A disease-associated gene desert directs macrophage inflammation through ETS2 DOI Creative Commons
Christina T. Stankey, Christophe Bourges, Lea-Maxie Haag

et al.

Nature, Journal Year: 2024, Volume and Issue: 630(8016), P. 447 - 456

Published: June 5, 2024

Abstract Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health 1 . This is compounded by the limited efficacy available treatments high failure during drug development 2 , highlighting an urgent need better understand mechanisms. Here we show how functional genomics could address this challenge. By investigating intergenic haplotype on chr21q22—which has been independently linked bowel disease, ankylosing spondylitis, primary sclerosing cholangitis Takayasu’s arteritis 3–6 —we identify that causal gene, ETS2 central regulator macrophages delineate shared mechanism amplifies expression. Genes regulated were prominently expressed in diseased tissues more enriched for GWAS hits than most previously described pathways. Overexpressing resting reproduced state observed chr21q22-associated diseases, with upregulation multiple targets, including TNF IL-23. Using database cellular signatures 7 identified drugs might modulate pathway validated potent anti-inflammatory activity one class small molecules vitro ex vivo. Together, illustrates power genomics, applied directly cells, immune-mediated mechanisms potential therapeutic opportunities.

Language: Английский

FinnGen provides genetic insights from a well-phenotyped isolated population DOI Creative Commons
Mitja Kurki,

Juha Karjalainen,

Priit Palta

et al.

Nature, Journal Year: 2023, Volume and Issue: 613(7944), P. 508 - 518

Published: Jan. 18, 2023

Abstract Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These survived the founding bottleneck rather than being distributed over large ultrarare variants. Although this effect is well established Mendelian genetics, its value common disease genetics less explored 1,2 . FinnGen aims to study genome and national health register data 500,000 Finnish individuals. Given relatively high median age participants (63 years) substantial fraction hospital-based recruitment, enriched for end points. Here we analyse from 224,737 15 diseases that have previously been investigated genome-wide association studies (GWASs). We also include meta-analyses biobank Estonia United Kingdom. identified 30 new associations, primarily variants, population. A GWAS 1,932 2,733 significant associations (893 phenome-wide (PWS), P 2.6 × 10 –11 ) at 2,496 (771 PWS) independent loci with 807 (247 Among these, fine-mapping implicated 148 (73 coding associated 83 (42 Moreover, 91 (47 had an <5% non-Finnish European individuals, which 62 (32 were by more twofold Finland. findings demonstrate power bottlenecked populations find entry points into biology through low-frequency, impact

Language: Английский

Citations

2175
Ensembl 2022 DOI Creative Commons
Fiona Cunningham, James E. Allen, Jamie Allen

et al.

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 50(D1), P. D988 - D995

Published: Oct. 19, 2021

Ensembl (https://www.ensembl.org) is unique in its flexible infrastructure for access to genomic data and annotation. It has been designed efficiently deliver annotation at scale all eukaryotic life, it also provides deep comprehensive key species. Genomes representing a greater diversity of species are increasingly being sequenced. In response, we have focussed our recent efforts on expediting the new assemblies. Here, report release greatest annual number newly annotated genomes history via dedicated Rapid Release platform (http://rapid.ensembl.org). We developed method generate comparative analyses these assemblies and, first time, non-vertebrate eukaryotes. Meanwhile, continually improve, extend update high-value reference vertebrate details here. range specific software tools tasks, such as Variant Effect Predictor (VEP) interface Recoder. All data, freely available download accessible programmatically.

Language: Английский

Citations

1644
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
Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics DOI Creative Commons
Maya Ghoussaini, Edward Mountjoy, Miguel Carmona

et al.

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 49(D1), P. D1311 - D1320

Published: Sept. 17, 2020

Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction conformation from a wide range of cell types tissues to make robust connections between GWAS-associated loci, variants likely causal genes. This enables systematic identification prioritisation genes across all published trait-associated loci. In this paper, we describe the public resources aggregate, technology analyses use, functionality portal offers. can be searched by variant, or study/phenotype. It offers tools enable users prioritise at disease-associated loci access cross-disease disease-molecular trait colocalization analysis 92 eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional credible sets overlap studies PheWAS plots explore signals in depth. The integrated made available through web portal, for bulk download via GraphQL API, software open source. Applications include novel targets drug discovery repurposing.

Language: Английский

Citations

497
An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci DOI
Edward Mountjoy, Ellen M. Schmidt, Miguel Carmona

et al.

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(11), P. 1527 - 1533

Published: Oct. 28, 2021

Language: Английский

Citations

420
Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes DOI
Jeremy Schwartzentruber, Sarah Cooper, Jimmy Z. Liu

et al.

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(3), P. 392 - 402

Published: Feb. 15, 2021

Language: Английский

Citations

408
Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets DOI Creative Commons
Jing Hua Zhao, David Stacey, Niclas Eriksson

et al.

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(9), P. 1540 - 1551

Published: Aug. 10, 2023

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted genome-wide protein quantitative trait locus (pQTL) study 91 plasma measured using the Olink Target platform 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration pQTL data with eQTL disease association studies provided insight into pathogenesis, implicating lymphotoxin-α multiple sclerosis. Using Mendelian randomization (MR) to assess causality etiology, both shared distinct effects specific across immune-mediated diseases, including directionally discordant CD40 risk rheumatoid arthritis versus sclerosis inflammatory bowel disease. MR implicated CXCL5 etiology ulcerative colitis (UC) show elevated gut transcript expression patients UC. These results targets existing drugs provide powerful resource facilitate future drug target prioritization.

Language: Английский

Citations

362
FinnGen: Unique genetic insights from combining isolated population and national health register data DOI Creative Commons
Mitja Kurki,

Juha Karjalainen,

Priit Palta

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: March 6, 2022

ABSTRACT Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles any gene is often concentrated on a small number low-frequency variants (0.1% ≤ minor allele frequency < 5%), which survived founding bottleneck, opposed to being distributed over much larger ultra--rare variants. While this advantage well-- established Mendelian genetics, its value common disease genetics has been less explored. FinnGen aims study genome and national health register data 500,000 Finns, already reaching 224,737 genotyped phenotyped participants. Given relatively high median age participants (63 years) dominance hospital-based recruitment, enriched for many endpoints underrepresented population-based (e.g., rarer immune-mediated diseases late onset degenerative ophthalmologic endpoints). We report here genome-wide association (GWAS) 1,932 clinical defined from nationwide registries. identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding associated with 202 endpoints, 104 low (AF<10%) 62 were two-fold Finland. studied benchmark set 15 that had previously investigated large studies. discovery analyses meta-analysed Estonian UK biobanks. 30 novel associations, primarily strongly enriched, or specific to, Finnish population Uralic language family neighbors Estonia Russia. These findings demonstrate power bottlenecked populations find unique entry points into biology through low-frequency, impact Such have potential contribute medical translation including drug discovery.

Language: Английский

Citations

347
Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles DOI Creative Commons
Heidi Hautakangas, Bendik S. Winsvold, Sanni Ruotsalainen

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(2), P. 152 - 160

Published: Feb. 1, 2022

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed genome-wide association study of 102,084 migraine cases and 771,257 controls identified 123 loci, which 86 are previously These loci provide an opportunity to evaluate shared distinct components in the two main subtypes: with aura without aura. Stratification risk using 29,679 subtype information indicated three variants that seem specific for (in HMOX2, CACNA1A MPPED2), (near SPINK2 near FECH) nine increase susceptibility regardless subtype. The new include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated were enriched both vascular central nervous system tissue/cell types, supporting unequivocally neurovascular mechanisms underlie pathophysiology.

Language: Английский

Citations

256
Gene regulatory network inference in the era of single-cell multi-omics DOI
Pau Badia-i-Mompel, Lorna Wessels, Sophia Müller‐Dott

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(11), P. 739 - 754

Published: June 26, 2023

Language: Английский

Citations

187