H. Snieder

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 and stability of resting blood pressure

We examined the contribution of genetic and environmental influences to variation in resting systolic (SBP) and diastolic (DBP) blood pressure in participants from 4 twin studies carried out between 1986 and 2003. A total of 1577 subjects (682 males, 895 females) participated. There were 580 monozygotic twins, 664 dizygotic twins and 333 of their siblings. The 4 studies sampled subjects in different age groups (average age 17, 32, 37, 44 years), allowing for comparison of the relative contribution of genetic and environmental factors across the first part of the life span. Blood pressure was assessed under laboratory conditions in 3 studies and by ambulatory monitoring in 1 study. Univariate analyses of SBP and DBP showed significant heritability of blood pressure in all studies (SBP h(2) 48% to 60%, DBP h(2) 34% to 67%). Overall, there was little evidence for sex differences in blood pressure heritability, and no evidence for differences in heritability due to measurement strategy (laboratory vs. ambulatory). For 431 subjects there were data from 2 or more occasions that allowed us to assess the tracking of blood pressure over time and to estimate the genetic and environmental contributions to blood pressure tracking. Correlations over time across an average period of 7.1 years (tracking) were between .41 and .70. Multivariate genetic analyses showed that blood pressure tracking was entirely explained by the same genetic factors being expressed across time. It was concluded that whole genome scans for resting blood pressure can safely pool data from males and females, laboratory and ambulatory recordings, and different age cohorts.

Dissecting the genetic architecture of lipids, lipoproteins and apolipoproteins, Lessons from twin studies

We review the ways in which twin studies have been used to investigate the genetic architecture of lipids, lipoproteins, and apolipoproteins. We focus on the age dependency of genetic effects and the importance of pleiotropy for the lipid system. Finally, consequences are discussed of age dependency and pleiotropy for the design and power of twin studies aimed at detecting the actual quantitative trait loci (QTLs) involved. It is concluded that twin studies have played an important role and will remain highly valuable for the elucidation of the genetic architecture of lipids, lipoproteins, and apolipoproteins. Twins can efficiently be used to identify the location and function of QTLs. Taking account of pleiotropy and age-dependent gene expression in study design and data analysis will improve the power and efficiency to find these QTLs for components of the lipid system.

Developmental Genetic Trends in Blood Pressure Levels and Blood Pressure Reactivity to Stress

This chapter has two main aims. The first is to describe the changes in heritability of blood pressure levels and blood pressure reactivity that occur during the life span. The second is to disentangle the genetic and nongenetic causes of stability and change in these parameters. In order to achieve these goals, both empirical studies and developmental models will be discussed.

The psychophysiological effects of adrenaline infusions as a function of trait anxiety and aerobic fitness

Abstract This study compares changes in anxiety and cardiovascular variables elicited by intravenously infused adrenaline in 45 male university students who were selected on the basis of their trait anxiety. During the infusion cognitive anxiety, somatic anxiety, systolic blood pressure and heart rate increased and diastolic blood pressure and pre-ejection period decreased, dose-dependently. High trait anxiety was associated with higher levels of adrenaline-induced anxiety. Across all subjects, adrenaline-induced anxiety was inversely related to aerobic fitness. Emotional and cardiovascular reactivity was similar in low- and high-anxious subjects, but high autonomic instability may be associated with enhanced emotional reactivity to infused adrenaline. Thus, anxiety in the central nervous system can be elicited by a peripheral stimulant such as adrenaline, but controlling for physical fitness and autonomic lability may be necessary.

Influence of mental stress on fibrinogen, von Willebrand factor and tissue-type plasmonigen activator antigen

Summary To investigate the effect of mental stress on fibrinogen, von Willebrand factor (vWf) and tissue-type plasminogen activator antigen (t-PA:ag), blood samples were obtained before (ca. 10:45 AM) and after (ca. 1:30 PM) a period in which subjects were exposed to 3 mental stressors. Subjects were 61 males and 114 females aged 30–65 years. Fibrinogen, vWf and t-PA:ag decreased significantly during these mental stress tasks for both males and females. The decrease in fibrinogen and vWf may have largely been caused by a comparable decrease in hematocrit. The much stronger decline in t-PA:ag may have been due to a circadian rhythm. At any rate, neither males nor females showed an increase in fibrinogen, vWf or t-PA:ag. Probably the expected rise in coagulation and fibrinolysis in response to mental stressors has been overruled by circadian rhythms and/or factors influencing plasma volume.