Prioritizing disease-related rare variants by integrating gene expression data DOI Creative Commons
Hanmin Guo, Alexander E. Urban, Wing Hung Wong

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 10, 2024

Abstract Rare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on diseases compared common variants. Here we present carrier statistic, statistical framework prioritize disease-related rare variants by integrating gene expression data. By quantifying the expression, statistic can those that large functional consequence in diseased patients. Through simulation studies and analyzing real multi-omics dataset, demonstrated is applicable with limited sample size (a few hundreds) achieves substantially higher sensitivity than existing association methods. Application Alzheimer's disease reveals 16 within 15 genes extreme statistics. We also found strong excess among top prioritized patients healthy individuals. The method be applied various variant types adaptable other omics data modalities, offering powerful tool for investigating molecular mechanisms underlying complex diseases.

Language: Английский

The schizophrenia syndrome, circa 2024: What we know and how that informs its nature DOI Open Access

Rajiv Tandon,

Henry A. Nasrallah, Schahram Akbarian

et al.

Schizophrenia Research, Journal Year: 2023, Volume and Issue: 264, P. 1 - 28

Published: Dec. 12, 2023

Language: Английский

Citations

60
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

58
Isoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric disorders in the human brain DOI Creative Commons
Arjun Bhattacharya, Daniel Vo, Connor Jops

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(12), P. 2117 - 2128

Published: Nov. 30, 2023

Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as molecular outcome measure. This challenge is particularly relevant for the brain, which extensive splicing generates multiple distinct transcript-isoforms per gene. Due complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, multivariate, stepwise framework genetics, phenotypic associations. Compared gene-level methods, isoTWAS improves both isoform prediction, yielding more testable genes, increased power discovery trait associations within genome-wide association study loci across 15 neuropsychiatric traits. We illustrate undetectable gene-level, prioritizing isoforms AKT3, CUL3 HSPD1 schizophrenia PCLO disorders. Results highlight importance incorporating resolution integrative approaches increase associations, especially brain-relevant

Language: Английский

Citations

32
Molecular mechanisms of schizophrenia: Insights from human genetics DOI Creative Commons
Zohreh Farsi, Morgan Sheng

Current Opinion in Neurobiology, Journal Year: 2023, Volume and Issue: 81, P. 102731 - 102731

Published: May 26, 2023

Schizophrenia is a debilitating psychiatric disorder that affects millions of people worldwide; however, its etiology poorly understood at the molecular and neurobiological levels. A particularly important advance in recent years discovery rare genetic variants associated with greatly increased risk developing schizophrenia. These primarily loss-of-function are found genes overlap those implicated by common involved regulation glutamate signaling, synaptic function, DNA transcription, chromatin remodeling. Animal models harboring mutations these large-effect schizophrenia show promise providing additional insights into mechanisms disease.

Language: Английский

Citations

24
Large-scale neurophysiology and single-cell profiling in human neuroscience DOI
Anthony T. Lee, Edward F. Chang, Mercedes F. Paredes

et al.

Nature, Journal Year: 2024, Volume and Issue: 630(8017), P. 587 - 595

Published: June 19, 2024

Language: Английский

Citations

12
Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes DOI
Eduardo A. Maury, Attila Jones, Vladimir B. Seplyarskiy

et al.

Science, Journal Year: 2024, Volume and Issue: 386(6718), P. 217 - 224

Published: Oct. 10, 2024

Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about role mosaic somatic in context SCZ. Deep (239×) whole-genome sequencing (WGS) brain neurons from 61 SCZ cases and 25 controls postmortem identified occurring during prenatal neurogenesis. showed increased variants open chromatin, with CpG transversions (CpG>GpG) T>G at transcription factor binding sites (TFBSs) overlapping a result not seen controls. Some these alter gene expression, including genes involved neurodevelopment. Although mutational processes can reflect difference factors indirectly disease, developmental TFBSs could also potentially contribute to

Language: Английский

Citations

4
Integrating rare variant genetics and brain transcriptome data implicates novel schizophrenia putative risk genes DOI
Shengtong Han,

M Gilmartin,

Wenhui Sheng

et al.

Schizophrenia Research, Journal Year: 2025, Volume and Issue: 276, P. 205 - 213

Published: Feb. 1, 2025

Language: Английский

Citations

0
Whole Genome Sequencing of Pedigrees With High Density of Substance Use and Psychiatric Disorders: A Meeting Report DOI Creative Commons
Shirley Y. Hill, Howard J. Edenberg, Aiden Corvin

et al.

Genes Brain & Behavior, Journal Year: 2025, Volume and Issue: 24(1)

Published: Feb. 1, 2025

ABSTRACT The National Institute of Drug Abuse convened a panel scientists with expertise in substance use disorders (SUD) and genetic methodologies primarily to determine the feasibility performing whole genome sequencing utilizing existing pedigree collections high density SUD psychiatric disorders. A major focus was on determining if there had been any successes identifying variants for complex traits family‐based designs. Such information could provide assurance that might significant pay‐offs particularly pursuit rare copy number variants. An important goal discuss evaluate optimal strategies studying human samples. Specific topics were (a) consider whether smaller cases typically available family studies versus larger biobanks can reveal unique information; (b) identify potential gaps biobank data be supplemented data; (c) phenotypic definitions (e.g., quantity use, problem‐oriented) collection instruments (self‐report or clinician administered) are both practical efficient collect, likely insights concerning prevention, intervention, medication development. Conclusions reached by included optimism about have occurred ascertained include densely affected pedigrees. Evaluation led, overall, consensus steps should taken utilize conjunction investigations variant discovery.

Language: Английский

Citations

0
Transcriptomic profiling of murine GnRH neurons reveals developmental trajectories linked to human reproduction and infertility DOI Creative Commons

Yassine Zouaghi,

Daniel Alpern, Vincent Gardeux

et al.

Theranostics, Journal Year: 2025, Volume and Issue: 15(8), P. 3673 - 3692

Published: Feb. 26, 2025

Rationale: Neurons producing Gonadotropin-Releasing Hormone (GnRH) are essential for human reproduction and have to migrate from nose brain during prenatal life. Impaired GnRH neuron biology results in alterations of the reproductive axis, including delayed puberty infertility, with considerable effects on quality life metabolic health. Although various genes been implicated, molecular causes these conditions remain elusive, most patients lacking a genetic diagnosis. Methods: neurons non-GnRH cells were FACS-isolated mouse embryo microdissections perform high-resolution transcriptomic profiling embryonic development. We analyzed our dataset reveal identity, gene expression dynamics, cell-to-cell communication. The spatial context candidate was validated using situ hybridization analysis. possible links health disease explored enrichment analysis GWAS data analyzing burden congenital deficiency. Results: undergo profound transcriptional shift as they display trajectories associating distinct biological processes, cell migration, neuronal projections, synapse formation. revealed timely spatially restricted modulation signaling pathways involving known novel molecules, Semaphorins Neurexins, respectively. A particular set genes, whose rises late developmental stages, showed strong association linked onset. Finally, some identified harbor diagnostic potential hypogonadism. This is supported by large cohort affected deficiency, revealing high mutation compared healthy controls. Conclusion: charted landscape dynamics underlying murine Our study highlights new development provides insights linking those reproduction.

Language: Английский

Citations

0
Rare loss-of-function variants in HECTD2 and AKAP11 confer risk of bipolar disorder DOI Creative Commons
Thorgeir E. Thorgeirsson, Vinicius Tragante, Garðar Sveinbjörnsson

et al.

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

Bipolar disorder is a highly heritable psychiatric disorder; genome-wide association studies of bipolar have yielded over 60 risk loci harboring common variants. To harness the information contained in rare loss-of-function (LOF) variants, holding promise for informing on underlying biology, we performed variant burden analysis using gene-based aggregation LOF variants whole-genome sequencing data from Iceland (4,197 cases, more than 200,000 controls) and UK Biobank (1,881 426,622 controls). We found that HECTD2 was associated with confirmed it Exome dataset. Meta-analysis also revealed AKAP11 were disorder. Both associations are new, but has previously been psychosis schizophrenia. The products interact GSK3β, protein inhibited by lithium, most effective mood stabilizer available to treat Analysis identifies an excess individuals diagnosed

Language: Английский

Citations

0