Dataset Information

Behavioral predictors of autism recurrence are genetically independent and influence social reciprocity: evidence that polygenic ASD risk is mediated by separable elements of developmental liability.

ABSTRACT: The preponderance of causal influence on total population attributable risk for autism is polygenic in nature, but it is not known how such liability engenders the development of the syndrome. In 348 epidemiologically ascertained toddler twins, we explored associations between autistic traits and three robust, highly heritable predictors of familial autism recurrence: variation in attention, motor coordination, and parental autistic trait burden. We observed that these predictors-despite collectively accounting for over one third of variance in clinical recurrence-are genetically independent in early childhood, and jointly account for a comparable share of inherited influence on early reciprocal social behavior in the general population. Thus, combinations of what are otherwise discrete, inherited behavioral liabilities-some not specific to autism-appear to jointly mediate common genetic risk for autism. Linking genetic variants and neural signatures to these independent traits prior to the onset of the development of autism will enhance understanding of mechanisms of causation in familial autistic syndromes. Moreover, ongoing biomarker discovery efforts will benefit from controlling for the effects of these common liabilities, which aggregate in individuals with autism but are also continuously distributed in "controls". Finally, early inherited liabilities that participate in the early ontogeny of autistic syndromes represent parsimonious intervention targets for polygenic forms of the condition, and represent candidate trans-diagnostic endophenotypes of potential relevance to a diversity of neuropsychiatric syndromes.

SUBMITTER: Pohl A

PROVIDER: S-EPMC6706410 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Behavioral predictors of autism recurrence are genetically independent and influence social reciprocity: evidence that polygenic ASD risk is mediated by separable elements of developmental liability.

Pohl Alexa A Jones Warren R WR Marrus Natasha N Zhang Yi Y Klin Ami A Constantino John N JN

Translational psychiatry 20190822 1

The preponderance of causal influence on total population attributable risk for autism is polygenic in nature, but it is not known how such liability engenders the development of the syndrome. In 348 epidemiologically ascertained toddler twins, we explored associations between autistic traits and three robust, highly heritable predictors of familial autism recurrence: variation in attention, motor coordination, and parental autistic trait burden. We observed that these predictors-despite collect ...[more]

PMID: 31439834

Similar Datasets

Project description:BACKGROUND:In 1998 secretin, a gastrointestinal hormone, was suggested as an effective treatment for autism spectrum disorders (ASD) based on anecdotal evidence. OBJECTIVES:To assess whether intravenous secretin improves the core features of ASD, other aspects of behaviour or function such as self-injurious behaviour, and the quality of life of affected individuals and their carers. We also assessed whether secretin causes harm. This is an updated version of our review of this topic originally published in 2005. SEARCH METHODS:We searched CENTRAL (2010 Issue 1), MEDLINE (1950 to January 2010) , EMBASE (1980 to 2010 Week 2), PsycINFO (1806 to 2010 Week 2), CINAHL (1938 to January 2010), ERIC (1966 to January 2010), Sociological Abstracts (1952 to January 2010). Sociofile and HealthStar were searched in March 2005 when this review was first published, but were not available for this update. Records were limited to studies published since 1998 as this is when secretin was first proposed as a possible treatment for ASD. We searched reference lists of trials and reviews; we also contacted experts and trialists to find unpublished studies. SELECTION CRITERIA:Randomised controlled trials of intravenous secretin compared to a placebo treatment in children or adults diagnosed with ASD, where at least one standardised outcome measure was reported. DATA COLLECTION AND ANALYSIS:Sixteen studies met the inclusion criteria but for two of these, conducted by Repligen, the only available multisite data were reported in press releases. All outcome data from the other 14 trials were continuous. Where trials used cross-over designs, we conducted analysis on results from the first treatment phase. Where mean change from baseline was reported, we used this in preference to post-treatment scores for meta-analyses or forest plots. Meta-analysis was able to be attempted for only one outcome (Childhood Autism Rating Scale). Insufficient data were available to conduct sensitivity or subgroup analyses to assess the impact of study quality, clinical differences in the intervention or clinically relevant differences between groups, such as age or presence of gastrointestinal symptoms. MAIN RESULTS:Over 900 children were recruited for the secretin trials. Twenty-five established standardised outcome measures were reported to assess core features of ASD, communication, behaviour, visuospatial skills, affect and adverse events. One standardised measure of global impression was also used. No more than four studies used any one outcome measure similarly. When duration from the start of the intervention to outcome assessment was known, outcomes were reported at between three and six weeks. Meta-analysis of data was not possible but there is now consistency of findings, with RCTs of the efficacy of secretin in autism not showing improvements for core features of ASD. AUTHORS' CONCLUSIONS:There is no evidence that single or multiple dose intravenous secretin is effective and as such currently it should not be recommended or administered as a treatment for ASD. Further experimental assessment of secretin's effectiveness for ASD can only be justified if there is new high-quality and replicated scientific evidence that either finds that secretin has a role in neurotransmission in a way that could benefit all children with ASD or identifies important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing.

Project description:ImportanceSchizophrenia is a clinically heterogeneous disorder. It is currently unclear how variability in symptom dimensions and cognitive ability is associated with genetic liability for schizophrenia.ObjectiveTo determine whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence.Design, setting, and participantsIn a genetic association study, 3 cross-sectional samples of 1220 individuals with a diagnosis of schizophrenia were recruited from community, inpatient, and voluntary sector mental health services across the UK. Confirmatory factor analysis was used to create phenotypic dimensions from lifetime ratings of the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and the MATRICS Consensus Cognitive Battery. Analyses of polygenic risk scores (PRSs) were used to assess whether genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence were associated with these phenotypic dimensions. Data collection for the cross-sectional studies occurred between 1993 and 2016. Data analysis for this study occurred between January 2019 and March 2021.Main outcomes and measuresOutcome measures included phenotypic dimensions defined from confirmatory factor analysis relating to positive symptoms, negative symptoms of diminished expressivity, negative symptoms of motivation and pleasure, disorganized symptoms, and current cognitive ability. Exposure measures included PRSs for schizophrenia, bipolar disorder, major depression, attention-deficit/hyperactivity disorder, autism spectrum disorder, and intelligence.ResultsOf the 1220 study participants, 817 were men (67.0%). Participants' mean (SD) age at interview was 43.10 (12.74) years. Schizophrenia PRS was associated with increased disorganized symptom dimension scores in both a 5-factor model (β = 0.14; 95% CI, 0.07-0.22; P = 2.80 × 10-4) and a 3-factor model across all samples (β = 0.10; 95% CI, 0.05-0.15; P = 2.80 × 10-4). Current cognitive ability was associated with genetic liability to schizophrenia (β = -0.11; 95% CI, -0.19 to -0.04; P = 1.63 × 10-3) and intelligence (β = 0.23; 95% CI, 0.16-0.30; P = 1.52 × 10-10). After controlling for estimated premorbid IQ, current cognitive performance was associated with schizophrenia PRS (β = -0.08; 95% CI, -0.14 to -0.02; P = 8.50 × 10-3) but not intelligence PRS.Conclusions and relevanceThe findings of this study suggest that genetic liability for schizophrenia is associated with higher disorganized dimension scores but not other symptom dimensions. Cognitive performance in schizophrenia appears to reflect distinct contributions from genetic liabilities to both intelligence and schizophrenia.

Dataset Information

Behavioral predictors of autism recurrence are genetically independent and influence social reciprocity: evidence that polygenic ASD risk is mediated by separable elements of developmental liability.

Publications

Behavioral predictors of autism recurrence are genetically independent and influence social reciprocity: evidence that polygenic ASD risk is mediated by separable elements of developmental liability.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure