Leveraging electronic health records and knowledge networks for Alzheimer’s disease prediction and sex-specific biological insights DOI Creative Commons
Alice Tang, Katherine P. Rankin, Gabriel Cerono

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: 4(3), P. 379 - 395

Published: Feb. 21, 2024

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible progression. We demonstrate that electronic health records from the University California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction AD and (2) prioritization biological hypotheses, (3) contextualization sex dimorphism. trained random forest models predicted on a cohort 749 individuals with 250,545 controls mean area under receiver operating characteristic 0.72 (7 years prior) to 0.81 (1 day prior). further harnessed matched identify conditions predictive power onset. Knowledge highlight shared genes between multiple top predictors APOE, ACTB, IL6 INS). Genetic colocalization analysis supports association hyperlipidemia at APOE locus, as well stronger female osteoporosis locus near MS4A6A. therefore show how clinical data be utilized early identification personalized hypotheses.

Language: Английский

Genome-wide enhancer maps link risk variants to disease genes DOI
Joseph Nasser, Drew T. Bergman, Charles P. Fulco

et al.

Nature, Journal Year: 2021, Volume and Issue: 593(7858), P. 238 - 243

Published: April 7, 2021

Language: Английский

Citations

533
Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants DOI Creative Commons
Krishna G. Aragam, Tao Jiang, Anuj Goel

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(12), P. 1803 - 1815

Published: Dec. 1, 2022

The discovery of genetic loci associated with complex diseases has outpaced the elucidation mechanisms disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery (CAD) comprising 181,522 cases among 1,165,690 participants predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis Japanese GWAS yielded 38 additional prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations less than five in 95% credible set. Similarity-based clustering suggested roles early developmental processes, cell cycle signaling and vascular migration proliferation pathogenesis CAD. 220 candidate genes, combining eight complementary approaches, 123 supported by three or more approaches. Using CRISPR-Cas9, experimentally validated effect an enhancer MYO9B, which appears to mediate CAD risk regulating motility. Our analysis identifies systematically characterizes >250 inform experimental interrogation putative

Language: Английский

Citations

401
Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function DOI Open Access
Gökçen Eraslan, Eugene Drokhlyansky, Shankara Anand

et al.

Science, Journal Year: 2022, Volume and Issue: 376(6594)

Published: May 12, 2022

Understanding gene function and regulation in homeostasis disease requires knowledge of the cellular tissue contexts which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen types from 16 donors 25 samples, generating a cross-tissue atlas 209,126 nuclei profiles, integrated across tissues, donors, laboratory with conditional variational autoencoder. Using resulting atlas, highlight shared tissue-specific features tissue-resident cell populations; identify that might contribute neuromuscular, metabolic, immune components monogenic diseases biological processes involved their pathology; determine modules underlie mechanisms for complex traits analyzed by genome-wide association studies.

Language: Английский

Citations

280
The next-generation Open Targets Platform: reimagined, redesigned, rebuilt DOI Creative Commons
David Ochoa, Andrew Hercules, Miguel Carmona

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 51(D1), P. D1353 - D1359

Published: Nov. 18, 2022

The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, rebuilt the in order streamline data integration harmonisation, expand ways which users can explore data, improve user experience. gene-disease causal evidence has been enhanced expanded better capture disease causality across rare, common, somatic diseases. For annotations, incorporated new features that help assess safety tractability, including genetic constraint, PROTACtability assessments, AlphaFold structure predictions. We also introduced machine learning applications for knowledge extraction from published literature, clinical trial information, labels. technologies frameworks since update will ease introduction of creation separate instances adapted requirements. Our Community forum, training materials, outreach programme support a range use cases.

Language: Английский

Citations

264
Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors DOI Creative Commons

Niamh Mullins,

Jooeun Kang, Adrián I. Campos

et al.

Biological Psychiatry, Journal Year: 2021, Volume and Issue: 91(3), P. 313 - 327

Published: Sept. 9, 2021

Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are major source disability social economic burden. Both have substantial genetic etiology, partially shared distinct from that related psychiatric disorders.

Language: Английский

Citations

175
Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases DOI
E. Weeks, Jacob C. Ulirsch,

Nathan Cheng

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(8), P. 1267 - 1276

Published: July 13, 2023

Language: Английский

Citations

173
Systematic differences in discovery of genetic effects on gene expression and complex traits DOI
Hakhamanesh Mostafavi, Jeffrey P. Spence,

Sahin Naqvi

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(11), P. 1866 - 1875

Published: Oct. 19, 2023

Language: Английский

Citations

157
AI-powered therapeutic target discovery DOI Creative Commons
Frank W. Pun, Ivan V. Ozerov, Alex Zhavoronkov

et al.

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(9), P. 561 - 572

Published: July 19, 2023

Disease modeling and target identification are the most crucial initial steps in drug discovery, influence probability of success at every step development. Traditional is a time-consuming process that takes years to decades usually starts an academic setting. Given its advantages analyzing large datasets intricate biological networks, artificial intelligence (AI) playing growing role modern identification. We review recent advances focusing on breakthroughs AI-driven therapeutic exploration. also discuss importance striking balance between novelty confidence selection. An increasing number AI-identified targets being validated through experiments several AI-derived drugs entering clinical trials; we highlight current limitations potential pathways for moving forward.

Language: Английский

Citations

140
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

132
Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity DOI
Steven Gazal, Omer Weissbrod, Farhad Hormozdiari

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(6), P. 827 - 836

Published: June 1, 2022

Language: Английский

Citations

125