E.J.C. de Geus

Effects of Work Stress on Ambulatory Blood Pressure, Heart Rate, and Heart Rate Variability

Work stress has repeatedly been associated with an increased risk for cardiovascular disease. This study tested whether this relationship could be explained by exaggerated cardiovascular reactivity to work or impaired recovery in leisure time. Vagal tone was assessed as a possible determinant of these work stress effects. Participants included 109 male white-collar workers (age, 47.2+/-5. 3) who were monitored on 2 workdays and 1 nonworkday for ambulatory blood pressure, heart rate, and heart rate variability. Chronic work stress was defined according to Siegrists model as (1) high imbalance, a combination of high effort and low reward at work, or (2) high overcommitment, an exhaustive work-related coping style indexing the inability to unwind. All findings were adjusted for possible differences in posture and physical activity between the work stress groups. High imbalance was associated with a higher heart rate during work and directly after work, a higher systolic blood pressure during work and leisure time, and a lower 24-hour vagal tone on all 3 measurement days. Overcommitment was not associated with an unfavorable ambulatory profile. Logistic regression analysis revealed that heart rate [odds ratio 1-SD increase 1.95 (95% CI, 1.02 to 3.77)] and vagal tone [odds ratio 1-SD decrease 2.67 (95% CI, 1.24 to 5.75)] were independently associated with incident mild hypertension. Surprisingly, the values during sleep were more predictive for mild hypertension than the values during work. The results from the present study suggest that the detrimental effects of work stress are partly mediated by increased heart rate reactivity to a stressful workday, an increase in systolic blood pressure level, and lower vagal tone.

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10−7 for rs2715148 and 1.2 × 10−6 for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 × 10−8 for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

The heritability of general cognitive ability increases linearly from childhood to young adulthood

Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite lifes ‘slings and arrows of outrageous fortune’, do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype–environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.

Genetic contributions to human brain morphology and intelligence

Variation in gray matter (GM) and white matter (WM) volume of the adult human brain is primarily genetically determined. Moreover, total brain volume is positively correlated with general intelligence, and both share a common genetic origin. However, although genetic effects on morphology of specific GM areas in the brain have been studied, the heritability of focal WM is unknown. Similarly, it is unresolved whether there is a common genetic origin of focal GM and WM structures with intelligence. We explored the genetic influence on focal GM and WM densities in magnetic resonance brain images of 54 monozygotic and 58 dizygotic twin pairs and 34 of their siblings. For genetic analyses, we used structural equation modeling and voxel-based morphometry. To explore the common genetic origin of focal GM and WM areas with intelligence, we obtained cross-trait/cross-twin correlations in which the focal GM and WM densities of each twin are correlated with the psychometric intelligence quotient of his/her cotwin. Genes influenced individual differences in left and right superior occipitofrontal fascicle (heritability up to 0.79 and 0.77), corpus callosum (0.82, 0.80), optic radiation (0.69, 0.79), corticospinal tract (0.78, 0.79), medial frontal cortex (0.78, 0.83), superior frontal cortex (0.76, 0.80), superior temporal cortex (0.80, 0.77), left occipital cortex (0.85), left postcentral cortex (0.83), left posterior cingulate cortex (0.83), right parahippocampal cortex (0.69), and amygdala (0.80, 0.55). Intelligence shared a common genetic origin with superior occipitofrontal, callosal, and left optical radiation WM and frontal, occipital, and parahippocampal GM (phenotypic correlations up to 0.35). These findings point to a neural network that shares a common genetic origin with human intelligence.

Poor replication of candidate genes for major depressive disorder using genome-wide association data.

Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case–control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95–1.29; OR TT=1.21, 95% confidence interval (CI) 1.01–1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55–0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13–1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.

Heritability of cortisol levels: review and simultaneous analysis of twin studies

Cortisol has a pivotal role in physical and mental health, but relatively few studies have paid attention to individual differences in cortisol levels and the etiology of these differences, in particular their possible genetic basis. In this article we review the existing literature on the heritability of cortisol levels. Most of the studies, which have been carried out in genetically informative samples, lack methodological consistency with regard to frequency and timing of sample collection. The circadian rhythm in cortisol levels was often not taken into account. A power analysis shows that none of these studies used adequate sample sizes to distinguish genetic from shared environmental influences as a cause for familial aggregation. Results of a simultaneous analysis of 5 comparable twin studies suggest a heritability of 62%. Hence, we conclude that, to understand the contribution of genetic and (shared) environmental influences to variation in basal cortisol levels, future studies should be designed more rigorously with strict collection and sampling protocols, sufficient sample size and repeated measures across multiple days.

Meta-analysis of genome-wide association studies for personality

Personality can be thought of as a set of characteristics that influence peoples thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in 10 discovery samples (17 375 adults) and five in silico replication samples (3294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data of ∼2.4M single-nucleotide polymorphisms (SNPs; directly typed and imputed using HapMap data) were available. In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P=2.8 × 10−8 and 3.1 × 10−8) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P=4.9 × 10−8). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.

Are smarter brains running faster? Heritability of alpha peak frequency, IQ, and their interrelation.

It has often been proposed that faster central nervous system (CNS) processing amounts to a smarter brain. One way to index speed of CNS processing is through the assessment of brain oscillations via electroencephalogram (EEG) recordings. The dominant frequency (peak frequency) with which neuronal feedback loops in an adult human brain oscillate in a relaxed state is around 10 cycles/sec, but large individual differences exist in peak frequencies. Earlier studies have found high peak frequencies to be associated with higher intelligence. In the present study, data from 271 extended twin families (688 participants) were collected as part of a large, ongoing project on the genetics of adult brain function and cognition. IQ was assessed with the Dutch version of the Wechsler Adult Intelligence Scale (WAIS-IIIR), from which four dimensions were calculated (verbal comprehension, working memory, perceptual organization, and processing speed). Individual peak frequencies were picked according to the method described by Klimesch (1999) and averaged 9.9 Hz (SD 1.01). Structural equation modeling indicated that both peak frequency and the dimensions of IQ were highly heritable (range, 66% to 83%). A large part of the genetic variance in alpha peak frequency as well as in working memory and processing speed was due to nonadditive factors. There was no evidence of a genetic correlation between alpha peak frequency and any of the four WAIS dimensions: Smarter brains do not seem to run faster.

Meta-Analysis of Genome-Wide Association Data of Bipolar Disorder and Major Depressive Disorder

Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder