The contributions of rare inherited and polygenic risk to ASD in multiplex families

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(31)

Published: July 28, 2023

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing largest cohort multiplex families date, consisting 4,551 individuals 1,004 having two more autistic children. Using this study design, identify seven previously unrecognized ASD genes supported by majority variants, finding support for total 74 our 152 after combined analysis other studies. Autistic children demonstrate an increased burden protein-truncating variants known genes. We also find that score (PGS) is overtransmitted nonautistic parents who harbor consistent combinatorial effects offspring, which may explain reduced penetrance these parents. observe addition social dysfunction, language delay associated PGS overtransmission. These results are additive further suggest core biological feature

Language: Английский

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Contribution of autosomal rare and de novo variants to sex differences in autism

The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Autism is four times more prevalent in males than females. To study whether this reflects a difference genetic predisposition attributed to autosomal rare variants, we evaluated sex differences effect size of damaging protein-truncating and missense variants on autism 47,061 autistic individuals using liability model with differing thresholds. Given the rates cognitive impairment among individuals, also compared sizes between without or motor delay. Although these mediated different likelihoods versus difficulties, their scale did not differ significantly by exome wide genes sex-differentially expressed cortex. De novo mutations were enriched male-biased expression adult cortex, but show significant scale, nor conferred from other similar loss-of-function intolerance sex-averaged cortical expression. Exome-wide female bias de mutation observed was driven high-confidence syndromic autism-predisposition genes. In summary, coding confer for females males.

Language: Английский

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Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 197, P. 106520 - 106520

Published: May 3, 2024

Autism spectrum disorder (ASD) is a neurodevelopmental affecting 1 in 36 children and associated with physiological abnormalities, most notably mitochondrial dysfunction, at least subset of individuals. This systematic review meta-analysis discovered 204 relevant articles which evaluated biomarkers dysfunction ASD Significant elevations (all p < 0.01) the prevalence lactate (17%), pyruvate (41%), alanine (15%) creatine kinase (9%) were found ASD. Individuals had significant differences moderate to large effect sizes (Cohen's d' ≥ 0.6) compared controls mean pyruvate, lactate-to-pyruvate ratio, ATP, kinase. Some studies abnormal TCA cycle metabolites Thirteen controlled reported DNA (mtDNA) deletions or variations group blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, brain. Meta-analyses (p copy number mtDNA overall ND1, ND4 CytB genes. Four linked specific haplogroups A series subgroup elevated respiration was increased sensitivity mitochondria stressors regression. Lactate, carnitine, acyl-carnitines clinical features such as delays language, social interaction, cognition, motor skills, repetitive behaviors gastrointestinal symptoms, although not all an association. acyl-carnitines, CoQ10, well variants, heteroplasmy, severity. Variability across biomarker primarily due collection processing techniques intrinsic heterogeneity population. Several alterations metabolism mothers neonates who develop Treatments targeting mitochondria, particularly carnitine ubiquinol, appear beneficial The link between common abnormalities individuals including disorders, oxidative stress, immune outlined. subtypes are discussed, one related regression, another microbiome metabolites, acyl-carnitines. Mechanisms linking function prenatal brain development postnatal Given multisystem complexity some ASD, this presents evidence for being central by contributing development, comorbidities diagnostic approach identify From evidence, it clear that many have may need be addressed order achieve optimal outcomes. fact during pregnancy early life eventually provides promise predictive Further improve understanding role better defining subgroups molecular mechanisms driving unique changes those

Language: Английский

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Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(8), P. 100609 - 100609

Published: July 16, 2024

Little is known about the role of non-coding regions in etiology autism spectrum disorder (ASD). We examined three classes regions: human accelerated (HARs), which show signatures positive selection humans; experimentally validated neural VISTA enhancers (VEs); and conserved predicted to act as (CNEs). Targeted whole-genome analysis >16,600 samples >4,900 ASD probands revealed that likely recessive, rare, inherited variants HARs, VEs, CNEs substantially contribute risk whose parents share ancestry, enriches for recessive contributions, but modestly contribute, if at all, simplex family structures. identified multiple patient HARs near IL1RAPL1 VEs OTX1 SIM1 showed they change enhancer activity. Our results implicate both human-evolved evolutionarily suggest potential mechanisms how regulatory changes can modulate social behavior.

Language: Английский

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The developing visual system: a building block on the path to autism

Developmental Cognitive Neuroscience, Journal Year: 2025, Volume and Issue: 73, P. 101547 - 101547

Published: March 13, 2025

Longitudinal neuroimaging studies conducted over the past decade provide evidence of atypical visual system development in first years life autism spectrum disorder (ASD). Findings from genomic analyses, family studies, and postmortem investigations suggest that changes ASD are linked to genetic factors, making an important neural phenotype along path genes behavior deserves further study. This article reviews what is known about developing life; it also explores potential canalizing role maturation may have emergence by placing findings context developmental cascades involving brain development, attention, social cognitive development. Critical gaps our understanding human discussed, future research directions proposed improve as a complex neurodevelopmental with origins early

Language: Английский

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Sex mechanisms as nonbinary influences on cognitive diversity

Hormones and Behavior, Journal Year: 2024, Volume and Issue: 162, P. 105544 - 105544

Published: April 20, 2024

Essentially all neuropsychiatric diagnoses show some degree of sex and/or gender differences in their etiology, diagnosis, or prognosis. As a result, the roles sex-related variables behavior and cognition are strong interest to many, with several lines research showing effects on executive functions value-based decision making particular. These findings often framed within binary, females described as less optimal than male "defaults"-- framing that pits males against each other deemphasizes enormous overlap fundamental neural mechanisms across sexes. Here, we propose an alternative framework which factors encompass just one subset many sources valuable diversity cognition. First, review literature establishing multidimensional, nonbinary impacts related chromosomes endocrine cognition, focusing value- based decision-making tasks. Next, present two suggestions for interpretations analyses data can be implemented by behavioral neuroscientists without devoting laboratory resources delving into underlying differences. We recommend (1) shifting away from performance metrics towards strategy assessments avoid fallacy is worse another; (2) asking how much variance explains measures whether any mosaic rather assuming separate inextricably correlated. Nonbinary frameworks will allow neuroscience represent full spectrum brains behaviors.

Language: Английский

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Are there distinct levels of language comprehension in autistic individuals – cluster analysis

npj Mental Health Research, Journal Year: 2024, Volume and Issue: 3(1)

Published: April 10, 2024

Abstract Autism is a neurodevelopmental condition characterized by deficits in social communication. We assessed 14-language comprehension abilities 31,845 autistic individuals 4 to 21 years of age using parent-generated reports. Data-driven cluster analysis identified three distinct levels language comprehension: (1) the command-language-phenotype were limited simple commands; (2) modifier-language-phenotype showed additional color, size, and number modifiers; 3) most-advanced syntactic-language-phenotype added spatial prepositions, verb tenses, flexible syntax, possessive pronouns, complex narratives. The observation was consistent across different groups. Autistic individuals’ communication level currently commonly as nonverbal , minimally-verbal or verbal . This one-dimensional description not ideal for characterizing an individual’s ability. In fact, individual with may have normal ability communicate albeit nonverbally, while person does any means. Identification language-comprehension-phenotypes provides opportunity enhance characterization level. A composite terms both, language-comprehension-level, will only be more precise, but can improve therapy focusing it on both aspects development.

Language: Английский

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Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: May 10, 2024

Abstract Classical metabolomic and new metabolic network methods were used to study the developmental features of autism spectrum disorder (ASD) in newborns ( n = 205) 5-year-old children 53). Eighty percent impact ASD was caused by 14 shared biochemical pathways that led decreased anti-inflammatory antioxidant defenses, increased physiologic stress molecules like lactate, glycerol, cholesterol, ceramides. CIRCOS plots a parameter, $$\dot{{{\boldsymbol{V}}}}\!$$ V ° net , revealed differences both kind degree connectivity. Of 50 450 polar lipid metabolites examined, regulation purine most changed. Purine hub analysis 17-fold reversal typically developing children. This did not occur ASD. These results previously unknown phenotypes, identified states correlation network, underscored role mitochondrial functional changes, metabolism, purinergic signaling disorder.

Language: Английский

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Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: Sept. 27, 2024

Language: Английский

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Variability in Neural Circuit Formation

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 16(3), P. a041504 - a041504

Published: Jan. 22, 2024

Kevin J. Mitchell Smurfit Institute of Genetics and Neuroscience, Trinity College Dublin, Dublin D02 PN40, Ireland Correspondence: kevin.mitchell{at}tcd.ie

Language: Английский

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