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; Jose Manuel Olmos; Carmen Valero; Jesus Castillo; Jose 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 Gonzalez-Sarmiento; Joshua R Lewis; Richard L Prince; Patrizia D'Amelio; Natàlia Garcia-Giralt; Xavier Nogues; Simona Mencej-Bedrac; Janja Marc; Orit Wolstein; John A Eisman; Ling Oei; Carolina Medina-Gomez; Katharina Schraut; Pau Navarro; James F Wilson; Gail Davies; John Starr; Ian Deary; Toshiko Tanaka; Luigi Ferrucci; Fernando Gianfrancesco; Luigi Gennari; Gavin Lucas; Roberto Elosua; Andre 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, Jose Manuel Olmos, Carmen Valero, Jesus Castillo, Jose 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 Gonzalez-Sarmiento, Joshua R Lewis, Richard L Prince, Patrizia D'Amelio, Natàlia Garcia-Giralt, Xavier Nogues, Simona Mencej-Bedrac, Janja Marc, Orit Wolstein, John A Eisman, Ling Oei, Carolina Medina-Gomez, Katharina Schraut, Pau Navarro, James F Wilson, Gail Davies, John Starr, Ian Deary, Toshiko Tanaka, Luigi Ferrucci, Fernando Gianfrancesco, Luigi Gennari, Gavin Lucas, Roberto Elosua, Andre G. Uitterlinden, Fernando Rivadeneira, Stuart H Ralston

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

Abstract / Description of output

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
Number of pages	8
Journal	Annals of the Rheumatic Diseases
Volume	77
Issue number	3
Early online date	23 Nov 2017
DOIs	https://doi.org/10.1136/annrheumdis-2017-212469
Publication status	Published - Mar 2018

Keywords / Materials (for Non-textual outputs)

Osteoporosis
Gene polymorphism
bone mineral density
TTL
SLC20A1

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10.1136/annrheumdis-2017-212469

main_manuscript_ARD_29_sept_2017
This is the author's peer reviewed manuscript as accepted for publication.
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The Disconnected Mind Phase 3
Cox, S. & Deary, I.
1/04/16 → 31/03/23
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Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III
Wardlaw, J., Bastin, M. & Deary, I.
MRC
1/05/15 → 30/04/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
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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

@article{ac37c99c6c5047fd9400079d35290e5f,

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

abstract = "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 = "Osteoporosis, Gene polymorphism, bone mineral density, TTL, SLC20A1",

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 Yi-Hsiang Hsu 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, {Jose Manuel} and Carmen Valero and Jesus Castillo and Riancho, {Jose A.} and Husted, {Lise B} and Langdahl, {Bente L} and Brown, {Matthew A} and Duncan, {Emma L} and Stephen Kaptoge and Kay-Tee Khaw and Ricardo Usategui-Mart{\'i}n and {del Pino Montes}, Javier and Rogelio Gonzalez-Sarmiento and Lewis, {Joshua R} and Prince, {Richard L} and Patrizia D'Amelio and Nat{\`a}lia Garcia-Giralt and Xavier Nogues and Simona Mencej-Bedrac and Janja Marc and Orit Wolstein and Eisman, {John A} and Ling Oei and Carolina Medina-Gomez and Katharina Schraut 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, {Andre G.} and Fernando Rivadeneira and Ralston, {Stuart H}",

year = "2018",

month = mar,

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

language = "English",

volume = "77",

pages = "378--385",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "3",

}

Alonso, N, Estrada, K, Albagha, OME, Herrera, L, Reppe, S, Olstad, OK, Gautvik, KM, Ryan, NM, Evans, KL, Nielson, CM, Hsu, Y-H, 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, K-T, Usategui-Martín, R, del Pino Montes, J, Gonzalez-Sarmiento, R, Lewis, JR, Prince, RL, D'Amelio, P, Garcia-Giralt, N, Nogues, X, Mencej-Bedrac, S, Marc, J, Wolstein, O, Eisman, JA, Oei, L, Medina-Gomez, C, Schraut, K, 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

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, Jose Manuel

AU - Valero, Carmen

AU - Castillo, Jesus

AU - Riancho, Jose 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 - Gonzalez-Sarmiento, Rogelio

AU - Lewis, Joshua R

AU - Prince, Richard L

AU - D'Amelio, Patrizia

AU - Garcia-Giralt, Natàlia

AU - Nogues, Xavier

AU - Mencej-Bedrac, Simona

AU - Marc, Janja

AU - Wolstein, Orit

AU - Eisman, John A

AU - Oei, Ling

AU - Medina-Gomez, Carolina

AU - Schraut, Katharina

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, Andre G.

AU - Rivadeneira, Fernando

AU - Ralston, Stuart H

PY - 2018/3

Y1 - 2018/3

N2 - 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 - 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 - Osteoporosis

KW - Gene polymorphism

KW - bone mineral density

KW - TTL

KW - SLC20A1

U2 - 10.1136/annrheumdis-2017-212469

DO - 10.1136/annrheumdis-2017-212469

M3 - Article

SN - 0003-4967

VL - 77

SP - 378

EP - 385

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 3

ER -

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

The Disconnected Mind Phase 3

Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Cite this