We estimated the genetic and nongenetic (environmental) contributions to individual differences in the background EEG power spectrum in two age cohorts with mean ages of 26.2 and 49.4 years. ...Nineteen‐lead EEG was recorded with eyes closed from 142 monozygotic and 167 dizygotic twin pairs and their siblings, totaling 760 subjects. We obtained power spectra in 24 bins of 1 Hz ranging from 1.0 to 25.0 Hz. Generally, heritability was highest around the alpha peak frequency and lower in the theta and delta bands. In the beta band heritability gradually decreased with increasing frequency, especially in the temporal regions. Genetic correlations between power in the classical broad bands indicated that half to three‐quarters of the genetic variance can be attributed to a common source. We conclude that across the scalp and most of the frequency spectrum, individual differences in adult EEG are largely determined by genetic factors.
Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance of one or multiple proteins. Here we introduce a powerful strategy that integrates gene ...expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated with complex traits. We leverage expression imputation from genetic data to perform a transcriptome-wide association study (TWAS) to identify significant expression-trait associations. We applied our approaches to expression data from blood and adipose tissue measured in ∼ 3,000 individuals overall. We imputed gene expression into GWAS data from over 900,000 phenotype measurements to identify 69 new genes significantly associated with obesity-related traits (BMI, lipids and height). Many of these genes are associated with relevant phenotypes in the Hybrid Mouse Diversity Panel. Our results showcase the power of integrating genotype, gene expression and phenotype to gain insights into the genetic basis of complex traits.
The heritability of sensation seeking is investigated in an extended twin design, including mono- and dizygotic twins and their siblings. Besides a comparison of the phenotypic resemblance between ...monozygotic twins and dizygotic twins, the design allows for an explicit test of the assumption that results from twins may be generalized to the singleton population. Secondly, the design offers the opportunity to investigate to what extent the influence of common environment is the same for males and females and for twins and siblings, i.e. allowing for explicit tests of a special twin environment and of a sex-specific common environment. The results indicate that individual variation in sensation seeking is heritable, with few differences between males and females in heritability estimates for the sensation seeking dimensions. In contrast to prior studies, evidence is found for common environmental influences for thrill and adventure seeking in males, and experience seeking and boredom susceptibility in females. Evidence for a special twin environment was limited to boredom susceptibility in females.
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 life's '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.
The question whether symptom-free migraine patients show cognitive impairments compared to matched control subjects is addressed, and also whether migraine patients show transient cognitive ...impairments induced by an attack. The Neuropsychological Evaluation System (NES2) was administered once in an interictal period and twice within 30 h after different migraine attacks. Since cognitive impairments could be related to attack duration or severity, cognitive performance was compared during a postictal period after sumatriptan use and during a postictal period after habitual nonvasoactive medication use. Twenty migraineurs without aura, 10 migraineurs with aura, and 30 matched headache-free controls participated in the study. During a headache-free period, migraineurs without aura responded as quickly as controls, while migraineurs with aura were slower than controls during all tasks specifically requiring selective attention. These effects were not aggravated by a preceding migraine attack, irrespective of medication use and attack duration.
Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results ...from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.
Genomes of men and women differ in only a limited number of genes located on the sex chromosomes, whereas the transcriptome is far more sex-specific. Identification of sex-biased gene expression will ...contribute to understanding the molecular basis of sex-differences in complex traits and common diseases.
Sex differences in the human peripheral blood transcriptome were characterized using microarrays in 5,241 subjects, accounting for menopause status and hormonal contraceptive use. Sex-specific expression was observed for 582 autosomal genes, of which 57.7% was upregulated in women (female-biased genes). Female-biased genes were enriched for several immune system GO categories, genes linked to rheumatoid arthritis (16%) and genes regulated by estrogen (18%). Male-biased genes were enriched for genes linked to renal cancer (9%). Sex-differences in gene expression were smaller in postmenopausal women, larger in women using hormonal contraceptives and not caused by sex-specific eQTLs, confirming the role of estrogen in regulating sex-biased genes.
This study indicates that sex-bias in gene expression is extensive and may underlie sex-differences in the prevalence of common diseases.
Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated ...with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in 1) tau load and 2) spatial distribution of tau, measured with 18Fflortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic 18Fflortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18Fflortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial 18Fflortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18Fflortaucipir BPND. On visual inspection, Alzheimer's disease-like 18Fflortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18Fflortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; p = 0.01), neocortical (r = 0.59; p < 0.01) and global (r = 0.56; p < 0.01) regions, but not in the temporal region (r = 0.20; p = 0.10). The 18Fflortaucipir distribution pattern was significantly more similar between twins of the same pair (mean r = 0.27; SD = 0.09) than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (p < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18Fflortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18Fflortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37<β<0.56), physical activity (-0.41<β<-0.42) and social activity (-0.32<β<-0.36) (all p < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies.
Abstract
The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates ...the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association.
We included 78 cognitively unimpaired identical twins with 18Fflutemetamol (amyloid-β)-PET, 18Fflortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis.
At the individual level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (β = −0.37, P = 0.03) and memory functioning (β = −0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = −0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (β = −0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated, 51.6%).
Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.
Coomans & Tomassen et al. test associations between amyloid-β, tau, neurodegeneration and cognitive decline within pairs of identical twins using within-pair difference models, thereby ruling out potential confounding by genetic and shared environmental factors. The results are compatible with the amyloid cascade hypothesis.
To determine whether patients with different types of anxiety disorder (panic disorder, social phobia, generalized anxiety disorder) have higher heart rate and lower heart rate variability compared ...with healthy controls in a sample that was sufficiently powered to examine the confounding effects of lifestyle and antidepressants.
The standard deviation of the normal-to-normal intervals (SDNN), heart rate (HR), and respiratory sinus arrhythmia (RSA) were measured in 2059 subjects (mean age = 41.7 years, 66.8% female) participating in The Netherlands Study of Depression and Anxiety (NESDA). Based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) and Composite International Diagnostic Interview (CIDI), NESDA participants were classified as healthy controls (n = 616), subjects with an anxiety diagnosis earlier in life (n = 420), and subjects with current anxiety diagnosis (n = 1059).
Current anxious subjects had a significantly lower SDNN and RSA compared with controls. RSA was also significantly lower in remitted anxious subjects compared with controls. These associations were similar across the three different types of anxiety disorders. Adjustment for lifestyle had little impact. However, additional adjustment for antidepressant use reduced all significant associations between anxiety and HRV to nonsignificant. Anxious subjects who used a tricyclic antidepressant, a selective serotonin reuptake inhibitor, or another antidepressant showed significantly lower mean SDNN and RSA compared with controls (effect sizes = 0.20-0.80 for SDNN and 0.42-0.79 for RSA). Nonmedicated anxious subjects did not differ from controls in mean SDNN and RSA.
This study shows that anxiety disorders are associated with significantly lower HR variability, but the association seems to be driven by the effects of antidepressants.
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