Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling DOI
Nora I. Strom, Brad Verhulst, Silviu‐Alin Bacanu

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 5, 2024

Abstract The major anxiety disorders (ANX; including generalized disorder, panic and phobias ) are highly prevalent, often onset early, persist throughout life, cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases 729,881 controls. We identified 58 independent significant risk variants 66 genes with robust biological support. In an sample 1,175,012 self-report 1,956,379 controls, 51 the associated were replicated. As predicted by twin studies, found genetic correlation between depression, neuroticism, other internalizing phenotypes. Follow-up analyses demonstrated enrichment all brain regions highlighted GABAergic signaling as one potential mechanism underlying risk. These results advance our understanding architecture prioritize for functional follow-up studies.

Language: Английский

The complex genetic architecture of Alzheimer's disease: novel insights and future directions DOI Creative Commons
Shea J. Andrews, Alan E. Renton, Brian Fulton‐Howard

et al.

EBioMedicine, Journal Year: 2023, Volume and Issue: 90, P. 104511 - 104511

Published: March 10, 2023

Language: Английский

Citations

186
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

127
Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders DOI Open Access
Alexander S. Hatoum, Sarah M. C. Colbert, Emma C. Johnson

et al.

Nature Mental Health, Journal Year: 2023, Volume and Issue: 1(3), P. 210 - 223

Published: March 22, 2023

Language: Английский

Citations

126
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture DOI Creative Commons
Remi Stevelink, Ciarán Campbell, Siwei Chen

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(9), P. 1471 - 1482

Published: Aug. 31, 2023

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes epilepsy, 52,538 controls. We identify 26 significant loci, 19 specific genetic generalized epilepsy (GGE). implicate 29 likely causal genes underlying these loci. SNP-based heritability analyses show that common variants explain between 39.6% 90% risk for GGE its subtypes. Subtype analysis revealed markedly different architectures focal epilepsies. Gene-set signals synaptic processes in both excitatory inhibitory neurons the brain. Prioritized candidate overlap with monogenic targets antiseizure medications. Finally, leverage our results alternate drugs predicted efficacy if repurposed treatment.

Language: Английский

Citations

88
Step by step: towards a better understanding of the genetic architecture of Alzheimer’s disease DOI Creative Commons
Jean‐Charles Lambert, Alfredo Ramı́rez,

Benjamin Grenier‐Boley

et al.

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(7), P. 2716 - 2727

Published: May 2, 2023

Alzheimer's disease (AD) is considered to have a large genetic component. Our knowledge of this component has progressed over the last 10 years, thanks notably advent genome-wide association studies and establishment consortia that make it possible analyze hundreds thousands cases controls. The characterization dozens chromosomal regions associated with risk developing AD (in some loci) causal genes responsible for observed signal confirmed involvement major pathophysiological pathways (such as amyloid precursor protein metabolism) opened up new perspectives central role microglia inflammation). Furthermore, large-scale sequencing projects are starting reveal impact rare variants - even in like APOE on risk. This increasingly comprehensive now being disseminated through translational research; particular, development risk/polygenic scores helping identify subpopulations more at or less AD. Although difficult assess efforts still needed comprehensively characterize AD, several lines research can be improved initiated. Ultimately, genetics combination other biomarkers) might help redefine boundaries relationships between various neurodegenerative diseases.

Language: Английский

Citations

48
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

20
Identifying and correcting for misspecifications in GWAS summary statistics and polygenic scores DOI Creative Commons
Florian Privé, Julyan Arbel, Hugues Aschard

et al.

Human Genetics and Genomics Advances, Journal Year: 2022, Volume and Issue: 3(4), P. 100136 - 100136

Published: Aug. 18, 2022

Publicly available genome-wide association studies (GWAS) summary statistics exhibit uneven quality, which can impact the validity of follow-up analyses. First, we present an overview possible misspecifications that come with GWAS statistics. Then, in both simulations and real-data analyses, show additional information such as imputation INFO scores, allele frequencies, per-variant sample sizes be used to detect issues correct for One important motivation us is improve predictive performance polygenic scores built from these Unfortunately, owing lack reporting standards statistics, this not systematically reported. We also using well-matched linkage disequilibrium (LD) references model fit translate into more accurate prediction. Finally, discuss how make score methods lassosum LDpred2 robust their power.

Language: Английский

Citations

52
Inferring disease architecture and predictive ability with LDpred2-auto DOI
Florian Privé, Clara Albiñana, Julyan Arbel

et al.

The American Journal of Human Genetics, Journal Year: 2023, Volume and Issue: 110(12), P. 2042 - 2055

Published: Nov. 8, 2023

Language: Английский

Citations

26
Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis DOI Creative Commons
Andrew D. Grotzinger, Travis T. Mallard,

Zhaowen Liu

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 20, 2023

Abstract Recent work in imaging genetics suggests high levels of genetic overlap within cortical regions for thickness (CT) and surface area (SA). We model this multivariate system relationships by applying Genomic Structural Equation Modeling (Genomic SEM) parsimoniously define five genomic brain factors underlying both CT SA along with a general factor capturing across all regions. validate these demonstrating the generalizability to semi-independent sample show that align biologically functionally relevant parcellations cortex. apply Stratified SEM identify specific categories genes (e.g., neuronal cell types) are disproportionately associated pleiotropy subclusters regions, as indexed factors. Finally, we examine associations psychiatric cognitive correlates, finding broad aspects function null. These analyses provide key insights into architecture two critical features cerebral

Language: Английский

Citations

24
Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study DOI
Eleni Friligkou, Solveig Løkhammer, Brenda Cabrera‐Mendoza

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Language: Английский

Citations

14