Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Cindy G. Boer; Konstantinos Hatzikotoulas; Lorraine Southam; Lilja Stefansdottir; Yanfei  Zhang; Rodrigo  Coutinho de Almeida; Tian T.  wu; Jie Zhang; April E Hartley; Maris  Teder-Laving; Anne Heidi Skogholt; Chikashi  Terao; Eleni Zengini; George  Alexiadis; Andrei  Barysenka; Gyda Bjornsdottir; Maiken Gabrielsen; Arthur Gilly; Thorvaldur Ingvarsson; Marianne B.  Johnsen; Helgi Jonsson; Margreet Kloppenburg; Almut  Luetge; Sigrun H.  Lund; Reedik Mägi; Massimo Mangino; Rob Nelissen; Manu  Shivakumar; Julia Steinberg; Hiroshi  Takuwa; Laurent  Thomas; Margo  Tuerlings; George C Babis; Jason  Pui Yin Cheung; Jae Hee  Kang; Peter Kraft; Steven A.  Lietman; Dino  Samartzis; Eline  Slagboom; Kari Stefansson; Unnur Thorsteinsdottir; Jonathan H Tobias; André G Uitterlinden; Bendik S Winsvold; John-Anker Zwart; George Davey Smith; Pak Chung Sham; Gudmar Thorleifsson; Tom R Gaunt; Andrew  Morris; Ana M Valdes; Aspasia  Tsezou; Kathryn  S.E. Cheah; Shiro Ikegawa; Kristian Hveem; Tõnu Esko; J Mark Wilkinson; Ingrid Meulenbelt; Ming  Ta Michael Lee; Joyce B.J.  van Meurs; Unnur Styrkarsdottir; Eleftheria Zeggini

doi:10.1016/j.cell.2021.07.038

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Cindy G. Boer, Konstantinos Hatzikotoulas, Lorraine Southam, Lilja Stefansdottir, Yanfei Zhang, Rodrigo Coutinho de Almeida, Tian T. wu, Jie Zhang, April E Hartley, Maris Teder-Laving, Anne Heidi Skogholt, Chikashi Terao, Eleni Zengini, George Alexiadis, Andrei Barysenka, Gyda Bjornsdottir, Maiken Gabrielsen, Arthur Gilly, Thorvaldur Ingvarsson, Marianne B. JohnsenHelgi Jonsson, Margreet Kloppenburg, Almut Luetge, Sigrun H. Lund, Reedik Mägi, Massimo Mangino, Rob Nelissen, Manu Shivakumar, Julia Steinberg, Hiroshi Takuwa, Laurent Thomas, Margo Tuerlings, George C Babis, Jason Pui Yin Cheung, Jae Hee Kang, Peter Kraft, Steven A. Lietman, Dino Samartzis, Eline Slagboom, Kari Stefansson, Unnur Thorsteinsdottir, Jonathan H Tobias, André G Uitterlinden, Bendik S Winsvold, John-Anker Zwart, George Davey Smith, Pak Chung Sham, Gudmar Thorleifsson, Tom R Gaunt, Andrew Morris, Ana M Valdes, Aspasia Tsezou, Kathryn S.E. Cheah, Shiro Ikegawa, Kristian Hveem, Tõnu Esko, J Mark Wilkinson, Ingrid Meulenbelt, Ming Ta Michael Lee, Joyce B.J. van Meurs, Unnur Styrkarsdottir, Eleftheria Zeggini^*

^*Corresponding author for this work

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Abstract

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis), and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants, and identify differences in genetic effects between weight bearing and non-weight bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone and osteophytic cartilage), and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

Original language	English
Pages (from-to)	4784-4818.e17
Number of pages	53
Journal	Cell
Volume	184
Issue number	18
Early online date	26 Aug 2021
DOIs	https://doi.org/10.1016/j.cell.2021.07.038
Publication status	Published - 2 Sept 2021

Keywords

osteoarthritis
genome-wide association meta-analysis
genetic architecture
functional genomics
effector genes
drug targets

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
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Boer, C. G., Hatzikotoulas, K., Southam, L., Stefansdottir, L., Zhang, Y., Coutinho de Almeida, R., wu, T. T., Zhang, J., Hartley, A. E., Teder-Laving, M., Skogholt, A. H., Terao, C., Zengini, E., Alexiadis, G., Barysenka, A., Bjornsdottir, G., Gabrielsen, M., Gilly, A., Ingvarsson, T., ... Zeggini, E. (2021). Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell, 184(18), 4784-4818.e17. https://doi.org/10.1016/j.cell.2021.07.038

@article{af367862b6164c139ff350233bb428bc,

title = "Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations",

abstract = "Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis), and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants, and identify differences in genetic effects between weight bearing and non-weight bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone and osteophytic cartilage), and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.",

keywords = "osteoarthritis, genome-wide association meta-analysis, genetic architecture, functional genomics, effector genes, drug targets",

author = "Boer, \{Cindy G.\} and Konstantinos Hatzikotoulas and Lorraine Southam and Lilja Stefansdottir and Yanfei Zhang and \{Coutinho de Almeida\}, Rodrigo and wu, \{Tian T.\} and Jie Zhang and Hartley, \{April E\} and Maris Teder-Laving and Skogholt, \{Anne Heidi\} and Chikashi Terao and Eleni Zengini and George Alexiadis and Andrei Barysenka and Gyda Bjornsdottir and Maiken Gabrielsen and Arthur Gilly and Thorvaldur Ingvarsson and Johnsen, \{Marianne B.\} and Helgi Jonsson and Margreet Kloppenburg and Almut Luetge and Lund, \{Sigrun H.\} and Reedik M{\"a}gi and Massimo Mangino and Rob Nelissen and Manu Shivakumar and Julia Steinberg and Hiroshi Takuwa and Laurent Thomas and Margo Tuerlings and Babis, \{George C\} and \{Pui Yin Cheung\}, Jason and Kang, \{Jae Hee\} and Peter Kraft and Lietman, \{Steven A.\} and Dino Samartzis and Eline Slagboom and Kari Stefansson and Unnur Thorsteinsdottir and Tobias, \{Jonathan H\} and Uitterlinden, \{Andr{\'e} G\} and Winsvold, \{Bendik S\} and John-Anker Zwart and \{Davey Smith\}, George and Sham, \{Pak Chung\} and Gudmar Thorleifsson and Gaunt, \{Tom R\} and Andrew Morris and Valdes, \{Ana M\} and Aspasia Tsezou and \{S.E. Cheah\}, Kathryn and Shiro Ikegawa and Kristian Hveem and T{\~o}nu Esko and Wilkinson, \{J Mark\} and Ingrid Meulenbelt and \{Ta Michael Lee\}, Ming and \{van Meurs\}, \{Joyce B.J.\} and Unnur Styrkarsdottir and Eleftheria Zeggini",

year = "2021",

month = sep,

day = "2",

doi = "10.1016/j.cell.2021.07.038",

language = "English",

volume = "184",

pages = "4784--4818.e17",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "18",

}

Boer, CG, Hatzikotoulas, K, Southam, L, Stefansdottir, L, Zhang, Y, Coutinho de Almeida, R, wu, TT, Zhang, J, Hartley, AE, Teder-Laving, M, Skogholt, AH, Terao, C, Zengini, E, Alexiadis, G, Barysenka, A, Bjornsdottir, G, Gabrielsen, M, Gilly, A, Ingvarsson, T, Johnsen, MB, Jonsson, H, Kloppenburg, M, Luetge, A, Lund, SH, Mägi, R, Mangino, M, Nelissen, R, Shivakumar, M, Steinberg, J, Takuwa, H, Thomas, L, Tuerlings, M, Babis, GC, Pui Yin Cheung, J, Kang, JH, Kraft, P, Lietman, SA, Samartzis, D, Slagboom, E, Stefansson, K, Thorsteinsdottir, U, Tobias, JH, Uitterlinden, AG, Winsvold, BS, Zwart, J-A, Davey Smith, G, Sham, PC, Thorleifsson, G, Gaunt, TR, Morris, A, Valdes, AM, Tsezou, A, S.E. Cheah, K, Ikegawa, S, Hveem, K, Esko, T, Wilkinson, JM, Meulenbelt, I, Ta Michael Lee, M, van Meurs, JBJ, Styrkarsdottir, U & Zeggini, E 2021, 'Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations', Cell, vol. 184, no. 18, pp. 4784-4818.e17. https://doi.org/10.1016/j.cell.2021.07.038

TY - JOUR

T1 - Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

AU - Boer, Cindy G.

AU - Hatzikotoulas, Konstantinos

AU - Southam, Lorraine

AU - Stefansdottir, Lilja

AU - Zhang, Yanfei

AU - Coutinho de Almeida, Rodrigo

AU - wu, Tian T.

AU - Zhang, Jie

AU - Hartley, April E

AU - Teder-Laving, Maris

AU - Skogholt, Anne Heidi

AU - Terao, Chikashi

AU - Zengini, Eleni

AU - Alexiadis, George

AU - Barysenka, Andrei

AU - Bjornsdottir, Gyda

AU - Gabrielsen, Maiken

AU - Gilly, Arthur

AU - Ingvarsson, Thorvaldur

AU - Johnsen, Marianne B.

AU - Jonsson, Helgi

AU - Kloppenburg, Margreet

AU - Luetge, Almut

AU - Lund, Sigrun H.

AU - Mägi, Reedik

AU - Mangino, Massimo

AU - Nelissen, Rob

AU - Shivakumar, Manu

AU - Steinberg, Julia

AU - Takuwa, Hiroshi

AU - Thomas, Laurent

AU - Tuerlings, Margo

AU - Babis, George C

AU - Pui Yin Cheung, Jason

AU - Kang, Jae Hee

AU - Kraft, Peter

AU - Lietman, Steven A.

AU - Samartzis, Dino

AU - Slagboom, Eline

AU - Stefansson, Kari

AU - Thorsteinsdottir, Unnur

AU - Tobias, Jonathan H

AU - Uitterlinden, André G

AU - Winsvold, Bendik S

AU - Zwart, John-Anker

AU - Davey Smith, George

AU - Sham, Pak Chung

AU - Thorleifsson, Gudmar

AU - Gaunt, Tom R

AU - Morris, Andrew

AU - Valdes, Ana M

AU - Tsezou, Aspasia

AU - S.E. Cheah, Kathryn

AU - Ikegawa, Shiro

AU - Hveem, Kristian

AU - Esko, Tõnu

AU - Wilkinson, J Mark

AU - Meulenbelt, Ingrid

AU - Ta Michael Lee, Ming

AU - van Meurs, Joyce B.J.

AU - Styrkarsdottir, Unnur

AU - Zeggini, Eleftheria

PY - 2021/9/2

Y1 - 2021/9/2

N2 - Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis), and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants, and identify differences in genetic effects between weight bearing and non-weight bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone and osteophytic cartilage), and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

AB - Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis), and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants, and identify differences in genetic effects between weight bearing and non-weight bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone and osteophytic cartilage), and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

KW - osteoarthritis

KW - genome-wide association meta-analysis

KW - genetic architecture

KW - functional genomics

KW - effector genes

KW - drug targets

U2 - 10.1016/j.cell.2021.07.038

DO - 10.1016/j.cell.2021.07.038

M3 - Article (Academic Journal)

C2 - 34450027

SN - 0092-8674

VL - 184

SP - 4784-4818.e17

JO - Cell

JF - Cell

IS - 18

ER -

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

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