Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes; from clinical manifestations towards personalized treatment options.

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial 'mirror phenotype' with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the 'typical' 16p11.2 BP4-BP5 (29.6-30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8-29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases' phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.

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.

A systematic review of artificial intelligence impact assessments.

Artificial intelligence (AI) is producing highly beneficial impacts in many domains, from transport to healthcare, from energy distribution to marketing, but it also raises concerns about undesirable ethical and social consequences. AI impact assessments (AI-IAs) are a way of identifying positive and negative impacts early on to safeguard AI's benefits and avoid its downsides. This article describes the first systematic review of these AI-IAs. Working with a population of 181 documents, the authors identified 38 actual AI-IAs and subjected them to a rigorous qualitative analysis with regard to their purpose, scope, organisational context, expected issues, timeframe, process and methods, transparency and challenges. The review demonstrates some convergence between AI-IAs. It also shows that the field is not yet at the point of full agreement on content, structure and implementation. The article suggests that AI-IAs are best understood as means to stimulate reflection and discussion concerning the social and ethical consequences of AI ecosystems. Based on the analysis of existing AI-IAs, the authors describe a baseline process of implementing AI-IAs that can be implemented by AI developers and vendors and that can be used as a critical yardstick by regulators and external observers to evaluate organisations' approaches to AI.

Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias.

BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays. RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.

Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. RESULTS: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. CONCLUSION: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Exploring the genetic overlap between twelve psychiatric disorders.

The widespread comorbidity among psychiatric disorders demonstrated in epidemiological studies1-5 is mirrored by non-zero, positive genetic correlations from large-scale genetic studies6-10. To identify shared biological processes underpinning this observed phenotypic and genetic covariance and enhance molecular characterization of general psychiatric disorder liability11-13, we used several strategies aimed at uncovering pleiotropic, that is, cross-trait-associated, single-nucleotide polymorphisms (SNPs), genes and biological pathways. We conducted cross-trait meta-analysis on 12 psychiatric disorders to identify pleiotropic SNPs. The meta-analytic signal was driven by schizophrenia, hampering interpretation and joint biological characterization of the cross-trait meta-analytic signal. Subsequent pairwise comparisons of psychiatric disorders identified substantial pleiotropic overlap, but mainly among pairs of psychiatric disorders, and mainly at less stringent P-value thresholds. Only annotations related to evolutionarily conserved genomic regions were significant for multiple (9 out of 12) psychiatric disorders. Overall, identification of shared biological mechanisms remains challenging due to variation in power and genetic architecture between psychiatric disorders.

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

The phenotypic spectrum and genotype-phenotype correlations in 106 patients with variants in major autism gene CHD8.

CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies have shown that intellectual developmental disorder with autism and macrocephaly (IDDAM), the syndrome caused by pathogenic variants in CHD8, consists of a broad range of phenotypic abnormalities. We collected and reviewed 106 individuals with IDDAM, including 36 individuals not previously published, thus enabling thorough genotype-phenotype analyses, involving the CHD8 mutation spectrum, characterization of the CHD8 DNA methylation episignature, and the systematic analysis of phenotypes collected in Human Phenotype Ontology (HPO). We identified 29 unique nonsense, 25 frameshift, 24 missense, and 12 splice site variants. Furthermore, two unique inframe deletions, one larger deletion (exons 26-28), and one translocation were observed. Methylation analysis was performed for 13 patients, 11 of which showed the previously established episignature for IDDAM (85%) associated with CHD8 haploinsufficiency, one analysis was inconclusive, and one showing a possible gain-of-function signature instead of the expected haploinsufficiency signature was observed. Consistent with previous studies, phenotypical abnormalities affected multiple organ systems. Many neurological abnormalities, like intellectual disability (68%) and hypotonia (29%) were observed, as well as a wide variety of behavioural abnormalities (88%). Most frequently observed behavioural problems included autism spectrum disorder (76%), short attention span (32%), abnormal social behaviour (31%), sleep disturbance (29%) and impaired social interactions (28%). Furthermore, abnormalities in the digestive (53%), musculoskeletal (79%) and genitourinary systems (18%) were noted. Although no significant difference in severity was observed between males and females, individuals with a missense variant were less severely affected. Our study provides an extensive review of all phenotypic abnormalities in patients with IDDAM and provides clinical recommendations, which will be of significant value to individuals with a pathogenic variant in CHD8, their families, and clinicians as it gives a more refined insight into the clinical and molecular spectrum of IDDAM, which is essential for accurate care and counselling.

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways.

Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.

Polygenic risk for ADHD and ASD and their relation with cognitive measures in school children.

BACKGROUND: Attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are child-onset neurodevelopmental disorders frequently accompanied by cognitive difficulties. In the current study, we aim to examine the genetic overlap between ADHD and ASD and cognitive measures of working memory (WM) and attention performance among schoolchildren using a polygenic risk approach. METHODS: A total of 1667 children from a population-based cohort aged 7-11 years with data available on genetics and cognition were included in the analyses. Polygenic risk scores (PRS) were calculated for ADHD and ASD using results from the largest GWAS to date (N = 55 374 and N = 46 351, respectively). The cognitive outcomes included verbal and numerical WM and the standard error of hit reaction time (HRTSE) as a measure of attention performance. These outcomes were repeatedly assessed over 1-year period using computerized version of the Attention Network Test and n-back task. Associations were estimated using linear mixed-effects models. RESULTS: Higher polygenic risk for ADHD was associated with lower WM performance at baseline time but not over time. These findings remained significant after adjusting by multiple testing and excluding individuals with an ADHD diagnosis but were limited to boys. PRS for ASD was only nominally associated with an increased improvement on verbal WM over time, although this association did not survive multiple testing correction. No associations were observed for HRTSE. CONCLUSIONS: Common genetic variants related to ADHD may contribute to worse WM performance among schoolchildren from the general population but not to the subsequent cognitive-developmental trajectory assessed over 1-year period.

White matter microstructural differences in children and genetic risk for multiple sclerosis: A population-based study.

BACKGROUND: MS patients show abnormalities in white matter (WM) on brain imaging, with heterogeneity in the location of WM lesions. The "pothole" method can be applied to diffusion-weighted images to identify spatially distinct clusters of divergent brain WM microstructure. OBJECTIVE: To investigate the association between genetic risk for MS and spatially independent clusters of decreased or increased fractional anisotropy (FA) in the brain. In addition, we studied sex- and age-related differences. METHODS: 3 Tesla diffusion tensor imaging (DTI) data were collected in 8- to 12-year-old children from a population-based study. Global and tract-based potholes (lower FA clusters) and molehills (higher FA clusters) were quantified in 3047 participants with usable DTI data. A polygenic risk score (PRS) for MS was calculated in genotyped individuals (n = 1087) and linear regression analyses assessed the relationship between the PRS and the number of potholes and molehills, correcting for multiple testing using the False Discovery Rate. RESULTS: The number of molehills increased with age, potholes decreased with age, and fewer potholes were observed in girls during typical development. The MS-PRS was positively associated with the number of molehills (ß = 0.9, SE = 0.29, p = 0.002). Molehills were found more often in the corpus callosum (ß = 0.3, SE = 0.09, p = 0.0003). CONCLUSION: Genetic risk for MS is associated with spatially distinct clusters of increased FA during childhood brain development.

Maternal Psychological Problems During Pregnancy and Child Externalizing Problems: Moderated Mediation Model with Child Self-regulated Compliance and Polygenic Risk Scores for Aggression.

A potential pathway underlying the association between prenatal exposure to maternal psychological problems and childhood externalizing problems is child self-regulation. This prospective study (N = 687) examined whether self-regulated compliance mediates the relation between maternal affective problems and hostility during pregnancy and childhood externalizing problems, and explored moderation by child polygenic risk scores for aggression and sex. Self-regulated compliance at age 3 was observed in mother-child interactions, and externalizing problems at age 6 were reported by mothers and teachers. Polygenic risk scores were calculated based on a genome-wide association study of aggressive behavior. Self-regulated compliance mediated the associations between maternal psychological problems and externalizing problems. Aggression PRS was associated with higher externalizing problems reported by mothers. No evidence was found of moderation by aggression PRS or sex. These findings support the hypothesis that maternal psychological problems during pregnancy might influence externalizing problems through early self-regulation, regardless of child genetic susceptibility or sex.

Schizophrenia polygenic risk is associated with child mental health problems through early childhood adversity: evidence for a gene-environment correlation.

Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene-environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02-1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01-1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5-23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene-environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities.

Multivariate analysis reveals shared genetic architecture of brain morphology and human behavior.

Human variation in brain morphology and behavior are related and highly heritable. Yet, it is largely unknown to what extent specific features of brain morphology and behavior are genetically related. Here, we introduce a computationally efficient approach for multivariate genomic-relatedness-based restricted maximum likelihood (MGREML) to estimate the genetic correlation between a large number of phenotypes simultaneously. Using individual-level data (N = 20,190) from the UK Biobank, we provide estimates of the heritability of gray-matter volume in 74 regions of interest (ROIs) in the brain and we map genetic correlations between these ROIs and health-relevant behavioral outcomes, including intelligence. We find four genetically distinct clusters in the brain that are aligned with standard anatomical subdivision in neuroscience. Behavioral traits have distinct genetic correlations with brain morphology which suggests trait-specific relevance of ROIs. These empirical results illustrate how MGREML can be used to estimate internally consistent and high-dimensional genetic correlation matrices in large datasets.

T cell composition and polygenic multiple sclerosis risk: A population-based study in children.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population. METHODS: We included genotyped participants from the population-based Generation R study in whom immunophenotyping of blood T cells was performed at the age of 6 years. Analyses of variance were used to determine the impact of MS-PRSs on total T cell numbers (n = 1261), CD4+ and CD8+ lineages, and subsets therein (n= 675). In addition, T-cell-specific PRSs were constructed based on functional pathway data. RESULTS: The MS-PRS negatively correlated with CD8+ T cell frequencies (p = 2.92 × 10-3 ), which resulted in a positive association with CD4+ /CD8+ T cell ratios (p = 8.27 × 10-9 ). These associations were mainly driven by two of 195 genome-wide significant MS risk variants: the main genetic risk variant for MS, HLA-DRB1*15:01 and an HLA-B risk variant. We observed no significant associations for the T-cell-specific PRSs. CONCLUSIONS: Our results suggest that MS-associated genetic variants affect T cell composition during childhood in the general population.