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; Thorgeir E Thorgeirsson; Kirill Gromov; Mikael Ploug Boesen; Henrik Ullum; Sisse Rye Ostrowski; Ole Birger Pedersen; Kári Stefánsson; Anders Troelsen; DBDS Genomic Consortium

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, Thorgeir E Thorgeirsson, Kirill Gromov, Mikael Ploug Boesen, Henrik Ullum, Sisse Rye Ostrowski, Ole Birger PedersenKári Stefánsson, Anders Troelsen, DBDS Genomic Consortium

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

16 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
Journal	Annals of the Rheumatic Diseases
Volume	82
Pages (from-to)	384-392
ISSN	0003-4967
DOIs	https://doi.org/10.1136/ard-2022-223199
Publication status	Published - 2023

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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., Thorgeirsson, T. E., Gromov, K., Boesen, M. P., Ullum, H., Ostrowski, S. R., ... DBDS Genomic Consortium (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, 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; Stefánsdóttir, Lilja; Björnsdóttir, Gyda; Banasik, Karina ; Brunak, Søren; Erikstrup, Christian; Dinh, Khoa Manh; Hansen, Thomas Folkmann; Nielsen, Kaspar René; Bruun, Mie Topholm; Dowsett, Joseph; Brodersen, Thorsten; Thorgeirsson, Thorgeir E; Gromov, Kirill ; Boesen, Mikael Ploug; Ullum, Henrik; Ostrowski, Sisse Rye ; Pedersen, Ole Birger; Stefánsson, Kári; Troelsen, Anders; DBDS Genomic Consortium.

In: Annals of the Rheumatic Diseases, Vol. 82, 2023, p. 384-392.

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

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, Thorgeirsson, TE, Gromov, K , Boesen, MP, Ullum, H, Ostrowski, SR , Pedersen, OB, Stefánsson, K, Troelsen, A & DBDS Genomic Consortium 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, pp. 384-392. https://doi.org/10.1136/ard-2022-223199

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;82:384-392. https://doi.org/10.1136/ard-2022-223199

Henkel, Cecilie ; Styrkársdóttir, Unnur ; Thorleifsson, Gudmar ; Stefánsdóttir, Lilja ; Björnsdóttir, Gyda ; Banasik, Karina ; Brunak, Søren ; Erikstrup, Christian ; Dinh, Khoa Manh ; Hansen, Thomas Folkmann ; Nielsen, Kaspar René ; Bruun, Mie Topholm ; Dowsett, Joseph ; Brodersen, Thorsten ; Thorgeirsson, Thorgeir E ; Gromov, Kirill ; Boesen, Mikael Ploug ; Ullum, Henrik ; Ostrowski, Sisse Rye ; Pedersen, Ole Birger ; Stefánsson, Kári ; Troelsen, Anders ; DBDS Genomic Consortium. / Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement. In: Annals of the Rheumatic Diseases. 2023 ; Vol. 82. pp. 384-392.

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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.",

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 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 {DBDS Genomic Consortium}",

note = "{\textcopyright} Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2023",

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

language = "English",

volume = "82",

pages = "384--392",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "B M J Group",

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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 - 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

AU - DBDS Genomic Consortium

PY - 2023

Y1 - 2023

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.

U2 - 10.1136/ard-2022-223199

DO - 10.1136/ard-2022-223199

M3 - Journal article

C2 - 36376028

VL - 82

SP - 384

EP - 392

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

ER -