A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout
Abstract Gout is a chronic disease of monosodium urate crystal deposition in the setting of hyperuricemia that typically presents with recurrent flares of acute inflammatory arthritis that occur due to innate immune response to deposited crystals. The molecular mechanism of the progression from hyperuricemia to clinical gout is poorly understood. Here we provide insights into this progression from a genetic study of 2.6 million people, including 120,282 people with gout. We detected 376 loci and 410 genetically independent signals (148 new loci in urate and gout). We identified 1,768 candidate genes with subsequent pathway analysis revealing urate metabolism, type 2 diabetes, and chromatin modification and structure as top pathways in gout. Genes located within or statistically linked to significant GWAS loci were prioitized for their potential to control the progression from hyperuricemia to gout. This identified strong candidate immune genes involved in epigenetic remodelling, cell osmolarity, and regulation of NLRP3-inflammasome activity. The genetic association signal atXDH, encoding the urate-producing enzyme xanthine oxidoreductase (XOR), co-localizes with genetic control ofXDHexpression, but only in the prostate. We demonstrate XOR activity and urate production in the mouse prostate, and use single-cell RNA sequence data to propose a model of urate reuptake, synthesis, and secretion by the prostate. The gout-associated loci were over-represented for genes implicated in clonal hematopoeiesis of indeterminate potential (CHIP) and Mendelian randomization analysis provided evidence for a causal role of CHIP in gout. In concert with implication of epigenomic regulators, this provides support for epigenomic remodelling as causal in gout. We provide new insights into the molecular pathogenesis of gout and identify an array of candidate genes for a role in the inflammatory process of gout..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 02. Dez. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1101/2022.11.26.22281768 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI038025892 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI038025892 | ||
| 003 | DE-627 | ||
| 005 | 20231205091518.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 221201s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2022.11.26.22281768 |2 doi | |
| 035 | |a (DE-627)XBI038025892 | ||
| 035 | |a (biorXiv)10.1101/2022.11.26.22281768 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Major, Tanya J. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Gout is a chronic disease of monosodium urate crystal deposition in the setting of hyperuricemia that typically presents with recurrent flares of acute inflammatory arthritis that occur due to innate immune response to deposited crystals. The molecular mechanism of the progression from hyperuricemia to clinical gout is poorly understood. Here we provide insights into this progression from a genetic study of 2.6 million people, including 120,282 people with gout. We detected 376 loci and 410 genetically independent signals (148 new loci in urate and gout). We identified 1,768 candidate genes with subsequent pathway analysis revealing urate metabolism, type 2 diabetes, and chromatin modification and structure as top pathways in gout. Genes located within or statistically linked to significant GWAS loci were prioitized for their potential to control the progression from hyperuricemia to gout. This identified strong candidate immune genes involved in epigenetic remodelling, cell osmolarity, and regulation of NLRP3-inflammasome activity. The genetic association signal atXDH, encoding the urate-producing enzyme xanthine oxidoreductase (XOR), co-localizes with genetic control ofXDHexpression, but only in the prostate. We demonstrate XOR activity and urate production in the mouse prostate, and use single-cell RNA sequence data to propose a model of urate reuptake, synthesis, and secretion by the prostate. The gout-associated loci were over-represented for genes implicated in clonal hematopoeiesis of indeterminate potential (CHIP) and Mendelian randomization analysis provided evidence for a causal role of CHIP in gout. In concert with implication of epigenomic regulators, this provides support for epigenomic remodelling as causal in gout. We provide new insights into the molecular pathogenesis of gout and identify an array of candidate genes for a role in the inflammatory process of gout. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Takei, Riku |4 aut | |
| 700 | 1 | |a Matsuo, Hirotaka |4 aut | |
| 700 | 1 | |a Leask, Megan P. |4 aut | |
| 700 | 1 | |a Topless, Ruth K. |4 aut | |
| 700 | 1 | |a Shirai, Yuya |4 aut | |
| 700 | 1 | |a Li, Zhiqiang |4 aut | |
| 700 | 1 | |a Ji, Aichang |4 aut | |
| 700 | 1 | |a Cadzow, Murray J. |4 aut | |
| 700 | 1 | |a Sumpter, Nicholas A. |4 aut | |
| 700 | 1 | |a Merriman, Marilyn E. |4 aut | |
| 700 | 1 | |a Phipps-Green, Amanda J. |4 aut | |
| 700 | 1 | |a Urquiaga, Mariana |4 aut | |
| 700 | 1 | |a Kelley, Eric E. |4 aut | |
| 700 | 1 | |a King, Rachel D. |4 aut | |
| 700 | 1 | |a Lewis, Sara E. |4 aut | |
| 700 | 1 | |a Maxwell, Brooke A. |4 aut | |
| 700 | 1 | |a Wei, Wen-Hua |4 aut | |
| 700 | 1 | |a McCormick, Sally P.A. |4 aut | |
| 700 | 1 | |a Reynolds, Richard J. |4 aut | |
| 700 | 1 | |a Saag, Kenneth G. |4 aut | |
| 700 | 1 | |a Bixley, Matthew J. |4 aut | |
| 700 | 1 | |a Fadason, Tayaza |4 aut | |
| 700 | 1 | |a O’Sullivan, Justin M. |0 (orcid)0000-0003-2927-450X |4 aut | |
| 700 | 1 | |a Stamp, Lisa K. |4 aut | |
| 700 | 1 | |a Dalbeth, Nicola |4 aut | |
| 700 | 1 | |a Abhishek, Abhishek |4 aut | |
| 700 | 1 | |a Doherty, Michael |4 aut | |
| 700 | 1 | |a Roddy, Edward |4 aut | |
| 700 | 1 | |a Jacobsson, Lennart T.H. |4 aut | |
| 700 | 1 | |a Kapetanovic, Meliha C. |4 aut | |
| 700 | 1 | |a Melander, Olle |4 aut | |
| 700 | 1 | |a Andrés, Mariano |4 aut | |
| 700 | 1 | |a Pérez-Ruiz, Fernando |4 aut | |
| 700 | 1 | |a Torres, Rosa J |4 aut | |
| 700 | 1 | |a Radstake, Timothy |4 aut | |
| 700 | 1 | |a Jansen, Timothy L. |4 aut | |
| 700 | 1 | |a Janssen, Matthijs |4 aut | |
| 700 | 1 | |a Joosten, Leo A.B. |4 aut | |
| 700 | 1 | |a Liu, Ruiqi |4 aut | |
| 700 | 1 | |a Gaal, Orsi |4 aut | |
| 700 | 1 | |a Crişan, Tania O. |4 aut | |
| 700 | 1 | |a Rednic, Simona |4 aut | |
| 700 | 1 | |a Kurreeman, Fina |4 aut | |
| 700 | 1 | |a Huizinga, Tom W.J. |4 aut | |
| 700 | 1 | |a Toes, René |4 aut | |
| 700 | 1 | |a Lioté, Frédéric |4 aut | |
| 700 | 1 | |a Richette, Pascal |4 aut | |
| 700 | 1 | |a Bardin, Thomas |4 aut | |
| 700 | 1 | |a Ea, Hang Korng |4 aut | |
| 700 | 1 | |a Pascart, Tristan |4 aut | |
| 700 | 1 | |a McCarthy, Geraldine M. |4 aut | |
| 700 | 1 | |a Helbert, Laura |4 aut | |
| 700 | 1 | |a Stibůrková, Blanka |4 aut | |
| 700 | 1 | |a Tausche, Anne-K. |4 aut | |
| 700 | 1 | |a Uhlig, Till |4 aut | |
| 700 | 1 | |a Vitart, Véronique |4 aut | |
| 700 | 1 | |a Boutin, Thibaud S. |4 aut | |
| 700 | 1 | |a Hayward, Caroline |4 aut | |
| 700 | 1 | |a Riches, Philip L. |4 aut | |
| 700 | 1 | |a Ralston, Stuart H. |4 aut | |
| 700 | 1 | |a Campbell, Archie |4 aut | |
| 700 | 1 | |a MacDonald, Thomas M. |4 aut | |
| 700 | 1 | |a Nakayama, Akiyoshi |4 aut | |
| 700 | 1 | |a Takada, Tappei |4 aut | |
| 700 | 1 | |a Nakatochi, Masahiro |4 aut | |
| 700 | 1 | |a Shimizu, Seiko |4 aut | |
| 700 | 1 | |a Kawamura, Yusuke |4 aut | |
| 700 | 1 | |a Toyoda, Yu |4 aut | |
| 700 | 1 | |a Nakaoka, Hirofumi |4 aut | |
| 700 | 1 | |a Yamamoto, Ken |4 aut | |
| 700 | 1 | |a Matsuo, Keitaro |0 (orcid)0000-0003-1761-6314 |4 aut | |
| 700 | 1 | |a Shinomiya, Nariyoshi |4 aut | |
| 700 | 1 | |a Ichida, Kimiyoshi |4 aut | |
| 700 | 1 | |a Lee, Chaeyoung |4 aut | |
| 700 | 1 | |a Bradbury, Linda A. |4 aut | |
| 700 | 1 | |a Brown, Matthew A. |4 aut | |
| 700 | 1 | |a Robinson, Philip C. |4 aut | |
| 700 | 1 | |a Buchanan, Russell R.C. |4 aut | |
| 700 | 1 | |a Hill, Catherine L. |4 aut | |
| 700 | 1 | |a Lester, Susan |4 aut | |
| 700 | 1 | |a Smith, Malcolm D. |4 aut | |
| 700 | 1 | |a Rischmueller, Maureen |4 aut | |
| 700 | 1 | |a Choi, Hyon K. |4 aut | |
| 700 | 1 | |a Stahl, Eli A. |4 aut | |
| 700 | 1 | |a Miner, Jeff N. |4 aut | |
| 700 | 1 | |a Solomon, Daniel H. |4 aut | |
| 700 | 1 | |a Cui, Jing |4 aut | |
| 700 | 1 | |a Giacomini, Kathleen M. |4 aut | |
| 700 | 1 | |a Brackman, Deanna J. |4 aut | |
| 700 | 1 | |a Jorgenson, Eric M. |4 aut | |
| 700 | 1 | |a Wang, Wei |4 aut | |
| 700 | 1 | |a Shringarpure, Suyash |4 aut | |
| 700 | 1 | |a So, Alexander |4 aut | |
| 700 | 1 | |a Okada, Yukinori |0 (orcid)0000-0002-0311-8472 |4 aut | |
| 700 | 1 | |a Li, Changgui |4 aut | |
| 700 | 1 | |a Shi, Yongyong |4 aut | |
| 700 | 1 | |a Merriman, Tony R. |0 (orcid)0000-0003-0844-8726 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2023) vom: 02. Dez. |
| 773 | 1 | 8 | |g year:2023 |g day:02 |g month:12 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2022.11.26.22281768 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 02 |c 12 | ||