Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

Unnur Styrkarsdottir; Gudmar Thorleifsson; Hafdis T. Helgadottir; Nils Bomer; Sarah Metrustry; S. Bierma-Zeinstra; Annelieke M. Strijbosch; Evangelos Evangelou; Deborah Hart; Marian Beekman; Aslaug Jonasdottir; Asgeir Sigurdsson; Finnur F. Eiriksson; Margret Thorsteinsdottir; Michael L. Frigge; Augustine Kong; Sigurjon A. Gudjonsson; Olafur T. Magnusson; Gisli Masson; Albert Hofman; Nigel K. Arden; Thorvaldur Ingvarsson; Stefan Lohmander; Margreet Kloppenburg; Fernando Rivadeneira; Rob G.H.H. Nelissen; Tim Spector; Andre Uitterlinden; P. Eline Slagboom; Unnur Thorsteinsdottir; Ingileif Jonsdottir; Ana M. Valdes; Ingrid Meulenbelt; Joyce Van Meurs; Helgi Jonsson; Kari Stefansson

doi:10.1038/ng.2957

Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

Unnur Styrkarsdottir^*, Gudmar Thorleifsson, Hafdis T. Helgadottir, Nils Bomer, Sarah Metrustry, S. Bierma-Zeinstra, Annelieke M. Strijbosch, Evangelos Evangelou, Deborah Hart, Marian Beekman, Aslaug Jonasdottir, Asgeir Sigurdsson, Finnur F. Eiriksson, Margret Thorsteinsdottir, Michael L. Frigge, Augustine Kong, Sigurjon A. Gudjonsson, Olafur T. Magnusson, Gisli Masson, Albert HofmanNigel K. Arden, Thorvaldur Ingvarsson, Stefan Lohmander, Margreet Kloppenburg, Fernando Rivadeneira, Rob G.H.H. Nelissen, Tim Spector, Andre Uitterlinden, P. Eline Slagboom, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Ana M. Valdes, Ingrid Meulenbelt, Joyce Van Meurs, Helgi Jonsson, Kari Stefansson

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

87 Citations (Scopus)

Abstract

Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10-10) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10-10). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10-11 (rs3204689).

Original language	English
Pages (from-to)	498-502
Number of pages	5
Journal	Nature Genetics
Volume	46
Issue number	5
DOIs	https://doi.org/10.1038/ng.2957
Publication status	Published - May 2014

Bibliographical note

Funding Information:
1deCODE Genetics/Amgen, Reykjavik, Iceland. 2Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3Department of Twin Research, King’s College London, St. Thomas’ Hospital, London, UK. 4Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 5Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. 6Department of Epidemiology and Biostatistics, Imperial College London, London, UK. 7Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, The Netherlands. 8Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands. 9Arctic Mass, Reykjavik, Iceland. 10Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 11Full list of members and affiliations appears in the Supplementary Note. 12Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 13National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK. 14Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland. 15Institution of Health Science, University of Akureyri, Akureyri, Iceland. 16Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden. 17Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 18Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. 19Deptartment of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands. 20Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK. 21Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. Correspondence should be addressed to K.S. (kstefans@decode.is) or U.S. (unnur.styrkarsdottir@decode.is).

Funding Information:
We thank the subjects of the deCODE study, the Rotterdam study, the GARP, LLS, RAAK and PAPRIKA studies, the TwinsUK and Chingford studies, and the MDC study for their valuable participation. This work was supported by European Union Framework Programme 7 grant 200800 TREAT-OA. Full acknowledgments are given in the Supplementary Note.

Access to Document

10.1038/ng.2957

Cite this

Styrkarsdottir, U., Thorleifsson, G., Helgadottir, H. T., Bomer, N., Metrustry, S., Bierma-Zeinstra, S., Strijbosch, A. M., Evangelou, E., Hart, D., Beekman, M., Jonasdottir, A., Sigurdsson, A., Eiriksson, F. F., Thorsteinsdottir, M., Frigge, M. L., Kong, A., Gudjonsson, S. A., Magnusson, O. T., Masson, G., ... Stefansson, K. (2014). Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nature Genetics, 46(5), 498-502. https://doi.org/10.1038/ng.2957

@article{e75b65645fdb4f479c2b94eb4039f2b0,

title = "Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31",

abstract = "Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10-10) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10-10). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10-11 (rs3204689).",

author = "Unnur Styrkarsdottir and Gudmar Thorleifsson and Helgadottir, {Hafdis T.} and Nils Bomer and Sarah Metrustry and S. Bierma-Zeinstra and Strijbosch, {Annelieke M.} and Evangelos Evangelou and Deborah Hart and Marian Beekman and Aslaug Jonasdottir and Asgeir Sigurdsson and Eiriksson, {Finnur F.} and Margret Thorsteinsdottir and Frigge, {Michael L.} and Augustine Kong and Gudjonsson, {Sigurjon A.} and Magnusson, {Olafur T.} and Gisli Masson and Albert Hofman and Arden, {Nigel K.} and Thorvaldur Ingvarsson and Stefan Lohmander and Margreet Kloppenburg and Fernando Rivadeneira and Nelissen, {Rob G.H.H.} and Tim Spector and Andre Uitterlinden and Slagboom, {P. Eline} and Unnur Thorsteinsdottir and Ingileif Jonsdottir and Valdes, {Ana M.} and Ingrid Meulenbelt and {Van Meurs}, Joyce and Helgi Jonsson and Kari Stefansson",

note = "Funding Information: 1deCODE Genetics/Amgen, Reykjavik, Iceland. 2Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3Department of Twin Research, King{\textquoteright}s College London, St. Thomas{\textquoteright} Hospital, London, UK. 4Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 5Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. 6Department of Epidemiology and Biostatistics, Imperial College London, London, UK. 7Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, The Netherlands. 8Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands. 9Arctic Mass, Reykjavik, Iceland. 10Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 11Full list of members and affiliations appears in the Supplementary Note. 12Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 13National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK. 14Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland. 15Institution of Health Science, University of Akureyri, Akureyri, Iceland. 16Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden. 17Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 18Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. 19Deptartment of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands. 20Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK. 21Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. Correspondence should be addressed to K.S. (kstefans@decode.is) or U.S. (unnur.styrkarsdottir@decode.is). Funding Information: We thank the subjects of the deCODE study, the Rotterdam study, the GARP, LLS, RAAK and PAPRIKA studies, the TwinsUK and Chingford studies, and the MDC study for their valuable participation. This work was supported by European Union Framework Programme 7 grant 200800 TREAT-OA. Full acknowledgments are given in the Supplementary Note.",

year = "2014",

month = may,

doi = "10.1038/ng.2957",

language = "English",

volume = "46",

pages = "498--502",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

Styrkarsdottir, U, Thorleifsson, G, Helgadottir, HT, Bomer, N, Metrustry, S, Bierma-Zeinstra, S, Strijbosch, AM, Evangelou, E, Hart, D, Beekman, M, Jonasdottir, A, Sigurdsson, A, Eiriksson, FF , Thorsteinsdottir, M, Frigge, ML, Kong, A, Gudjonsson, SA, Magnusson, OT, Masson, G, Hofman, A, Arden, NK, Ingvarsson, T, Lohmander, S, Kloppenburg, M, Rivadeneira, F, Nelissen, RGHH, Spector, T, Uitterlinden, A, Slagboom, PE, Thorsteinsdottir, U, Jonsdottir, I, Valdes, AM, Meulenbelt, I, Van Meurs, J, Jonsson, H & Stefansson, K 2014, 'Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31', Nature Genetics, vol. 46, no. 5, pp. 498-502. https://doi.org/10.1038/ng.2957

TY - JOUR

T1 - Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

AU - Styrkarsdottir, Unnur

AU - Thorleifsson, Gudmar

AU - Helgadottir, Hafdis T.

AU - Bomer, Nils

AU - Metrustry, Sarah

AU - Bierma-Zeinstra, S.

AU - Strijbosch, Annelieke M.

AU - Evangelou, Evangelos

AU - Hart, Deborah

AU - Beekman, Marian

AU - Jonasdottir, Aslaug

AU - Sigurdsson, Asgeir

AU - Eiriksson, Finnur F.

AU - Thorsteinsdottir, Margret

AU - Frigge, Michael L.

AU - Kong, Augustine

AU - Gudjonsson, Sigurjon A.

AU - Magnusson, Olafur T.

AU - Masson, Gisli

AU - Hofman, Albert

AU - Arden, Nigel K.

AU - Ingvarsson, Thorvaldur

AU - Lohmander, Stefan

AU - Kloppenburg, Margreet

AU - Rivadeneira, Fernando

AU - Nelissen, Rob G.H.H.

AU - Spector, Tim

AU - Uitterlinden, Andre

AU - Slagboom, P. Eline

AU - Thorsteinsdottir, Unnur

AU - Jonsdottir, Ingileif

AU - Valdes, Ana M.

AU - Meulenbelt, Ingrid

AU - Van Meurs, Joyce

AU - Jonsson, Helgi

AU - Stefansson, Kari

N1 - Funding Information: 1deCODE Genetics/Amgen, Reykjavik, Iceland. 2Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3Department of Twin Research, King’s College London, St. Thomas’ Hospital, London, UK. 4Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 5Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. 6Department of Epidemiology and Biostatistics, Imperial College London, London, UK. 7Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, The Netherlands. 8Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands. 9Arctic Mass, Reykjavik, Iceland. 10Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 11Full list of members and affiliations appears in the Supplementary Note. 12Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 13National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK. 14Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland. 15Institution of Health Science, University of Akureyri, Akureyri, Iceland. 16Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden. 17Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 18Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. 19Deptartment of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands. 20Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK. 21Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. Correspondence should be addressed to K.S. (kstefans@decode.is) or U.S. (unnur.styrkarsdottir@decode.is). Funding Information: We thank the subjects of the deCODE study, the Rotterdam study, the GARP, LLS, RAAK and PAPRIKA studies, the TwinsUK and Chingford studies, and the MDC study for their valuable participation. This work was supported by European Union Framework Programme 7 grant 200800 TREAT-OA. Full acknowledgments are given in the Supplementary Note.

PY - 2014/5

Y1 - 2014/5

N2 - Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10-10) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10-10). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10-11 (rs3204689).

AB - Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10-10) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10-10). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10-11 (rs3204689).

UR - http://www.scopus.com/inward/record.url?scp=84899638695&partnerID=8YFLogxK

U2 - 10.1038/ng.2957

DO - 10.1038/ng.2957

M3 - Article

C2 - 24728293

AN - SCOPUS:84899638695

VL - 46

SP - 498

EP - 502

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 5

ER -

Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

Abstract

Bibliographical note

Access to Document

Fingerprint

Cite this