Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

Nerea Alonso; Karol Estrada; Omar M.E. Albagha; Lizbeth Herrera; Sjur Reppe; Ole K. Olstad; Kaare M. Gautvik; Niamh M. Ryan; Kathryn L. Evans; Carrie M. Nielson; Yi Hsiang Hsu; Douglas P. Kiel; George Markozannes; Evangelia E. Ntzani; Evangelos Evangelou; Bjarke Feenstra; Xueping Liu; Mads Melbye; Laura Masi; Maria Luisa Brandi; Philip Riches; Anna Daroszewska; José Manuel Olmos; Carmen Valero; Jesús Castillo; José A. Riancho; Lise B. Husted; Bente L. Langdahl; Matthew A. Brown; Emma L. Duncan; Stephen Kaptoge; Kay Tee Khaw; Ricardo Usategui-Martín; Javier Del Pino-Montes; Rogelio González-Sarmiento; Joshua R. Lewis; Richard L. Prince; Patrizia D'Amelio; Natalia García-Giralt; Xavier Nogués; Simona Mencej-Bedrac; Janja Marc; Orit Wolstein; John A. Eisman; Ling Oei; Carolina Medina-Gómez; Katharina E. Schraut; Pau Navarro; James F. Wilson; Gail Davies; John Starr; Ian Deary; Toshiko Tanaka; Luigi Ferrucci; Fernando Gianfrancesco; Luigi Gennari; Gavin Lucas; Roberto Elosua; André G. Uitterlinden; Fernando Rivadeneira; Stuart H. Ralston

doi:10.1136/annrheumdis-2017-212469

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

Nerea Alonso, Karol Estrada, Omar M.E. Albagha, Lizbeth Herrera, Sjur Reppe, Ole K. Olstad, Kaare M. Gautvik, Niamh M. Ryan, Kathryn L. Evans, Carrie M. Nielson, Yi Hsiang Hsu, Douglas P. Kiel, George Markozannes, Evangelia E. Ntzani, Evangelos Evangelou, Bjarke Feenstra, Xueping Liu, Mads Melbye, Laura Masi, Maria Luisa BrandiPhilip Riches, Anna Daroszewska, José Manuel Olmos, Carmen Valero, Jesús Castillo, José A. Riancho, Lise B. Husted, Bente L. Langdahl, Matthew A. Brown, Emma L. Duncan, Stephen Kaptoge, Kay Tee Khaw, Ricardo Usategui-Martín, Javier Del Pino-Montes, Rogelio González-Sarmiento, Joshua R. Lewis, Richard L. Prince, Patrizia D'Amelio, Natalia García-Giralt, Xavier Nogués, Simona Mencej-Bedrac, Janja Marc, Orit Wolstein, John A. Eisman, Ling Oei, Carolina Medina-Gómez, Katharina E. Schraut, Pau Navarro, James F. Wilson, Gail Davies, John Starr, Ian Deary, Toshiko Tanaka, Luigi Ferrucci, Fernando Gianfrancesco, Luigi Gennari, Gavin Lucas, Roberto Elosua, André G. Uitterlinden, Fernando Rivadeneira, Stuart H. Ralston

Department of Medicine

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

11 Citations (Scopus)

Abstract

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

Original language	English
Pages (from-to)	378-385
Journal	Annals of the Rheumatic Diseases
Volume	77
Issue number	3
DOIs	https://doi.org/10.1136/annrheumdis-2017-212469
Publication status	Published - 1 Mar 2018

Keywords

bone mineral density
gene polymorphism
osteoporosis

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Alonso, N., Estrada, K., Albagha, O. M. E., Herrera, L., Reppe, S., Olstad, O. K., Gautvik, K. M., Ryan, N. M., Evans, K. L., Nielson, C. M., Hsu, Y. H., Kiel, D. P., Markozannes, G., Ntzani, E. E., Evangelou, E., Feenstra, B., Liu, X., Melbye, M., Masi, L., ... Ralston, S. H. (2018). Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density. Annals of the Rheumatic Diseases, 77(3), 378-385. https://doi.org/10.1136/annrheumdis-2017-212469

Alonso, Nerea ; Estrada, Karol ; Albagha, Omar M.E. ; Herrera, Lizbeth ; Reppe, Sjur ; Olstad, Ole K. ; Gautvik, Kaare M. ; Ryan, Niamh M. ; Evans, Kathryn L. ; Nielson, Carrie M. ; Hsu, Yi Hsiang ; Kiel, Douglas P. ; Markozannes, George ; Ntzani, Evangelia E. ; Evangelou, Evangelos ; Feenstra, Bjarke ; Liu, Xueping ; Melbye, Mads ; Masi, Laura ; Brandi, Maria Luisa ; Riches, Philip ; Daroszewska, Anna ; Olmos, José Manuel ; Valero, Carmen ; Castillo, Jesús ; Riancho, José A. ; Husted, Lise B. ; Langdahl, Bente L. ; Brown, Matthew A. ; Duncan, Emma L. ; Kaptoge, Stephen ; Khaw, Kay Tee ; Usategui-Martín, Ricardo ; Del Pino-Montes, Javier ; González-Sarmiento, Rogelio ; Lewis, Joshua R. ; Prince, Richard L. ; D'Amelio, Patrizia ; García-Giralt, Natalia ; Nogués, Xavier ; Mencej-Bedrac, Simona ; Marc, Janja ; Wolstein, Orit ; Eisman, John A. ; Oei, Ling ; Medina-Gómez, Carolina ; Schraut, Katharina E. ; Navarro, Pau ; Wilson, James F. ; Davies, Gail ; Starr, John ; Deary, Ian ; Tanaka, Toshiko ; Ferrucci, Luigi ; Gianfrancesco, Fernando ; Gennari, Luigi ; Lucas, Gavin ; Elosua, Roberto ; Uitterlinden, André G. ; Rivadeneira, Fernando ; Ralston, Stuart H. / Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density. In: Annals of the Rheumatic Diseases. 2018 ; Vol. 77, No. 3. pp. 378-385.

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title = "Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density",

abstract = "{\textcopyright} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.",

keywords = "bone mineral density, gene polymorphism, osteoporosis",

author = "Nerea Alonso and Karol Estrada and Albagha, {Omar M.E.} and Lizbeth Herrera and Sjur Reppe and Olstad, {Ole K.} and Gautvik, {Kaare M.} and Ryan, {Niamh M.} and Evans, {Kathryn L.} and Nielson, {Carrie M.} and Hsu, {Yi Hsiang} and Kiel, {Douglas P.} and George Markozannes and Ntzani, {Evangelia E.} and Evangelos Evangelou and Bjarke Feenstra and Xueping Liu and Mads Melbye and Laura Masi and Brandi, {Maria Luisa} and Philip Riches and Anna Daroszewska and Olmos, {Jos{\'e} Manuel} and Carmen Valero and Jes{\'u}s Castillo and Riancho, {Jos{\'e} A.} and Husted, {Lise B.} and Langdahl, {Bente L.} and Brown, {Matthew A.} and Duncan, {Emma L.} and Stephen Kaptoge and Khaw, {Kay Tee} and Ricardo Usategui-Mart{\'i}n and {Del Pino-Montes}, Javier and Rogelio Gonz{\'a}lez-Sarmiento and Lewis, {Joshua R.} and Prince, {Richard L.} and Patrizia D'Amelio and Natalia Garc{\'i}a-Giralt and Xavier Nogu{\'e}s and Simona Mencej-Bedrac and Janja Marc and Orit Wolstein and Eisman, {John A.} and Ling Oei and Carolina Medina-G{\'o}mez and Schraut, {Katharina E.} and Pau Navarro and Wilson, {James F.} and Gail Davies and John Starr and Ian Deary and Toshiko Tanaka and Luigi Ferrucci and Fernando Gianfrancesco and Luigi Gennari and Gavin Lucas and Roberto Elosua and Uitterlinden, {Andr{\'e} G.} and Fernando Rivadeneira and Ralston, {Stuart H.}",

year = "2018",

month = mar,

day = "1",

doi = "10.1136/annrheumdis-2017-212469",

language = "English",

volume = "77",

pages = "378--385",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

number = "3",

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Alonso, N, Estrada, K, Albagha, OME, Herrera, L, Reppe, S, Olstad, OK, Gautvik, KM, Ryan, NM, Evans, KL, Nielson, CM, Hsu, YH, Kiel, DP, Markozannes, G, Ntzani, EE, Evangelou, E, Feenstra, B, Liu, X, Melbye, M, Masi, L, Brandi, ML, Riches, P, Daroszewska, A, Olmos, JM, Valero, C, Castillo, J, Riancho, JA, Husted, LB, Langdahl, BL, Brown, MA, Duncan, EL, Kaptoge, S, Khaw, KT, Usategui-Martín, R, Del Pino-Montes, J, González-Sarmiento, R, Lewis, JR, Prince, RL, D'Amelio, P, García-Giralt, N, Nogués, X, Mencej-Bedrac, S, Marc, J, Wolstein, O, Eisman, JA, Oei, L, Medina-Gómez, C, Schraut, KE, Navarro, P, Wilson, JF, Davies, G, Starr, J, Deary, I, Tanaka, T, Ferrucci, L, Gianfrancesco, F, Gennari, L, Lucas, G, Elosua, R, Uitterlinden, AG, Rivadeneira, F & Ralston, SH 2018, 'Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density', Annals of the Rheumatic Diseases, vol. 77, no. 3, pp. 378-385. https://doi.org/10.1136/annrheumdis-2017-212469

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density. / Alonso, Nerea; Estrada, Karol; Albagha, Omar M.E.; Herrera, Lizbeth; Reppe, Sjur; Olstad, Ole K.; Gautvik, Kaare M.; Ryan, Niamh M.; Evans, Kathryn L.; Nielson, Carrie M.; Hsu, Yi Hsiang; Kiel, Douglas P.; Markozannes, George; Ntzani, Evangelia E.; Evangelou, Evangelos; Feenstra, Bjarke; Liu, Xueping; Melbye, Mads; Masi, Laura; Brandi, Maria Luisa; Riches, Philip; Daroszewska, Anna; Olmos, José Manuel; Valero, Carmen; Castillo, Jesús; Riancho, José A.; Husted, Lise B.; Langdahl, Bente L.; Brown, Matthew A.; Duncan, Emma L.; Kaptoge, Stephen; Khaw, Kay Tee; Usategui-Martín, Ricardo; Del Pino-Montes, Javier; González-Sarmiento, Rogelio; Lewis, Joshua R.; Prince, Richard L.; D'Amelio, Patrizia; García-Giralt, Natalia; Nogués, Xavier; Mencej-Bedrac, Simona; Marc, Janja; Wolstein, Orit; Eisman, John A.; Oei, Ling; Medina-Gómez, Carolina; Schraut, Katharina E.; Navarro, Pau; Wilson, James F.; Davies, Gail; Starr, John; Deary, Ian; Tanaka, Toshiko; Ferrucci, Luigi; Gianfrancesco, Fernando; Gennari, Luigi; Lucas, Gavin; Elosua, Roberto; Uitterlinden, André G.; Rivadeneira, Fernando; Ralston, Stuart H.

In: Annals of the Rheumatic Diseases, Vol. 77, No. 3, 01.03.2018, p. 378-385.

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

TY - JOUR

T1 - Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

AU - Alonso, Nerea

AU - Estrada, Karol

AU - Albagha, Omar M.E.

AU - Herrera, Lizbeth

AU - Reppe, Sjur

AU - Olstad, Ole K.

AU - Gautvik, Kaare M.

AU - Ryan, Niamh M.

AU - Evans, Kathryn L.

AU - Nielson, Carrie M.

AU - Hsu, Yi Hsiang

AU - Kiel, Douglas P.

AU - Markozannes, George

AU - Ntzani, Evangelia E.

AU - Evangelou, Evangelos

AU - Feenstra, Bjarke

AU - Liu, Xueping

AU - Melbye, Mads

AU - Masi, Laura

AU - Brandi, Maria Luisa

AU - Riches, Philip

AU - Daroszewska, Anna

AU - Olmos, José Manuel

AU - Valero, Carmen

AU - Castillo, Jesús

AU - Riancho, José A.

AU - Husted, Lise B.

AU - Langdahl, Bente L.

AU - Brown, Matthew A.

AU - Duncan, Emma L.

AU - Kaptoge, Stephen

AU - Khaw, Kay Tee

AU - Usategui-Martín, Ricardo

AU - Del Pino-Montes, Javier

AU - González-Sarmiento, Rogelio

AU - Lewis, Joshua R.

AU - Prince, Richard L.

AU - D'Amelio, Patrizia

AU - García-Giralt, Natalia

AU - Nogués, Xavier

AU - Mencej-Bedrac, Simona

AU - Marc, Janja

AU - Wolstein, Orit

AU - Eisman, John A.

AU - Oei, Ling

AU - Medina-Gómez, Carolina

AU - Schraut, Katharina E.

AU - Navarro, Pau

AU - Wilson, James F.

AU - Davies, Gail

AU - Starr, John

AU - Deary, Ian

AU - Tanaka, Toshiko

AU - Ferrucci, Luigi

AU - Gianfrancesco, Fernando

AU - Gennari, Luigi

AU - Lucas, Gavin

AU - Elosua, Roberto

AU - Uitterlinden, André G.

AU - Rivadeneira, Fernando

AU - Ralston, Stuart H.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

AB - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

KW - bone mineral density

KW - gene polymorphism

KW - osteoporosis

U2 - 10.1136/annrheumdis-2017-212469

DO - 10.1136/annrheumdis-2017-212469

M3 - Article

VL - 77

SP - 378

EP - 385

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 3

ER -