GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets DOI Creative Commons
Nick Dand, Philip E. Stuart, John Bowes

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 28, 2025

Abstract Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to not fully explained variation at robustly risk loci. To refine map susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls 109 distinct loci, 46 that been previously reported. These include variants loci in which therapeutic targets IL17RA AHR are encoded, deleterious coding supporting potential new drug (including STAP2 , CPVL POU2F3 ). We conducted transcriptome-wide association study identify regulatory effects cross-referenced these against single cell expression profiles psoriasis-affected skin, highlighting roles for transcriptional regulation haematopoietic development epigenetic modulation interferon signalling pathobiology.

Language: Английский

Pharmacogenomics: current status and future perspectives DOI
Munir Pirmohamed

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(6), P. 350 - 362

Published: Jan. 27, 2023

Language: Английский

Citations

173
Principles and methods for transferring polygenic risk scores across global populations DOI
Linda Kachuri, Nilanjan Chatterjee, Jibril Hirbo

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 25(1), P. 8 - 25

Published: Aug. 24, 2023

Language: Английский

Citations

140
A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease DOI Creative Commons
Aniruddh P. Patel, Minxian Wang, Yunfeng Ruan

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(7), P. 1793 - 1803

Published: July 1, 2023

Abstract Identification of individuals at highest risk coronary artery disease (CAD)—ideally before onset—remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable stratification, reflecting the substantial inherited component CAD risk. Here we develop a new and significantly improved score for CAD, termed GPS Mult , that incorporates association data across five ancestries (>269,000 cases >1,178,000 controls) ten factors. strongly associated with prevalent (odds ratio per standard deviation 2.14, 95% confidence interval 2.10–2.19, P < 0.001) in UK Biobank participants European ancestry, identifying 20.0% population 3-fold increased conversely 13.9% decreased as compared those middle quintile. was also incident events (hazard 1.73, 1.70–1.76, 0.001), 3% healthy future equivalent existing improving discrimination reclassification. Across multiethnic, external validation datasets inclusive 33,096, 124,467, 16,433 16,874 African, European, Hispanic South Asian respectively, demonstrated strength associations all outperformed available previously published scores. These contribute field provide generalizable framework how large-scale integration genetic related traits from diverse populations can meaningfully improve prediction.

Language: Английский

Citations

130
Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens DOI Open Access
John Morris, Christina M. Caragine, Zharko Daniloski

et al.

Science, Journal Year: 2023, Volume and Issue: 380(6646)

Published: May 4, 2023

Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome unknown effects. Using ancestrally diverse, biobank-scale GWAS data, massively parallel CRISPR screens, single-cell transcriptomic proteomic sequencing, we discovered 124

Language: Английский

Citations

112
Taiwan Biobank: A rich biomedical research database of the Taiwanese population DOI Creative Commons
Yen‐Chen Anne Feng, Chia‐Yen Chen, Tzu‐Ting Chen

et al.

Cell Genomics, Journal Year: 2022, Volume and Issue: 2(11), P. 100197 - 100197

Published: Oct. 12, 2022

The Taiwan Biobank (TWB) is an ongoing prospective study of >150,000 individuals aged 20-70 in Taiwan. A comprehensive list phenotypes was collected for each consented participant at recruitment and follow-up visits through structured interviews physical measurements. Biomarkers genetic data were generated from blood urine samples. We present here overview TWB's quality, population structure, familial relationship, which consists predominantly Han Chinese ancestry, highlight its important attributes findings thus far. linkage to Taiwan's National Health Insurance database >25 years other registries underway enrich the phenotypic spectrum enable deep longitudinal investigations. TWB provides one largest biobank resources biomedical public health research East Asia that will contribute our understanding basis disease global populations collaborative studies with biobanks.

Language: Английский

Citations

91
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

82
Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure DOI Creative Commons
Michael G. Levin, Noah L. Tsao, Pankhuri Singhal

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 14, 2022

Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution common genetic variation to heart risk has not been fully elucidated, particularly in comparison other cardiometabolic traits. We report multi-ancestry genome-wide association study meta-analysis all-cause including up 115,150 cases 1,550,331 controls diverse ancestry, identifying 47 loci. also perform multivariate studies that integrate with related cardiac magnetic resonance imaging endophenotypes, 61 Gene-prioritization analyses colocalization transcriptome-wide identify known previously unreported candidate cardiomyopathy genes cellular processes, which we validate gene-expression profiling failing healthy human hearts. Colocalization, gene expression profiling, Mendelian randomization provide convergent evidence for roles BCKDHA circulating branch-chain amino acids structure. Finally, proteome-wide identifies 9 proteins associated or quantitative These highlight similarities differences among implicate pathogenesis failure, may represent treatment targets.

Language: Английский

Citations

81
Nuclear genetic control of mtDNA copy number and heteroplasmy in humans DOI Creative Commons
Rahul Gupta, Masahiro Kanai, Timothy Durham

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7975), P. 839 - 848

Published: Aug. 16, 2023

Abstract Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation 1 . Heteroplasmy refers to the presence of mixture mtDNA alleles in an individual and has been associated with disease ageing. Mechanisms underlying common variation human heteroplasmy, influence nuclear on this variation, remain insufficiently explored. Here we quantify copy number (mtCN) heteroplasmy using blood-derived whole-genome sequences from 274,832 individuals perform genome-wide association studies identify loci. Following blood cell composition correction, find that mtCN declines linearly age variants at 92 We observe nearly everyone harbours heteroplasmic obeying two principles: (1) single nucleotide tend arise somatically accumulate sharply after 70 years, whereas (2) indels are inherited as mixtures relative levels 42 loci involved replication, maintenance novel pathways. These may act by conferring replicative advantage certain alleles. As illustrative example, length variant carried more than 50% humans position chrM:302 within G-quadruplex previously proposed mediate transcription/replication switching 2,3 exerts cis -acting genetic control over abundance itself in- trans encoding machinery regulatory switch. Our study suggests can shape dynamics across population.

Language: Английский

Citations

78
Causal effects on complex traits are similar for common variants across segments of different continental ancestries within admixed individuals DOI
Kangcheng Hou, Yi Ding,

Ziqi Xu

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(4), P. 549 - 558

Published: March 20, 2023

Language: Английский

Citations

75
Genotyping and population characteristics of the China Kadoorie Biobank DOI Creative Commons
Robin Walters, Iona Y. Millwood, Kuang Lin

et al.

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(8), P. 100361 - 100361

Published: July 20, 2023

The China Kadoorie Biobank (CKB) is a population-based prospective cohort of >512,000 adults recruited from 2004 to 2008 10 geographically diverse regions across China. Detailed data questionnaires and physical measurements were collected at baseline, with additional three resurveys involving ∼5% surviving participants. Analyses genome-wide genotyping, for >100,000 participants using custom-designed Axiom arrays, reveal extensive relatedness, recent consanguinity, signatures reflecting large-scale population movements Chinese history. Systematic association studies incident disease, captured through electronic linkage death disease registries the national health insurance system, replicate established loci identify 14 novel associations. Together candidate drug targets risk factors contributions international genetics consortia, these demonstrate breadth, depth, quality CKB data. Ongoing high-throughput omics assays biosamples planned whole-genome sequencing will further enhance scientific value this biobank.

Language: Английский

Citations

75