From genotype to EEG endophenotype: a route for post-genomic understanding of complex psychiatric disease?

Twin and family studies have shown the importance of biological variation in psychiatric disorders. Heritability estimates vary from 50% to 80% for cognitive disorders, such as schizophrenia, attention deficit hyperactivity disorder and autism, and from 40% to 65% for affective disorders, such as major depression, anxiety disorders and substance abuse. Pinpointing the actual genetic variants responsible for this heritability has proven difficult, even in the recent wave of genome-wide association studies. Brain endophenotypes derived from electroencephalography (EEG) have been proposed as a way to support gene-finding efforts. A variety of EEG and event-related-potential endophenotypes are linked to psychiatric disorders, and twin studies have shown a striking genetic contribution to these endophenotypes. However, the clear need for very large sample sizes strongly limits the usefulness of EEG endophenotypes in gene-finding studies. They require extended laboratory recordings with sophisticated and expensive equipment that are not amenable to epidemiology-scaled samples. Instead, EEG endophenotypes are far more promising as tools to make sense of candidate genetic variants that derive from association studies; existing clinical data from patients or questionnaire-based assessment of psychiatric symptoms in the population at large are better suited for the association studies themselves. EEG endophenotypes can help us understand where in the brain, in which stage and during what type of information processing these genetic variants have a role. Such testing can be done in the more modest samples that are feasible for EEG research. With increased understanding of how genes affect the brain, combinations of genetic risk scores and brain endophenotypes may become part of the future classification of psychiatric disorders

Heritability of Problem Drinking and the Genetic Overlap with Personality in a General Population Sample

This study examined the heritability of problem drinking and investigated the phenotypic and genetic relationships between problem drinking and personality. In a sample of 5,870 twins and siblings and 4,420 additional family members from the Netherlands Twin Register. Data on problem drinking (assessed with the AUDIT and CAGE; 12 items) and personality [NEO Five-Factor Inventory (FFI); 60 items] were collected in 2009/2010 by surveys. Confirmatory factor analysis on the AUDIT and CAGE items showed that the items clustered on two separate but highly correlated (r = 0.74) underlying factors. A higher-order factor was extracted that reflected those aspects of problem drinking that are common to the AUDIT and CAGE, which showed a heritability of 40%. The correlations between problem drinking and the five dimensions of personality were small but significant, ranging from 0.06 for Extraversion to −0.12 for Conscientiousness. All personality dimensions (with broad-sense heritabilities between 32 and 55%, and some evidence for non-additive genetic influences) were genetically correlated with problem drinking. The genetic correlations were small to modest (between |0.12| and |0.41|). Future studies with longitudinal data and DNA polymorphisms are needed to determine the biological mechanisms that underlie the genetic link between problem drinking and personality

Evidence for genetic factors explaining the association between birth weight and low-density lipoprotein cholesterol and possible intrauterine factors influencing the association between birth weight and high-density lipoprotein cholesterol: Analysis in twins

Recent studies have demonstrated an association between low weight at birth and an atherogenic lipid profile in later life. To examine the influences of intrauterine and genetic factors, we investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. Regression analysis demonstrated that low birth weight was associated with high levels of total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (-0.17 mmol/liter per kg, P = 0.07; -0.18 mmol/liter per kg, P = 0.04; and -0.07 g/liter per kg, P = 0.02, respectively) and with low levels of high-density lipoprotein (HDL) cholesterol (+0.04 mmol/liter per kg, P = 0.1), after adjustment for age, sex, and body mass index. Intrapair differences in birth weight were significantly associated with differences in total cholesterol, LDL cholesterol, and apolipoprotein B in dizygotic twins after adjustment for differences in current body mass index (-0.49 mmol/liter per kg, P = 0.02; -0.51 mmol/liter per kg, P = 0.01; and -0.10 g/liter per kg, P = 0.04, respectively), demonstrating that the larger the difference in birth weight, the higher these risk factors in the twin with the lower birth weight, compared with the cotwin with the higher birth weight. In monozygotic twins, however, the associations between intrapair differences in birth weight and differences in total cholesterol, LDL cholesterol, and apolipoprotein B were in the opposite direction (+0.32 mmol/liter per kg, P = 0.03; +0.23 mmol/liter per kg, P = 0.08; and +0.06 g/liter per kg, P = 0.04, respectively). The association between intrapair differences in birth weight and differences in HDL cholesterol was not significant in dizygotic twins (+0.04 mmol/liter per kg, P = 0.6) and of borderline significance in monozygotic twins (+0.11 mmol/liter per kg, P = 0.05). These data suggest that genetic factors account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association between birth weight and HDL cholesterol

Genetic correlation of exercise with heart rate and respiratory sinus arrhythmia

Purpose: A twin design was used to test whether the association between exercise behavior and heart rate and the association between exercise behavior and respiratory sinus arrhythmia (RSA) derive from a common genetic factor. Methods: Data were available from 157 adolescent (aged 13-22) and 208 middle-aged twin pairs (aged 35-62), divided into five sex by zygosity groups (male and female monozygotic twin pairs, and dizygotic twin pairs of same or opposite sex). Exercise behavior was assessed as the average weekly METs spent on sports activities or other vigorous activities in leisure time (sportMETS) in the last 3 months. RSA and heart period (HP) were assessed in the time domain from the combined ECG and respiration signals. Results: Heritability estimates were 16% and 29% for RSA, 64% and 68% for HP, and 79% and 41% for sportMETS in young and middle-aged twins, respectively. A significant association was found between RSA and sportMETS (0.17) in the adolescent twins that derived entirely from a common genetic factor. No association was found between sportMETS and RSA in the older twins. A significant association was found between HP and sportMETS in both adolescent (0.35) and middle-aged (0.18) twins. A large contribution of common genetic factors to these associations was found amounting to 84% and 88% in the young and middle-aged twins, respectively. Conclusions: Although the results of this study do not preclude causal effects of exercise on RSA and heart rate, they show that the association between exercise and these cardiovascular risk factors largely derives from a common genetic factor

Resting heart rate and antisocial behaviour: a Mendelian randomisation study

Observational studies frequently report phenotypic associations between low resting heart rate (RHR) and higher levels of antisocial behaviour (ASB), although it remains unclear whether this relationship reflects causality. To triangulate evidence, we conducted two-sample univariable Mendelian randomisation (MR), multivariable MR and linkage disequilibrium score regression (LDSC) analyses. Genetic data were accessed from published genome-wide association studies (GWAS) for RHR (n = 458,835) and ASB (n = 85,359) for the univariable analyses, along with a third GWAS for heart rate variability (HRV; n = 53,174) for all other analyses. Genome-wide significant (p < 5 × 10-8) single-nucleotide polymorphisms associated with RHR (n = 278) were selected as instrumental variables and the outcome was a composite measure of ASB. No causal association was observed between RHR and ASB (BIVW =  - 0.0004, p = 0.841). The multivariable MR analyses including RHR and HRV also suggested no causal associations (BIVW = 0.016, p = 0.914) and no genetic correlations between the heart rate measures and ASB were observed using LDSC (rg = 0.057, p = 0.169). Sensitivity analyses suggested that our results are not likely to be affected by heterogeneity, pleiotropic effects, or reverse causation. These findings suggest that individual differences in autonomic nervous system functioning indexed by RHR are not likely to directly contribute to the development of ASB. Therefore, previously observed associations between RHR and ASB may arise from confounding, reverse causation, and/or additional study characteristics. Further causally informative longitudinal research is required to confirm our findings, and caution should be applied when using measures of RHR in interventions targeting ASB