Candidate biomarkers in psychiatric disorders: state of the field

World Psychiatry, Journal Year: 2023, Volume and Issue: 22(2), P. 236 - 262

Published: May 9, 2023

The field of psychiatry is hampered by a lack robust, reliable and valid biomarkers that can aid in objectively diagnosing patients providing individualized treatment recommendations. Here we review critically evaluate the evidence for most promising psychiatric neuroscience literature autism spectrum disorder, schizophrenia, anxiety disorders post‐traumatic stress major depression bipolar substance use disorders. Candidate reviewed include various neuroimaging, genetic, molecular peripheral assays, purposes determining susceptibility or presence illness, predicting response safety. This highlights critical gap biomarker validation process. An enormous societal investment over past 50 years has identified numerous candidate biomarkers. However, to date, overwhelming majority these measures have not been proven sufficiently reliable, useful be adopted clinically. It time consider whether strategic investments might break this impasse, focusing on limited number candidates advance through process definitive testing specific indication. Some N170 signal, an event‐related brain potential measured using electroencephalography, subgroup identification within disorder; striatal resting‐state functional magnetic resonance imaging (fMRI) measures, such as connectivity index (SCI) abnormalities (FSA) index, prediction schizophrenia; error‐related negativity (ERN), electrophysiological first onset generalized structural connectomic social disorder. Alternate forms classification may conceptualizing Collaborative efforts allowing inclusion biosystems beyond genetics neuroimaging are needed, online remote acquisition selected naturalistic setting mobile health tools significantly field. Setting benchmarks well‐defined target application, along with development appropriate funding partnership mechanisms, would also crucial. Finally, it should never forgotten that, actionable, will need clinically predictive at individual level viable clinical settings.

Language: Английский

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Genomic architecture of autism from comprehensive whole-genome sequence annotation

Cell, Journal Year: 2022, Volume and Issue: 185(23), P. 4409 - 4427.e18

Published: Nov. 1, 2022

Language: Английский

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ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D

Nature, Journal Year: 2024, Volume and Issue: 630(8016), P. 437 - 446

Published: April 10, 2024

Language: Английский

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Autism severity and its relationship to disability

Autism Research, Journal Year: 2023, Volume and Issue: 16(4), P. 685 - 696

Published: Feb. 14, 2023

Autism severity is currently defined and measured based exclusively on the levels of two core symptom domains: social-communication restricted or repetitive patterns behaviors interests. Autistic individuals, however, are often diagnosed with other medical, developmental, psychological co-occurring conditions. These additional challenges such as intellectual disability, limited expressive and/or receptive language, anxiety disorders, can have a tremendous impact day-to-day lives autistic for both their adaptive functioning well sense wellbeing. Furthermore, initial presentation symptoms likelihood changing over time influenced by presence In order to truly understand how person's autism impacts life, should be considered. This approach was recently taken byThe Lancet Commission future care clinical research in autism, which proposed term "profound autism" subgroup individuals presenting high severity, little no who require extensive long-term care. Considering individual factors daily living skills, specific support needs environmental resources would also enhance evaluation disability individuals. As employed assessment multidimensional could provide more comprehensive system classification impairment. At present, there formal way designate combined effect these different aspects life. A outlook that acknowledges impairments, capabilities, conditions, useful identifying subgroups determining strengths assessments.

Language: Английский

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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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Phenotypic effects of genetic variants associated with autism

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(7), P. 1671 - 1680

Published: June 26, 2023

Abstract While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis autism. Nor do we fully appreciate phenotypic diversity beyond formal autism diagnosis. Based on data from more than 13,000 and 210,000 undiagnosed individuals, estimated odds ratios for to rare loss-of-function (LoF) 185 alongside 2,492 displaying intolerance LoF variants. In contrast autism-centric approaches, investigated correlates these We show that are small but significant decrease fluid intelligence, qualification level income an increase metrics related material deprivation. These effects were larger autism-associated other LoF-intolerant genes. Using brain imaging 21,040 UK Biobank, could not detect differences overall anatomy between carriers non-carriers. Our results highlight importance studying effect genetic categorical need research understand association sociodemographic factors, best support carrying

Language: Английский

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A 25-year odyssey of genomic technology advances and structural variant discovery

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1024 - 1037

Published: Jan. 29, 2024

Language: Английский

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Massively parallel characterization of regulatory elements in the developing human cortex

Science, Journal Year: 2024, Volume and Issue: 384(6698)

Published: May 23, 2024

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays primary human cells from mid-gestation cortex cerebral organoids, we interrogated the cis-regulatory activity 102,767 open chromatin regions, including thousands sequences with cell type-specific accessibility variants associated brain regulation. In cells, identified 46,802 active enhancer 164 that alter activity. Activity was comparable organoids suggesting provide an adequate model for developing cortex. deep learning decoded sequence basis upstream regulators This work establishes a comprehensive catalog functional development.

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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Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease

Cell Reports, Journal Year: 2025, Volume and Issue: unknown, P. 115355 - 115355

Published: March 1, 2025

Highlights•ITSN1 haploinsufficiency confers a ∼10-fold increased risk of Parkinson's disease (PD)•Effect size surpasses other well-established loci, including GBA1 and LRRK2•In vivo in vitro studies suggest an interaction between ITSN1 α-synuclein•Findings implicate synaptic vesicle trafficking dysfunction PD pathogenesisSummaryDespite its significant heritability, the genetic basis (PD) remains incompletely understood. Here, analyzing whole-genome sequence data from 3,809 cases 247,101 controls UK Biobank, we discover that protein-truncating variants confer substantially (p = 6.1 × 10−7; odds ratio [95% confidence interval] 10.5 [5.2, 21.3]). We replicate this association three independent datasets totaling 8,407 413,432 (combined p 4.5 10−12). Notably, has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, find loss ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity motor deficits, assays further physical α-synuclein. These results firmly establish as gene effect exceeding previously established vesicular pathogenesis, potentially open new avenues for therapeutic development.Graphical abstract

Language: Английский

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