Genome-Wide Analyses of Vocabulary Size in Infancy and Toddlerhood:Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits

Background: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta–genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD). Methods: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15–18 months), late-phase expressive (toddlerhood, 24–38 months), and late-phase receptive (toddlerhood, 24–38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism–based heritability (SNP-h2) and genetic correlations (rg) and modeled underlying factor structures with multivariate models. Results: Early-life vocabulary size was modestly heritable (SNP-h2 = 0.08–0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg = 0.07), although each measure was moderately related to toddler expressive vocabulary (rg = 0.69 and rg = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: rg = 0.58 and rg = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: rg = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; rg = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (rg = −0.74), highlighting developmental heterogeneity. Conclusions: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits.</p

De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes

Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n(effective) = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (vertical bar r(g)vertical bar > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range vertical bar r(g)vertical bar = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.Peer reviewe

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe

Genome-wide association meta-analysis of age at first cannabis use

Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identify associations with genetic variants. A twin-based heritability analysis using 8,055 twins from three cohorts was performed. We then carried-out a genome wide survival meta-analysis of age at first cannabis use in a discovery sample of 24,953 individuals from nine European, North American, and Australian cohorts, and a replication sample of 3,735 individuals. The twin-based heritability for age at first cannabis use was 38% (95% confidence interval [CI] 19-60%). Shared and unique environmental factors explained 39% (95% CI 20-56%) and 22% (95% CI 16-29%). The genome wide survival meta-analysis identified five SNPs on chromosome 16 within the Calcium-transporting ATPase gene (ATP2C2) at P 0.8) with the strongest association at the intronic variant rs1574587 (P=4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P=1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been previously associated with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. Age at cannabis initiation appears to be moderately heritable in Western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders

Identical twins carry a persistent epigenetic signature of early genome programming

The mechanisms underlying how monozygotic (or identical) twins arise are yet to be determined. Here, the authors investigate this in an epigenome-wide association study, showing that monozygotic twinning has a characteristic DNA methylation signature in adult somatic tissues.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.Molecular Epidemiolog