Structural models of genome-wide covariance identify multiple common dimensions in autism.

Common genetic variation has been associated with multiple phenotypic features in Autism Spectrum Disorder (ASD). However, our knowledge of shared genetic factor structures contributing to this highly heterogeneous phenotypic spectrum is limited. Here, we developed and implemented a structural equation modelling framework to directly model genomic covariance across core and non-core ASD phenotypes, studying autistic individuals of European descent with a case-only design. We identified three independent genetic factors most strongly linked to language performance, behaviour and developmental motor delay, respectively, studying an autism community sample (N = 5331). The three-factorial structure was largely confirmed in independent ASD-simplex families (N = 1946), although we uncovered, in addition, simplex-specific genetic overlap between behaviour and language phenotypes. Multivariate models across cohorts revealed novel associations, including links between language and early mastering of self-feeding. Thus, the common genetic architecture in ASD is multi-dimensional with overarching genetic factors contributing, in combination with ascertainment-specific patterns, to phenotypic heterogeneity.

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.

Polygenic risk for mental disorder reveals distinct association profiles across social behaviour in the general population.

Many mental health conditions present a spectrum of social difficulties that overlaps with social behaviour in the general population including shared but little characterised genetic links. Here, we systematically investigate heterogeneity in shared genetic liabilities with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BP), major depression (MD) and schizophrenia across a spectrum of different social symptoms. Longitudinally assessed low-prosociality and peer-problem scores in two UK population-based cohorts (4-17 years; parent- and teacher-reports; Avon Longitudinal Study of Parents and Children(ALSPAC): N ≤ 6,174; Twins Early Development Study(TEDS): N ≤ 7,112) were regressed on polygenic risk scores for disorder, as informed by genome-wide summary statistics from large consortia, using negative binomial regression models. Across ALSPAC and TEDS, we replicated univariate polygenic associations between social behaviour and risk for ADHD, MD and schizophrenia. Modelling variation in univariate genetic effects jointly using random-effect meta-regression revealed evidence for polygenic links between social behaviour and ADHD, ASD, MD, and schizophrenia risk, but not BP. Differences in age, reporter and social trait captured 45-88% in univariate effect variation. Cross-disorder adjusted analyses demonstrated that age-related heterogeneity in univariate effects is shared across mental health conditions, while reporter- and social trait-specific heterogeneity captures disorder-specific profiles. In particular, ADHD, MD, and ASD polygenic risk were more strongly linked to peer problems than low prosociality, while schizophrenia was associated with low prosociality only. The identified association profiles suggest differences in the social genetic architecture across mental disorders when investigating polygenic overlap with population-based social symptoms spanning 13 years of child and adolescent development.

Discordant associations of educational attainment with ASD and ADHD implicate a polygenic form of pleiotropy.

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex co-occurring neurodevelopmental conditions. Their genetic architectures reveal striking similarities but also differences, including strong, discordant polygenic associations with educational attainment (EA). To study genetic mechanisms that present as ASD-related positive and ADHD-related negative genetic correlations with EA, we carry out multivariable regression analyses using genome-wide summary statistics (N = 10,610-766,345). Our results show that EA-related genetic variation is shared across ASD and ADHD architectures, involving identical marker alleles. However, the polygenic association profile with EA, across shared marker alleles, is discordant for ASD versus ADHD risk, indicating independent effects. At the single-variant level, our results suggest either biological pleiotropy or co-localisation of different risk variants, implicating MIR19A/19B microRNA mechanisms. At the polygenic level, they point to a polygenic form of pleiotropy that contributes to the detectable genome-wide correlation between ASD and ADHD and is consistent with effect cancellation across EA-related regions.

Multivariate genome-wide covariance analyses of literacy, language and working memory skills reveal distinct etiologies.

Several abilities outside literacy proper are associated with reading and spelling, both phenotypically and genetically, though our knowledge of multivariate genomic covariance structures is incomplete. Here, we introduce structural models describing genetic and residual influences between traits to study multivariate links across measures of literacy, phonological awareness, oral language, and phonological working memory (PWM) in unrelated UK youth (8-13 years, N = 6453). We find that all phenotypes share a large proportion of underlying genetic variation, although especially oral language and PWM reveal substantial differences in their genetic variance composition with substantial trait-specific genetic influences. Multivariate genetic and residual trait covariance showed concordant patterns, except for marked differences between oral language and literacy/phonological awareness, where strong genetic links contrasted near-zero residual overlap. These findings suggest differences in etiological mechanisms, acting beyond a pleiotropic set of genetic variants, and implicate variation in trait modifiability even among phenotypes that have high genetic correlations.

The developmental genetic architecture of vocabulary skills during the first three years of life: Capturing emerging associations with later-life reading and cognition.

Individual differences in early-life vocabulary measures are heritable and associated with subsequent reading and cognitive abilities, although the underlying mechanisms are little understood. Here, we (i) investigate the developmental genetic architecture of expressive and receptive vocabulary in early-life and (ii) assess timing of emerging genetic associations with mid-childhood verbal and non-verbal skills. We studied longitudinally assessed early-life vocabulary measures (15-38 months) and later-life verbal and non-verbal skills (7-8 years) in up to 6,524 unrelated children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We dissected the phenotypic variance of rank-transformed scores into genetic and residual components by fitting multivariate structural equation models to genome-wide genetic-relationship matrices. Our findings show that the genetic architecture of early-life vocabulary involves multiple distinct genetic factors. Two of these genetic factors are developmentally stable and also contribute to genetic variation in mid-childhood skills: One genetic factor emerging with expressive vocabulary at 24 months (path coefficient: 0.32(SE = 0.06)) was also related to later-life reading (path coefficient: 0.25(SE = 0.12)) and verbal intelligence (path coefficient: 0.42(SE = 0.13)), explaining up to 17.9% of the phenotypic variation. A second, independent genetic factor emerging with receptive vocabulary at 38 months (path coefficient: 0.15(SE = 0.07)), was more generally linked to verbal and non-verbal cognitive abilities in mid-childhood (reading path coefficient: 0.57(SE = 0.07); verbal intelligence path coefficient: 0.60(0.10); performance intelligence path coefficient: 0.50(SE = 0.08)), accounting for up to 36.1% of the phenotypic variation and the majority of genetic variance in these later-life traits (≥66.4%). Thus, the genetic foundations of mid-childhood reading and cognitive abilities are diverse. They involve at least two independent genetic factors that emerge at different developmental stages during early language development and may implicate differences in cognitive processes that are already detectable during toddlerhood.

The developmental origins of genetic factors influencing language and literacy: Associations with early-childhood vocabulary.

BACKGROUND: The heritability of language and literacy skills increases from early-childhood to adolescence. The underlying mechanisms are little understood and may involve (a) the amplification of genetic influences contributing to early language abilities, and/or (b) the emergence of novel genetic factors (innovation). Here, we investigate the developmental origins of genetic factors influencing mid-childhood/early-adolescent language and literacy. We evaluate evidence for the amplification of early-childhood genetic factors for vocabulary, in addition to genetic innovation processes. METHODS: Expressive and receptive vocabulary scores at 38 months, thirteen language- and literacy-related abilities and nonverbal cognition (7-13 years) were assessed in unrelated children from the Avon Longitudinal Study of Parents and Children (ALSPAC, Nindividuals  ≤ 6,092). We investigated the multivariate genetic architecture underlying early-childhood expressive and receptive vocabulary, and each of 14 mid-childhood/early-adolescent language, literacy or cognitive skills with trivariate structural equation (Cholesky) models as captured by genome-wide genetic relationship matrices. The individual path coefficients of the resulting structural models were finally meta-analysed to evaluate evidence for overarching patterns. RESULTS: We observed little support for the emergence of novel genetic sources for language, literacy or cognitive abilities during mid-childhood or early adolescence. Instead, genetic factors of early-childhood vocabulary, especially those unique to receptive skills, were amplified and represented the majority of genetic variance underlying many of these later complex skills (≤99%). The most predictive early genetic factor accounted for 29.4%(SE = 12.9%) to 45.1%(SE = 7.6%) of the phenotypic variation in verbal intelligence and literacy skills, but also for 25.7%(SE = 6.4%) in performance intelligence, while explaining only a fraction of the phenotypic variation in receptive vocabulary (3.9%(SE = 1.8%)). CONCLUSIONS: Genetic factors contributing to many complex skills during mid-childhood and early adolescence, including literacy, verbal cognition and nonverbal cognition, originate developmentally in early-childhood and are captured by receptive vocabulary. This suggests developmental genetic stability and overarching aetiological mechanisms.

Disentangling polygenic associations between attention-deficit/hyperactivity disorder, educational attainment, literacy and language.

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10-8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10-5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10-6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

Imaging genetics in neurodevelopmental psychopathology.

Neurodevelopmental disorders are defined by highly heritable problems during development and brain growth. Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and intellectual disability (ID) are frequent neurodevelopmental disorders, with common comorbidity among them. Imaging genetics studies on the role of disease-linked genetic variants on brain structure and function have been performed to unravel the etiology of these disorders. Here, we reviewed imaging genetics literature on these disorders attempting to understand the mechanisms of individual disorders and their clinical overlap. For ADHD and ASD, we selected replicated candidate genes implicated through common genetic variants. For ID, which is mainly caused by rare variants, we included genes for relatively frequent forms of ID occurring comorbid with ADHD or ASD. We reviewed case-control studies and studies of risk variants in healthy individuals. Imaging genetics studies for ADHD were retrieved for SLC6A3/DAT1, DRD2, DRD4, NOS1, and SLC6A4/5HTT. For ASD, studies on CNTNAP2, MET, OXTR, and SLC6A4/5HTT were found. For ID, we reviewed the genes FMR1, TSC1 and TSC2, NF1, and MECP2. Alterations in brain volume, activity, and connectivity were observed. Several findings were consistent across studies, implicating, for example, SLC6A4/5HTT in brain activation and functional connectivity related to emotion regulation. However, many studies had small sample sizes, and hypothesis-based, brain region-specific studies were common. Results from available studies confirm that imaging genetics can provide insight into the link between genes, disease-related behavior, and the brain. However, the field is still in its early stages, and conclusions about shared mechanisms cannot yet be drawn.