Genetic evidence for causal effects of immune dysfunction in psychiatric disorders: where are we? DOI Creative Commons
Olena Iakunchykova, Esten H. Leonardsen, Yunpeng Wang

et al.

Translational Psychiatry, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 26, 2024

Abstract The question of whether immune dysfunction contributes to risk psychiatric disorders has long been a subject interest. To assert this hypothesis plethora correlative evidence accumulated from the past decades; however, variety technical and practical obstacles impeded on cause-effect interpretation these data. With advent large-scale omics technology advanced statistical models, particularly Mendelian randomization, new studies testing old are accruing. Here we synthesize findings genomics genetic causal inference role in major reconcile data with pre-omics findings. By reconciling evidences, aim identify key gaps propose directions for future field.

Language: Английский

New insights from the last decade of research in psychiatric genetics: discoveries, challenges and clinical implications DOI Open Access
Ole A. Andreassen, Guy Hindley, Oleksandr Frei

et al.

World Psychiatry, Journal Year: 2023, Volume and Issue: 22(1), P. 4 - 24

Published: Jan. 14, 2023

Psychiatric genetics has made substantial progress in the last decade, providing new insights into genetic etiology of psychiatric disorders, and paving way for precision psychiatry, which individual profiles may be used to personalize risk assessment inform clinical decision‐making. Long recognized heritable, recent evidence shows that disorders are influenced by thousands variants acting together. Most these commonly occurring, meaning every a each disorder, from low high. A series large‐scale studies have discovered an increasing number common rare robustly associated with major disorders. The most convincing biological interpretation findings implicates altered synaptic function autism spectrum disorder schizophrenia. However, mechanistic understanding is still incomplete. In line their extensive epidemiological overlap, appear exist on continua share large degree one another. This provides further support notion current diagnoses do not represent distinct pathogenic entities, ongoing attempts reconceptualize nosology. also influences range behavioral somatic traits diseases, including brain structures, cognitive function, immunological phenotypes cardiovascular disease, suggesting shared potential importance. Current polygenic score tools, predict susceptibility illness, yet provide clinically actionable information. likely improve coming years, they eventually become part practice, stressing need educate clinicians patients about use misuse. review discusses key possible applications, suggests future directions.

Language: Английский

Citations

142
Annual Research Review: Perspectives on progress in ADHD science – from characterization to cause DOI Creative Commons
Edmund Sonuga‐Barke, Stephen Becker, Sven Bölte

et al.

Journal of Child Psychology and Psychiatry, Journal Year: 2022, Volume and Issue: 64(4), P. 506 - 532

Published: Oct. 11, 2022

The science of attention‐deficit/hyperactivity disorder (ADHD) is motivated by a translational goal – the discovery and exploitation knowledge about nature ADHD to benefit those individuals whose lives it affects. Over past fifty years, scientific research has made enormous strides in characterizing condition understanding its correlates causes. However, translation these insights into clinical benefits been limited. In this review, we provide selective focused survey field ADHD, providing our personal perspectives on what constitutes consensus, important new leads be highlighted, key outstanding questions addressed going forward. We cover two broad domains characterization and, risk factors, causal processes neuro‐biological pathways . Part one focuses developmental course co‐occurring characteristics conditions, functional impact living with including impairment, quality life, stigma. part two, explore genetic environmental influences putative mediating brain processes. final section, reflect future construct light cross‐cutting themes recent conceptual reformulations that cast traits as broader spectrum neurodivergence.

Language: Английский

Citations

87
Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals DOI Creative Commons
Hang Zhou, Rachel L. Kember, Joseph D. Deak

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(12), P. 3184 - 3192

Published: Dec. 1, 2023

Abstract Problematic alcohol use (PAU), a trait that combines disorder and alcohol-related problems assessed with questionnaire, is leading cause of death morbidity worldwide. Here we conducted large cross-ancestry meta-analysis PAU in 1,079,947 individuals (European, N = 903,147; African, 122,571; Latin American, 38,962; East Asian, 13,551; South 1,716 ancestries). We observed high degree cross-ancestral similarity the genetic architecture identified 110 independent risk variants within- analyses. Cross-ancestry fine mapping improved identification likely causal variants. Prioritizing genes through gene expression chromatin interaction brain tissues multiple associated PAU. existing medications for potential pharmacological studies by computational drug repurposing analysis. polygenic scores showed better performance association samples than single-ancestry scores. Genetic correlations between other traits were ancestries, substance having highest correlations. This study advances our knowledge etiology PAU, these findings may bring possible clinical applicability genetics insights—together neuroscience, biology data science—closer.

Language: Английский

Citations

84
Attention-deficit/hyperactivity disorder DOI
Stephen V. Faraone, Mark A. Bellgrove, Isabell Brikell

et al.

Nature Reviews Disease Primers, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 22, 2024

Language: Английский

Citations

84
Genomic findings in schizophrenia and their implications DOI Creative Commons
Michael J. Owen, Sophie E. Legge, Elliott Rees

et al.

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(9), P. 3638 - 3647

Published: Sept. 1, 2023

Abstract There has been substantial progress in understanding the genetics of schizophrenia over past 15 years. This revealed a highly polygenic condition with majority currently explained heritability coming from common alleles small effect but additional contributions rare copy number and coding variants. Many specific genes loci have implicated that provide firm basis upon which mechanistic research can proceed. These point to disturbances neuronal, particularly synaptic, functions are not confined brain regions circuits. Genetic findings also nature schizophrenia’s close relationship other conditions, bipolar disorder childhood neurodevelopmental disorders, provided an explanation for how risk persist population face reduced fecundity. Current genomic approaches only potentially explain around 40% heritability, proportion this is attributable robustly identified loci. The extreme polygenicity poses challenges biological mechanisms. high degree pleiotropy points need more transdiagnostic shortcomings current diagnostic criteria as means delineating biologically distinct strata. It inferring causality observational experimental studies both humans model systems. Finally, Eurocentric bias needs be rectified maximise benefits ensure these felt across diverse communities. Further advances likely come through application new emerging technologies, such whole-genome long-read sequencing, large samples. Substantive will require parallel functional genomics proteomics applied developmental stages. For efforts succeed identifying disease mechanisms defining novel strata they combined sufficiently granular phenotypic data.

Language: Английский

Citations

68
Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder DOI
Caroline M. Nievergelt, Adam X. Maihofer, Elizabeth G. Atkinson

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 792 - 808

Published: April 18, 2024

Language: Английский

Citations

55
An overview on neurobiology and therapeutics of attention-deficit/hyperactivity disorder DOI Creative Commons
Bruna Santos da Silva, Eugênio H. Grevet,

Luiza Carolina Fagundes Silva

et al.

Discover Mental Health, Journal Year: 2023, Volume and Issue: 3(1)

Published: Jan. 5, 2023

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition characterized by developmentally inappropriate symptoms of inattention and/or hyperactivity/impulsivity, which leads to impairments in the social, academic, and professional contexts. ADHD diagnosis relies solely on clinical assessment based symptom evaluation sometimes challenging due substantial heterogeneity disorder terms pathophysiological aspects. Despite difficulties imposed high complexity etiology, growing body research technological advances provide good perspectives for understanding neurobiology disorder. Such knowledge essential refining identifying new therapeutic options optimize treatment outcomes associated impairments, leading improvements all domains patient care. This review intended be an updated outline that addresses etiological neurobiological aspects its treatment, considering impact "omics" era disentangling multifactorial architecture ADHD.

Language: Английский

Citations

46
A cross-species proteomic map reveals neoteny of human synapse development DOI
Li Wang,

Kaifang Pang,

Li Zhou

et al.

Nature, Journal Year: 2023, Volume and Issue: 622(7981), P. 112 - 119

Published: Sept. 13, 2023

Language: Английский

Citations

46
Why are females less likely to be diagnosed with ADHD in childhood than males? DOI Creative Commons
Joanna Martin

The Lancet Psychiatry, Journal Year: 2024, Volume and Issue: 11(4), P. 303 - 310

Published: Feb. 7, 2024

ADHD is less likely to be diagnosed in females than males, especially childhood. Females also typically receive the diagnosis later males and are prescribed medication. Understanding why these sex differences clinical care treatment for occur key improving timely people affected by ADHD. This Personal View a conceptual review synthesising literature on this topic. publication considers potential biological explanations (eg, genetic factors), influence of diagnostic practices criteria suitability, overshadowing, sex-specific thresholds), sociocultural presentation compensatory behaviours), observed practice. outlines future research directions understanding recognition

Language: Английский

Citations

32
Genetic architecture of the structural connectome DOI Creative Commons
Michael Wainberg, Natalie J. Forde,

Salim Mansour

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 4, 2024

Abstract Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these remains unclear. We perform genome-wide association studies 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography 26,333 UK Biobank participants, each representing density myelinated within or a pair cortical networks, subcortical structures hemispheres. identify 30 independent significant variants after Bonferroni correction for number studied (126 at nominal significance) implicating genes involved in myelination ( SEMA3A ), neurite elongation guidance NUAK1 , STRN DPYSL2 EPHA3 HGF SHTN1 neural cell proliferation differentiation GMNC CELF4 neuronal migration CCDC88C cytoskeletal CTTNBP2 MAPT DAAM1 MYO16 PLEC metal transport SLC39A8 ). These have four broad patterns spatial with connectivity: some disproportionately strong associations corticothalamic connectivity, interhemispheric both, while others are more spatially diffuse. Structural highly polygenic, median 9.1 percent common estimated to non-zero effects on measure, exhibited signatures negative selection. genetic correlations variety neuropsychiatric cognitive traits, indicating connectivity-altering tend influence health function. Heritability is enriched regions increased chromatin accessibility adult oligodendrocytes (as well as microglia, inhibitory neurons astrocytes) multiple fetal types, suggesting control partially mediated by early development. Our results indicate pervasive, pleiotropic, structured white-matter via diverse neurodevelopmental pathways, support relevance this healthy

Language: Английский

Citations

22