had several strengths. First, the sample size
was sufficiently large and well powered to detect small genetic
effects. Second, the phenotype characterization was extensive and
involved use of reliable and validated rating scales. Third, different
facets of personality were assessed, including resilience factors
and competent functioning. Finally, we applied an analytical
method that allowed investigation of possible sex-specific
genotypic effects.
The study also had several possible limitations. First, the
participants of a longitudinal population-based study that requires
the completion of a long questionnaire may be psychologically
and physically healthier than non-responders or dropouts. In
addition, genetic information was only available for a selected
group, who survived approximately 10 years from baseline. In fact,
participation at follow-up was associated with higher emotional
stability, lower psychoticism and superior general health status.
27
If rs1006737 does confer vulnerability, this could result in an
underrepresentation of the risk allele and a reduction in
differences between genotypes. However, genotypes frequencies
were in Hardy--Weinberg equilibrium, and we may therefore
exclude this possibility in the present cohort. Second, even though
personality traits may be closer to biological disease correlates
than psychiatric diagnoses, their etiology is also complex and
dependent on the interplay between multiple loci and environ-
mental factors (see, for example, ref. 50,63). The present study
investigated a single-locus association within the context of a
complex interaction between genetic variants and environment.
Third, the effect size estimate of the genetic variant was based on
the effect reported by Erk et al.
12
In this first and only previous
study of the association between rs1006737 and neuroticism, the
effect was extremely high (winner’s curse). A more realistic effect
estimate for the genetic variant of r
2
¼0.00052, based on the
effect reported by Dao et al.,
10
returns power estimates of 40.99
for the genotype-by-sex interaction, and strongly reduces power
estimates for the main effect of the genetic variant. However, in
contrast to the effect estimate of Erk et al.,
12
the effect estimate of
CACNA1C and personality traits, resilience factors and depressive symptoms
J Strohmaier et al
611
Molecular Psychiatry (2013), 607 -- 613&2013 Macmillan Publishers Limited
Dao et al.
10
does not refer to neuroticism. Finally, our results were
not corrected for multiple testing. Bonferroni correction for
multiple testing (32 tests) resulted in a significance level of
P¼0.0016, and only the results for sense of coherence in women
remained significant. Considering the inter-correlation of the nine
measures assessed, we prefer to report nominal levels of
significance. Our rationale for this is that in the case of inter-
correlation, Bonferroni correction for multiple testing is likely to
provide an inadequate reduction of the power to detect small
effects.
In summary, the results of the present cohort support the
hypothesis of a sex-specific influence of the SNP rs1006737 within
CACNA1C on traits associated with emotional lability and resilience
in the general population. Our findings are important, as they
support the hypothesis of a correlation between psychiatric
vulnerability genes and personality traits, resilience factors and
depressive symptoms in the general population. They also
emphasize the importance of detailed phenotype characterization
in psychiatric genetic studies in ensuring coverage of the entire
continuum from competent to maladaptive functioning.
64
A
further important aspect of our findings is their support for the
hypothesis of a sex-specific mode of inheritance for rs1006737,
which results in sex-specific genotypic effects. Future genetic
association analyses should consider these sex-specific genotypic
effects and apply appropriate analytical methods.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
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.
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