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, ß=0.06, P<0.001; cord blood n=1712, ß=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.

Attentional switching forms a genetic link between attention problems and autistic traits in adults.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) symptoms and autistic traits often occur together. The pattern and etiology of co-occurrence are largely unknown, particularly in adults. This study investigated the co-occurrence between both traits in detail, and subsequently examined the etiology of the co-occurrence, using two independent adult population samples. Method Data on ADHD traits (Inattention and Hyperactivity/Impulsivity) were collected in a population sample (S1, n = 559) of unrelated individuals. Data on Attention Problems (AP) were collected in a population-based family sample of twins and siblings (S2, n = 560). In both samples five dimensions of autistic traits were assessed (social skills, routine, attentional switching, imagination, patterns). RESULTS: Hyperactive traits (S1) did not correlate substantially with the autistic trait dimensions. For Inattention (S1) and AP (S2), the correlations with the autistic trait dimensions were low, apart from a prominent correlation with the attentional switching scale (0.47 and 0.32 respectively). Analyses in the genetically informative S2 revealed that this association could be explained by a shared genetic factor. CONCLUSIONS: Our findings suggest that the co-occurrence of ADHD traits and autistic traits in adults is not determined by problems with hyperactivity, social skills, imagination or routine preferences. Instead, the association between those traits is due primarily to shared attention-related problems (inattention and attentional switching capacity). As the etiology of this association is purely genetic, biological pathways involving attentional control could be a promising focus of future studies aimed at unraveling the genetic causes of these disorders.

Novel directions for G × E analysis in psychiatry.

G × E in psychiatry may explain why environmental risk factors have big impact in some individuals but not in others, and conversely why relatives that are genetically at risk for disease do not all develop disease. Here we discuss two novel methods that use an aggregate genome-wide measure of genetic risk to detect G × E and estimate its effect in the population using data currently available and data we anticipate will be available in the near future. The first method exploits summary statistics from large-scale genome-wide association studies ignorant of the environmental conditions and detects G × E in an out-of-sample risk-profiling framework. The second method relies on larger samples and is based on a mixed linear model framework. It estimates variance explained directly from single nucleotide polymorphisms and environmental measures. Both methods have great potential to improve public health interventions focusing on risk-based screening that is informed by both genetic and environmental risk factors.

Common SNPs explain some of the variation in the personality dimensions of neuroticism and extraversion.

The personality traits of neuroticism and extraversion are predictive of a number of social and behavioural outcomes and psychiatric disorders. Twin and family studies have reported moderate heritability estimates for both traits. Few associations have been reported between genetic variants and neuroticism/extraversion, but hardly any have been replicated. Moreover, the ones that have been replicated explain only a small proportion of the heritability (<~2%). Using genome-wide single-nucleotide polymorphism (SNP) data from ~12,000 unrelated individuals we estimated the proportion of phenotypic variance explained by variants in linkage disequilibrium with common SNPs as 0.06 (s.e. = 0.03) for neuroticism and 0.12 (s.e. = 0.03) for extraversion. In an additional series of analyses in a family-based sample, we show that while for both traits ~45% of the phenotypic variance can be explained by pedigree data (that is, expected genetic similarity) one third of this can be explained by SNP data (that is, realized genetic similarity). A part of the so-called 'missing heritability' has now been accounted for, but some of the reported heritability is still unexplained. Possible explanations for the remaining missing heritability are that: (i) rare variants that are not captured by common SNPs on current genotype platforms make a major contribution; and/ or (ii) the estimates of narrow sense heritability from twin and family studies are biased upwards, for example, by not properly accounting for nonadditive genetic factors and/or (common) environmental factors.

Genetic influences on 'environmental' factors.

Childhood environment, social environment and behavior, leisure time activities and life events have been hypothesized to contribute to individual differences in cognitive abilities and physical and emotional well-being. These factors are often labeled 'environmental', suggesting they shape but not reflect individual differences in behavior. The aim of this study is to test the hypothesis that these factors are not randomly distributed across the population but reflect heritable individual differences. Self-report data on Childhood Environment, Social Environment and Behavior, Leisure Time Activities and Life Events were obtained from 560 adult twins and siblings (mean age 47.11 years). Results clearly show considerable genetic influences on these factors with mean broad heritability of 0.49 (0.00-0.87). This suggests that what we think of as measures of 'environment' are better described as external factors that might be partly under genetic control. Understanding causes of individual differences in external factors may aid in clarifying the intricate nature between genetic and environmental influences on complex traits.