Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association ...studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.
Paternal age and psychiatric disorders: A review de Kluiver, Hilde; Buizer‐Voskamp, Jacobine E.; Dolan, Conor V. ...
American journal of medical genetics. Part B, Neuropsychiatric genetics,
April 2017, Letnik:
174, Številka:
3
Journal Article
Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ ...twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.
Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption ...and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT.
To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases.
The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," r
=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (r
=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health.
This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.
The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we ...estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.
Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study ...meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.
An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.
One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.
Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.
Little is known about the age-specific prevalence of hoarding and obsessive compulsive symptoms (OCS), particularly in older age groups. The objectives of this study were to estimate the age-specific ...prevalence, severity, and relationships between hoarding and OCS in males and females using a large population-based sample.
We assessed the age-specific prevalence rates of hoarding disorder (HD) and OC disorder (OCD) in males and females (at various age ranges between 15 and 97 years) from the Netherlands Twins Register (N = 15,194). Provisional HD and OCD diagnoses were made according to Diagnostic and Statistical Manual of Mental Health Disorders, 5th Edition, criteria using self-report measures. We also assessed hoarding and OCS severity in the various age groups and explored specific hoarding and OCS patterns (e.g., difficulty discarding, excessive acquisition, clutter, checking, washing, perfectionism, and obsessions) with age.
Prevalence of provisional HD diagnoses (2.12%) increased linearly by 20% with every 5 years of age (z = 13.8, p < 0.0001) and did not differ between males and females. Provisional OCD diagnoses were most common in younger individuals and in individuals over age 65. Co-occurring OCD increased hoarding symptom severity (coefficient: 4.5; SE: 0.2; 95% CI: 4.1-4.9; t = 22.0, p < 0.0001). Difficulty discarding for HD and checking behaviors for OCD appeared to drive most increases in these diagnoses in older ages.
Increased prevalence and severity of HD with age appears to be primarily driven by difficulties with discarding. Increases in OCD prevalence with older age were unexpected and of potential clinical relevance.
Abstract
We investigate the influence of the classroom environment on educational performance and its dependency on parental socio-economic status (SES). The classroom environment can have a ...compensatory effect and decrease educational inequality, in which case the classroom context is more important for children originating from lower SES families. Alternatively, there can be an amplifying effect, in which case the classroom environment is more important for high-SES children. This would increase educational inequality. We investigate the two alternatives by applying a twin design to data from 4,216 twin pairs from the Netherlands Twin Register (birth cohorts 1991–2002). Some twin pairs share a classroom and other twins from the same pair are in different classrooms. We use this fact to decompose the variance in educational performance at the end of primary school into four components: genetic variance, classroom variance, shared environmental variance, and non-shared environmental variance. We find that of the total variance in educational performance, only a small part (2 per cent) can be attributed to differences between classrooms within schools. The influence of the classroom was larger when the level of parental SES was lower (up to 7.7 per cent) indicating a compensatory effect.
Urban life has been proposed as an environmental risk factor accounting for the increased prevalence of schizophrenia in urban areas. An alternative hypothesis is that individuals with increased ...genetic risk tend to live in urban/dense areas.
To assess whether adults with higher genetic risk for schizophrenia have an increased probability to live in more populated areas than those with lower risk.
Four large, cross-sectional samples of genotyped individuals of European ancestry older than 18 years with known addresses in Australia, the United Kingdom, and the Netherlands were included in the analysis. Data were based on the postcode of residence at the time of last contact with the participants. Community-based samples who took part in studies conducted by the Queensland Institute for Medical Research Berghofer Medical Research Institute (QIMR), UK Biobank (UKB), Netherlands Twin Register (NTR), or QSkin Sun and Health Study (QSKIN) were included. Genome-wide association analysis and mendelian randomization (MR) were included. The study was conducted between 2016 and 2018.
Polygenic risk scores for schizophrenia derived from genetic data (genetic risk is independently measured from the occurrence of the disease). Socioeconomic status of the area was included as a moderator in some of the models.
Population density of the place of residence of the participants determined from census data. Remoteness and socioeconomic status of the area were also tested.
The QIMR participants (15 544; 10 197 65.6% women; mean SD age, 54.4 13.2 years) living in more densely populated areas (people per square kilometer) had a higher genetic loading for schizophrenia (r2 = 0.12%; P = 5.69 × 10-5), a result that was replicated across all 3 other cohorts (UKB: 345 246; 187 469 54.3% women; age, 65.7 8.0 years; NTR: 11 212; 6727 60.0% women; age, 48.6 17.5 years; and QSKIN: 15 726; 8602 54.7% women; age, 57.0 7.9 years). This genetic association could account for 1.7% (95% CI, 0.8%-3.2%) of the schizophrenia risk. Estimates from MR analyses performed in the UKB sample were significant (b = 0.049; P = 3.7 × 10-7 using GSMR), suggesting that the genetic liability to schizophrenia may have a causal association with the tendency to live in urbanized locations.
The results of this study appear to support the hypothesis that individuals with increased genetic risk tend to live in urban/dense areas and suggest the need to refine the social stress model for schizophrenia by including genetics as well as possible gene-environment interactions.
Studies on neighbourhood characteristics and depression show equivocal results.AimsThis large-scale pooled analysis examines whether urbanisation, socioeconomic, physical and social neighbourhood ...characteristics are associated with the prevalence and severity of depression.
Cross-sectional design including data are from eight Dutch cohort studies (n = 32 487). Prevalence of depression, either DSM-IV diagnosis of depressive disorder or scoring for moderately severe depression on symptom scales, and continuous depression severity scores were analysed. Neighbourhood characteristics were linked using postal codes and included (a) urbanisation grade, (b) socioeconomic characteristics: socioeconomic status, home value, social security beneficiaries and non-Dutch ancestry, (c) physical characteristics: air pollution, traffic noise and availability of green space and water, and (d) social characteristics: social cohesion and safety. Multilevel regression analyses were adjusted for the individual's age, gender, educational level and income. Cohort-specific estimates were pooled using random-effects analysis.
The pooled analysis showed that higher urbanisation grade (odds ratio (OR) = 1.05, 95% CI 1.01-1.10), lower socioeconomic status (OR = 0.90, 95% CI 0.87-0.95), higher number of social security beneficiaries (OR = 1.12, 95% CI 1.06-1.19), higher percentage of non-Dutch residents (OR = 1.08, 95% CI 1.02-1.14), higher levels of air pollution (OR = 1.07, 95% CI 1.01-1.12), less green space (OR = 0.94, 95% CI 0.88-0.99) and less social safety (OR = 0.92, 95% CI 0.88-0.97) were associated with higher prevalence of depression. All four socioeconomic neighbourhood characteristics and social safety were also consistently associated with continuous depression severity scores.
This large-scale pooled analysis across eight Dutch cohort studies shows that urbanisation and various socioeconomic, physical and social neighbourhood characteristics are associated with depression, indicating that a wide range of environmental aspects may relate to poor mental health.Declaration of interestNone.
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