Gestational Vitamin D deficiency and autism-related traits: The Generation R Study

There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational Vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational Vitamin D deficiency and a continuous measure of autism-related traits at ∼6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyVitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l-1. Compared with the 25OHD sufficient group (25OHD>50 nmol l-1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, β=0.06, P<0.001; cord blood n=1712, β=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational Vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational Vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny

Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis

We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands sample (area under the curve, AUC = 0.65, CI95% = [0.62–0.68], p = 8.3 × 10−22). The maximum AUC achieved was 0.69 (CI95% = [0.66–0.71], p = 4.3 × 10−34) when cell-type proportion was included in the predictor

General cognitive ability and the interplay between genes and environment: ZIE STATUS/PROEFSCHRIFT ivm. (administratieve) toerekening van deze promotie aan FPP ipv. ALW

Verhage, M. [Promotor]Heutink, P. [Promotor]Posthuma, D. [Copromotor]Sluis, S. van der [Copromotor

Sex differences in adults' motivation to achieve

Achievement motivation is considered a prerequisite for success in academic as well as non-academic settings. We studied sex differences in academic and general achievement motivation in an adult sample of 338 men and 497 women (ages 18-70 years). Multi-group covariance and means structure analysis (MG-CMSA) for ordered categorical data was used to establish the location of possible sex differences, i.e., on the level of the latent factors or on the level of the observed items (i.e., sex-related item bias). Five of the 28 achievement motivation items showed severe bias with respect to sex, exemplifying the usefulness of MG-CMSA in locating the source of sex differences. The Academic Achievement Motivation scale consisted of two latent factors: Dedication and Persistence. Sex differences were observed for the factor Dedication only, with women showing more dedication towards their academic work than men. The General Achievement Motivation scale consisted of five latent factors: Pressure, Accomplishment, Work Approach, Future Orientation, and Competition. Sex differences were significant for the factor Future Orientation, with women contemplating less about the future than men, and a trend towards significance (p=.06) was observed for the factor Competition, with women being less actuated by competitive motives than men. These results suggest that sex-related item bias merits attention in achievement motivation research, but that men and women still differ in aspects of achievement motivation when biased items are eliminated from the analyses. © 2010

Research Review: Polygenic methods and their application to psychiatric traits

Background: Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years. Methods and scope: We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability. Findings: Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs. Conclusions: Increasing the sample size for genome wide association studies of psychiatric disorders will lead to the identification of more associated genetic variants, as already found for schizophrenia. These loci provide the starting point of functional analyses that might eventually lead to new prevention and treatment options and to improved biological validity of diagnostic constructs. Polygenic analyses will contribute further to our understanding of complex genetic traits as sample sizes increase and as sample resources become richer in phenotypic descriptors, both in terms of clinical symptoms and of nongenetic risk factors

Heritability of transforming growth factor-beta1 and tumor necrosis factor-receptor type 1 expression and vitamin D levels in healthy adolescent twins

Cytokines and vitamin D both have a role in modulating the immune system, and are also potentially useful biomarkers in mental illnesses such as major depressive disorder (MDD) and schizophrenia. Studying the variability of cytokines and vitamin D in a healthy population sample may add to understanding the association between these biomarkers and mental illness. To assess genetic and environmental contributions to variation in circulating levels of cytokines and vitamin D (25-hydroxy vitamin D: 25(OH)D3), we analyzed data from a healthy adolescent twin cohort (mean age 16.2 years; standard deviation 0.25). Plasma cytokine measures were available for 400 individuals (85 MZ, 115 DZ pairs), dried blood spot sample vitamin D measures were available for 378 individuals (70 MZ, 118 DZ pairs). Heritability estimates were moderate but significant for the cytokines transforming growth factor-β1 (TGF-β1), 0.57 (95% CI 0.26–0.80) and tumor necrosis factor-receptor type 1 (TNFR1), 0.50 (95% CI 0.11–0.63) respectively. Measures of 25(OH)D3 were within normal range and heritability was estimated to be high (0.86, 95% CI 0.61–0.94). Assays of other cytokines did not generate meaningful results. These potential biomarkers may be useful in mental illness, with further research warranted in larger sample sizes. They may be particularly important in adolescents with mental illness where diagnostic uncertainty poses a significant clinical challenge.Natalie T. Mills, Margie J. Wright, Anjali K. Henders, Darryl W. Eyles, Bernhard T. Baune, John J. McGrat