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 & 70 others 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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2051-2064
Number of pages14
JournalJournal of Bone and Mineral Research
Volume27
Issue number10
DOIs
StatePublished - Oct 2012
Externally publishedYes

Fingerprint

Bone Density
Genes
Single Nucleotide Polymorphism
Genome
Spine
Femur Neck
Sex Characteristics
Quantitative Trait Loci
Computational Biology
Meta-Analysis
Phenotype
Bone and Bones

Keywords

  • AGING
  • ASSOCIATION
  • BMD
  • GENE-BY-SEX INTERACTION

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Liu, C. T., Estrada, K., Yerges-Armstrong, L. M., Amin, N., Evangelou, E., Li, G., ... 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

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

In: Journal of Bone and Mineral Research, Vol. 27, No. 10, 10.2012, p. 2051-2064.

Research output: Contribution to journalArticle

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
Liu CT, Estrada K, Yerges-Armstrong LM, Amin N, Evangelou E, Li G et al. Assessment of gene-by-sex interaction effect on bone mineral density. Journal of Bone and Mineral Research. 2012 Oct;27(10):2051-2064. https://doi.org/10.1002/jbmr.1679
Liu, Ching Ti ; Estrada, Karol ; Yerges-Armstrong, Laura M. ; Amin, Najaf ; Evangelou, Evangelos ; Li, Guo ; Minster, Ryan L. ; Carless, Melanie A. ; Kammerer, Candace M. ; Oei, Ling ; Zhou, Yanhua ; Alonso, Nerea ; Dailiana, Zoe ; Eriksson, Joel ; García-Giralt, Natalia ; Giroux, Sylvie ; Husted, Lise Bjerre ; Khusainova, Rita I. ; Koromila, Theodora ; Kung, Annie Waichee ; Lewis, Joshua R. ; Masi, Laura ; Mencej-Bedrac, Simona ; Nogues, Xavier ; Patel, Millan S. ; Prezelj, Janez ; Richards, J. Brent ; Sham, Pak Chung ; Spector, Timothy ; Vandenput, Liesbeth ; Xiao, Su Mei ; Zheng, Hou Feng ; Zhu, Kun ; Balcells, Susana ; Brandi, Maria Luisa ; Frost, Morten ; Goltzman, David ; González-Macías, Jesús ; Karlsson, Magnus ; Khusnutdinova, Elza K. ; Kollia, Panagoula ; Langdahl, Bente Lomholt ; Ljunggren, Asten ; Lorentzon, Mattias ; Marc, Janja ; Mellström, Dan ; Ohlsson, Claes ; Olmos, José M. ; Ralston, Stuart H. ; Riancho, José A. ; Rousseau, François ; Urreizti, Roser ; Van Hul, Wim ; Zarrabeitia, María T. ; Castano-Betancourt, Martha ; Demissie, Serkalem ; Grundberg, Elin ; Herrera, Lizbeth ; Kwan, Tony ; Medina-Gõmez, Carolina ; Pastinen, Tomi ; Sigurdsson, Gunnar ; Thorleifsson, Gudmar ; Vanmeurs, Joyce B J ; Blangero, John ; Hofman, Albert ; Liu, Yongmei ; Mitchell, Braxton D. ; O'Connell, Jeffrey R. ; Oostra, Ben A. ; Rotter, Jerome I. ; Stefansson, Kari ; Streeten, Elizabeth A. ; Styrkarsdottir, Unnur ; Thorsteinsdottir, Unnur ; Tylavsky, Frances A. ; Uitterlinden, Andre ; Cauley, Jane A. ; Harris, Tamara B. ; Ioannidis, John P A ; Psaty, Bruce M. ; Robbins, John A ; Zillikens, M. Carola ; Vanduijn, Cornelia M. ; Prince, Richard L. ; Karasik, David ; Rivadeneira, Fernando ; Kiel, Douglas P. ; Cupples, L. Adrienne ; Hsu, Yi Hsiang. / Assessment of gene-by-sex interaction effect on bone mineral density. In: Journal of Bone and Mineral Research. 2012 ; Vol. 27, No. 10. pp. 2051-2064.
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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

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U2 - 10.1002/jbmr.1679

DO - 10.1002/jbmr.1679

M3 - Article

VL - 27

SP - 2051

EP - 2064

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 10

ER -