Assessment of gene-by-sex interaction effect on bone mineral density

Ching Ti Liu; Karol Estrada; Laura M. Yerges-Armstrong; Najaf Amin; Evangelos Evangelou; Guo Li; Ryan L. Minster; Melanie A. Carless; Candace M. Kammerer; Ling Oei; Yanhua Zhou; Nerea Alonso; Zoe Dailiana; Joel Eriksson; Natalia García-Giralt; Sylvie Giroux; Lise Bjerre Husted; Rita I. Khusainova; Theodora Koromila; Annie Waichee Kung; Joshua R. Lewis; Laura Masi; Simona Mencej-Bedrac; Xavier Nogues; Millan S. Patel; Janez Prezelj; J. Brent Richards; Pak Chung Sham; Timothy Spector; Liesbeth Vandenput; Su Mei Xiao; Hou Feng Zheng; Kun Zhu; Susana Balcells; Maria Luisa Brandi; Morten Frost; David Goltzman; Jesús González-Macías; Magnus Karlsson; Elza K. Khusnutdinova; Panagoula Kollia; Bente Lomholt Langdahl; Asten Ljunggren; Mattias Lorentzon; Janja Marc; Dan Mellström; Claes Ohlsson; José M. Olmos; Stuart H. Ralston; José A. Riancho; François Rousseau; Roser Urreizti; Wim Van Hul; María T. Zarrabeitia; Martha Castano-Betancourt; Serkalem Demissie; Elin Grundberg; Lizbeth Herrera; Tony Kwan; Carolina Medina-Gõmez; Tomi Pastinen; Gunnar Sigurdsson; Gudmar Thorleifsson; Joyce B.J. Vanmeurs; John Blangero; Albert Hofman; Yongmei Liu; Braxton D. Mitchell; Jeffrey R. O'Connell; Ben A. Oostra; Jerome I. Rotter; Kari Stefansson; Elizabeth A. Streeten; Unnur Styrkarsdottir; Unnur Thorsteinsdottir; Frances A. Tylavsky; Andre Uitterlinden; Jane A. Cauley; Tamara B. Harris; John P.A. Ioannidis; Bruce M. Psaty; John A. Robbins; M. Carola Zillikens; Cornelia M. Vanduijn; Richard L. Prince; David Karasik; Fernando Rivadeneira; Douglas P. Kiel; L. Adrienne Cupples; Yi Hsiang Hsu

doi:10.1002/jbmr.1679

Assessment of gene-by-sex interaction effect on bone mineral density

Ching Ti Liu, Karol Estrada, Laura M. Yerges-Armstrong, Najaf Amin, Evangelos Evangelou, Guo Li, Ryan L. Minster, Melanie A. Carless, Candace M. Kammerer, Ling Oei, Yanhua Zhou, Nerea Alonso, Zoe Dailiana, Joel Eriksson, Natalia García-Giralt, Sylvie Giroux, Lise Bjerre Husted, Rita I. Khusainova, Theodora Koromila, Annie Waichee KungJoshua R. Lewis, Laura Masi, Simona Mencej-Bedrac, Xavier Nogues, Millan S. Patel, Janez Prezelj, J. Brent Richards, Pak Chung Sham, Timothy Spector, Liesbeth Vandenput, Su Mei Xiao, Hou Feng Zheng, Kun Zhu, Susana Balcells, Maria Luisa Brandi, Morten Frost, David Goltzman, Jesús González-Macías, Magnus Karlsson, Elza K. Khusnutdinova, Panagoula Kollia, Bente Lomholt Langdahl, Asten Ljunggren, Mattias Lorentzon, Janja Marc, Dan Mellström, Claes Ohlsson, José M. Olmos, Stuart H. Ralston, José A. Riancho, François Rousseau, Roser Urreizti, Wim Van Hul, María T. Zarrabeitia, Martha Castano-Betancourt, Serkalem Demissie, Elin Grundberg, Lizbeth Herrera, Tony Kwan, Carolina Medina-Gõmez, Tomi Pastinen, Gunnar Sigurdsson, Gudmar Thorleifsson, Joyce B.J. Vanmeurs, John Blangero, Albert Hofman, Yongmei Liu, Braxton D. Mitchell, Jeffrey R. O'Connell, Ben A. Oostra, Jerome I. Rotter, Kari Stefansson, Elizabeth A. Streeten, Unnur Styrkarsdottir, Unnur Thorsteinsdottir, Frances A. Tylavsky, Andre Uitterlinden, Jane A. Cauley, Tamara B. Harris, John P.A. Ioannidis, Bruce M. Psaty, John A. Robbins, M. Carola Zillikens, Cornelia M. Vanduijn, Richard L. Prince, David Karasik, Fernando Rivadeneira, Douglas P. Kiel, L. Adrienne Cupples, Yi Hsiang Hsu

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

39 Scopus citations

Abstract

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10^-5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10^-5; female effect = -0.007 and p = 3.3 × 10^-2), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10^-8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP.

Original language	English (US)
Pages (from-to)	2051-2064
Number of pages	14
Journal	Journal of Bone and Mineral Research
Volume	27
Issue number	10
DOIs	https://doi.org/10.1002/jbmr.1679
State	Published - Oct 2012
Externally published	Yes

Keywords

AGING
ASSOCIATION
BMD
GENE-BY-SEX INTERACTION

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Orthopedics and Sports Medicine

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10.1002/jbmr.1679

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Liu, C. T., Estrada, K., Yerges-Armstrong, L. M., Amin, N., Evangelou, E., Li, G., Minster, R. L., Carless, M. A., Kammerer, C. M., Oei, L., Zhou, Y., Alonso, N., Dailiana, Z., Eriksson, J., García-Giralt, N., Giroux, S., Husted, L. B., Khusainova, R. I., Koromila, T., ... Hsu, Y. H. (2012). Assessment of gene-by-sex interaction effect on bone mineral density. Journal of Bone and Mineral Research, 27(10), 2051-2064. https://doi.org/10.1002/jbmr.1679

Liu, CT, Estrada, K, Yerges-Armstrong, LM, Amin, N, Evangelou, E, Li, G, Minster, RL, Carless, MA, Kammerer, CM, Oei, L, Zhou, Y, Alonso, N, Dailiana, Z, Eriksson, J, García-Giralt, N, Giroux, S, Husted, LB, Khusainova, RI, Koromila, T, Kung, AW, Lewis, JR, Masi, L, Mencej-Bedrac, S, Nogues, X, Patel, MS, Prezelj, J, Richards, JB, Sham, PC, Spector, T, Vandenput, L, Xiao, SM, Zheng, HF, Zhu, K, Balcells, S, Brandi, ML, Frost, M, Goltzman, D, González-Macías, J, Karlsson, M, Khusnutdinova, EK, Kollia, P, Langdahl, BL, Ljunggren, A, Lorentzon, M, Marc, J, Mellström, D, Ohlsson, C, Olmos, JM, Ralston, SH, Riancho, JA, Rousseau, F, Urreizti, R, Van Hul, W, Zarrabeitia, MT, Castano-Betancourt, M, Demissie, S, Grundberg, E, Herrera, L, Kwan, T, Medina-Gõmez, C, Pastinen, T, Sigurdsson, G, Thorleifsson, G, Vanmeurs, JBJ, Blangero, J, Hofman, A, Liu, Y, Mitchell, BD, O'Connell, JR, Oostra, BA, Rotter, JI, Stefansson, K, Streeten, EA, Styrkarsdottir, U, Thorsteinsdottir, U, Tylavsky, FA, Uitterlinden, A, Cauley, JA, Harris, TB, Ioannidis, JPA, Psaty, BM, Robbins, JA, Zillikens, MC, Vanduijn, CM, Prince, RL, Karasik, D, Rivadeneira, F, Kiel, DP, Cupples, LA & Hsu, YH 2012, 'Assessment of gene-by-sex interaction effect on bone mineral density', Journal of Bone and Mineral Research, vol. 27, no. 10, pp. 2051-2064. https://doi.org/10.1002/jbmr.1679

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title = "Assessment of gene-by-sex interaction effect on bone mineral density",

abstract = "Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10-5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10-5; female effect = -0.007 and p = 3.3 × 10-2), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10-8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP.",

keywords = "AGING, ASSOCIATION, BMD, GENE-BY-SEX INTERACTION",

author = "Liu, {Ching Ti} and Karol Estrada and Yerges-Armstrong, {Laura M.} and Najaf Amin and Evangelos Evangelou and Guo Li and Minster, {Ryan L.} and Carless, {Melanie A.} and Kammerer, {Candace M.} and Ling Oei and Yanhua Zhou and Nerea Alonso and Zoe Dailiana and Joel Eriksson and Natalia Garc{\'i}a-Giralt and Sylvie Giroux and Husted, {Lise Bjerre} and Khusainova, {Rita I.} and Theodora Koromila and Kung, {Annie Waichee} and Lewis, {Joshua R.} and Laura Masi and Simona Mencej-Bedrac and Xavier Nogues and Patel, {Millan S.} and Janez Prezelj and Richards, {J. Brent} and Sham, {Pak Chung} and Timothy Spector and Liesbeth Vandenput and Xiao, {Su Mei} and Zheng, {Hou Feng} and Kun Zhu and Susana Balcells and Brandi, {Maria Luisa} and Morten Frost and David Goltzman and Jes{\'u}s Gonz{\'a}lez-Mac{\'i}as and Magnus Karlsson and Khusnutdinova, {Elza K.} and Panagoula Kollia and Langdahl, {Bente Lomholt} and Asten Ljunggren and Mattias Lorentzon and Janja Marc and Dan Mellstr{\"o}m and Claes Ohlsson and Olmos, {Jos{\'e} M.} and Ralston, {Stuart H.} and Riancho, {Jos{\'e} A.} and Fran{\c c}ois Rousseau and Roser Urreizti and {Van Hul}, Wim and Zarrabeitia, {Mar{\'i}a T.} and Martha Castano-Betancourt and Serkalem Demissie and Elin Grundberg and Lizbeth Herrera and Tony Kwan and Carolina Medina-G{\~o}mez and Tomi Pastinen and Gunnar Sigurdsson and Gudmar Thorleifsson and Vanmeurs, {Joyce B.J.} and John Blangero and Albert Hofman and Yongmei Liu and Mitchell, {Braxton D.} and O'Connell, {Jeffrey R.} and Oostra, {Ben A.} and Rotter, {Jerome I.} and Kari Stefansson and Streeten, {Elizabeth A.} and Unnur Styrkarsdottir and Unnur Thorsteinsdottir and Tylavsky, {Frances A.} and Andre Uitterlinden and Cauley, {Jane A.} and Harris, {Tamara B.} and Ioannidis, {John P.A.} and Psaty, {Bruce M.} and Robbins, {John A.} and Zillikens, {M. Carola} and Vanduijn, {Cornelia M.} and Prince, {Richard L.} and David Karasik and Fernando Rivadeneira and Kiel, {Douglas P.} and Cupples, {L. Adrienne} and Hsu, {Yi Hsiang}",

year = "2012",

month = oct,

doi = "10.1002/jbmr.1679",

language = "English (US)",

volume = "27",

pages = "2051--2064",

journal = "Journal of Bone and Mineral Research",

issn = "0884-0431",

publisher = "Wiley-Blackwell",

number = "10",

}

TY - JOUR

T1 - Assessment of gene-by-sex interaction effect on bone mineral density

AU - Liu, Ching Ti

AU - Estrada, Karol

AU - Yerges-Armstrong, Laura M.

AU - Amin, Najaf

AU - Evangelou, Evangelos

AU - Li, Guo

AU - Minster, Ryan L.

AU - Carless, Melanie A.

AU - Kammerer, Candace M.

AU - Oei, Ling

AU - Zhou, Yanhua

AU - Alonso, Nerea

AU - Dailiana, Zoe

AU - Eriksson, Joel

AU - García-Giralt, Natalia

AU - Giroux, Sylvie

AU - Husted, Lise Bjerre

AU - Khusainova, Rita I.

AU - Koromila, Theodora

AU - Kung, Annie Waichee

AU - Lewis, Joshua R.

AU - Masi, Laura

AU - Mencej-Bedrac, Simona

AU - Nogues, Xavier

AU - Patel, Millan S.

AU - Prezelj, Janez

AU - Richards, J. Brent

AU - Sham, Pak Chung

AU - Spector, Timothy

AU - Vandenput, Liesbeth

AU - Xiao, Su Mei

AU - Zheng, Hou Feng

AU - Zhu, Kun

AU - Balcells, Susana

AU - Brandi, Maria Luisa

AU - Frost, Morten

AU - Goltzman, David

AU - González-Macías, Jesús

AU - Karlsson, Magnus

AU - Khusnutdinova, Elza K.

AU - Kollia, Panagoula

AU - Langdahl, Bente Lomholt

AU - Ljunggren, Asten

AU - Lorentzon, Mattias

AU - Marc, Janja

AU - Mellström, Dan

AU - Ohlsson, Claes

AU - Olmos, José M.

AU - Ralston, Stuart H.

AU - Riancho, José A.

AU - Rousseau, François

AU - Urreizti, Roser

AU - Van Hul, Wim

AU - Zarrabeitia, María T.

AU - Castano-Betancourt, Martha

AU - Demissie, Serkalem

AU - Grundberg, Elin

AU - Herrera, Lizbeth

AU - Kwan, Tony

AU - Medina-Gõmez, Carolina

AU - Pastinen, Tomi

AU - Sigurdsson, Gunnar

AU - Thorleifsson, Gudmar

AU - Vanmeurs, Joyce B.J.

AU - Blangero, John

AU - Hofman, Albert

AU - Liu, Yongmei

AU - Mitchell, Braxton D.

AU - O'Connell, Jeffrey R.

AU - Oostra, Ben A.

AU - Rotter, Jerome I.

AU - Stefansson, Kari

AU - Streeten, Elizabeth A.

AU - Styrkarsdottir, Unnur

AU - Thorsteinsdottir, Unnur

AU - Tylavsky, Frances A.

AU - Uitterlinden, Andre

AU - Cauley, Jane A.

AU - Harris, Tamara B.

AU - Ioannidis, John P.A.

AU - Psaty, Bruce M.

AU - Robbins, John A.

AU - Zillikens, M. Carola

AU - Vanduijn, Cornelia M.

AU - Prince, Richard L.

AU - Karasik, David

AU - Rivadeneira, Fernando

AU - Kiel, Douglas P.

AU - Cupples, L. Adrienne

AU - Hsu, Yi Hsiang

PY - 2012/10

Y1 - 2012/10

N2 - Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10-5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10-5; female effect = -0.007 and p = 3.3 × 10-2), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10-8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP.

AB - Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10-5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10-5; female effect = -0.007 and p = 3.3 × 10-2), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10-8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP.

KW - AGING

KW - ASSOCIATION

KW - BMD

KW - GENE-BY-SEX INTERACTION

UR - http://www.scopus.com/inward/record.url?scp=84866668118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866668118&partnerID=8YFLogxK

U2 - 10.1002/jbmr.1679

DO - 10.1002/jbmr.1679

M3 - Article

C2 - 22692763

AN - SCOPUS:84866668118

SN - 0884-0431

VL - 27

SP - 2051

EP - 2064

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 10

ER -

Assessment of gene-by-sex interaction effect on bone mineral density

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Keywords

ASJC Scopus subject areas

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