Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement

Cecilie Henkel; Unnur Styrkársdóttir; Gudmar Thorleifsson; Lilja Stefánsdóttir; Gyda Björnsdóttir; Karina Banasik; Søren Brunak; Christian Erikstrup; Khoa Manh Dinh; Thomas Folkmann Hansen; Kaspar René Nielsen; Mie Topholm Bruun; Joseph Dowsett; Thorsten Brodersen; DBDS Genomic Consortium; Thorgeir E Thorgeirsson; Kirill Gromov; Mikael Ploug Boesen; Henrik Ullum; Sisse Rye Ostrowski; Ole Birger Pedersen; Kári Stefánsson; Anders Troelsen; Mette Nyegaard

doi:10.1136/ard-2022-223199

Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement

Cecilie Henkel^*, Unnur Styrkársdóttir, Gudmar Thorleifsson, Lilja Stefánsdóttir, Gyda Björnsdóttir, Karina Banasik, Søren Brunak, Christian Erikstrup, Khoa Manh Dinh, Thomas Folkmann Hansen, Kaspar René Nielsen, Mie Topholm Bruun, Joseph Dowsett, Thorsten Brodersen, DBDS Genomic Consortium, Thorgeir E Thorgeirsson, Kirill Gromov, Mikael Ploug Boesen, Henrik Ullum, Sisse Rye OstrowskiOle Birger Pedersen, Kári Stefánsson, Anders Troelsen, Mette Nyegaard (Member of study group)

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

6 Citations (Scopus)

Abstract

OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement.

METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain.

RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups.

CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.

Original language	English
Article number	223199
Journal	Annals of the Rheumatic Diseases
Volume	82
Issue number	3
Pages (from-to)	384-392
Number of pages	9
ISSN	0003-4967
DOIs	https://doi.org/10.1136/ard-2022-223199
Publication status	Published - Mar 2023

Bibliographical note

Keywords

Orthopedic Procedures
Osteoarthritis
Osteoarthritis, Knee
Polymorphism, Genetic

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10.1136/ard-2022-223199

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Henkel, C., Styrkársdóttir, U., Thorleifsson, G., Stefánsdóttir, L., Björnsdóttir, G., Banasik, K., Brunak, S., Erikstrup, C., Dinh, K. M., Hansen, T. F., Nielsen, K. R., Bruun, M. T., Dowsett, J., Brodersen, T., DBDS Genomic Consortium, Thorgeirsson, T. E., Gromov, K., Boesen, M. P., Ullum, H., ... Nyegaard, M. (2023). Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement. Annals of the Rheumatic Diseases, 82(3), 384-392. Article 223199. Advance online publication. https://doi.org/10.1136/ard-2022-223199

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title = "Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement",

abstract = "OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement.METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain.RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups.CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.",

keywords = "Orthopedic Procedures, Osteoarthritis, Osteoarthritis, Knee, Polymorphism, Genetic",

author = "Cecilie Henkel and Unnur Styrk{\'a}rsd{\'o}ttir and Gudmar Thorleifsson and Lilja Stef{\'a}nsd{\'o}ttir and Gyda Bj{\"o}rnsd{\'o}ttir and Karina Banasik and S{\o}ren Brunak and Christian Erikstrup and Dinh, {Khoa Manh} and Hansen, {Thomas Folkmann} and Nielsen, {Kaspar Ren{\'e}} and Bruun, {Mie Topholm} and Joseph Dowsett and Thorsten Brodersen and {DBDS Genomic Consortium} and Thorgeirsson, {Thorgeir E} and Kirill Gromov and Boesen, {Mikael Ploug} and Henrik Ullum and Ostrowski, {Sisse Rye} and Pedersen, {Ole Birger} and K{\'a}ri Stef{\'a}nsson and Anders Troelsen and Mette Nyegaard",

note = "{\textcopyright} Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2023",

month = mar,

doi = "10.1136/ard-2022-223199",

language = "English",

volume = "82",

pages = "384--392",

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Henkel, C, Styrkársdóttir, U, Thorleifsson, G, Stefánsdóttir, L, Björnsdóttir, G, Banasik, K, Brunak, S, Erikstrup, C, Dinh, KM, Hansen, TF, Nielsen, KR, Bruun, MT, Dowsett, J, Brodersen, T, DBDS Genomic Consortium, Thorgeirsson, TE, Gromov, K, Boesen, MP, Ullum, H, Ostrowski, SR, Pedersen, OB, Stefánsson, K, Troelsen, A & Nyegaard, M 2023, 'Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement', Annals of the Rheumatic Diseases, vol. 82, no. 3, 223199, pp. 384-392. https://doi.org/10.1136/ard-2022-223199

Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement. / Henkel, Cecilie; Styrkársdóttir, Unnur; Thorleifsson, Gudmar et al.
In: Annals of the Rheumatic Diseases, Vol. 82, No. 3, 223199, 03.2023, p. 384-392.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement

AU - Henkel, Cecilie

AU - Styrkársdóttir, Unnur

AU - Thorleifsson, Gudmar

AU - Stefánsdóttir, Lilja

AU - Björnsdóttir, Gyda

AU - Banasik, Karina

AU - Brunak, Søren

AU - Erikstrup, Christian

AU - Dinh, Khoa Manh

AU - Hansen, Thomas Folkmann

AU - Nielsen, Kaspar René

AU - Bruun, Mie Topholm

AU - Dowsett, Joseph

AU - Brodersen, Thorsten

AU - DBDS Genomic Consortium

AU - Thorgeirsson, Thorgeir E

AU - Gromov, Kirill

AU - Boesen, Mikael Ploug

AU - Ullum, Henrik

AU - Ostrowski, Sisse Rye

AU - Pedersen, Ole Birger

AU - Stefánsson, Kári

AU - Troelsen, Anders

A2 - Nyegaard, Mette

PY - 2023/3

Y1 - 2023/3

N2 - OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement.METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain.RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups.CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.

AB - OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement.METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain.RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups.CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.

KW - Orthopedic Procedures

KW - Osteoarthritis

KW - Osteoarthritis, Knee

KW - Polymorphism, Genetic

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U2 - 10.1136/ard-2022-223199

DO - 10.1136/ard-2022-223199

M3 - Journal article

C2 - 36376028

SN - 0003-4967

VL - 82

SP - 384

EP - 392

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 3

M1 - 223199

ER -

Henkel C, Styrkársdóttir U, Thorleifsson G, Stefánsdóttir L, Björnsdóttir G, Banasik K et al. Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement. Annals of the Rheumatic Diseases. 2023 Mar;82(3):384-392. 223199. Epub 2022 Nov 14. doi: 10.1136/ard-2022-223199

Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement

Abstract

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Keywords

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