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

CT Liu; Karol Estrada Gil; LM Yerges-Armstrong; Najaf Amin; E Evangelou; G (Guo) Li; RL Minster; MA Carless; CM Kammerer; Ling Oei - Oei; YH Zhou; N Alonso; Z Dailiana; J Eriksson; N Garcia-Giralt; S Giroux; LB Husted; RI Khusainova; T Koromila; AW Kung; JR Lewis; L Masi; S Mencej-Bedrac; X Nogues; MS Patel; J Prezelj; JB Richards; PC Sham; T Spector; L Vandenput; SM Xiao; HF Zheng; K Zhu; S Balcells; ML Brandi; M Frost; D Goltzman; J Gonzalez-Macias; M Karlsson; EK Khusnutdinova; P Kollia; BL Langdahl; O Ljunggren; M Lorentzon; J Marc; D Mellstroem; C Ohlsson; JM Olmos; SH Ralston; JA Riancho; F Rousseau; R Urreizti; W van Hul; MT Zarrabeitia; M Castano-Betancourt; S Demissie; E Grundberg; L Herrera; T Kwan; C Medina-Gomez; T Pastinen; G Sigurdsson; G Thorleifsson; JBJ VanMeurs; J Blangero; Bert Hofman; YM Liu; BD Mitchell; JR O'Connell; Ben Oostra; JI Rotter; K Stefansson; EA Streeten; U Styrkarsdottir; U Thorsteinsdottir; FA Tylavsky; André Uitterlinden; JA Cauley; TB Harris; JPA Ioannidis; BM Psaty; JA Robbins; M.C. Zillikens; CM VanDuijn; RL Prince; D Karasik; Fernando Rivadeneira; DP Kiel; LA Cupples; YH Hsu

doi:10.1002/jbmr.1679

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

CT Liu, Karol Estrada Gil, LM Yerges-Armstrong, Najaf Amin, E Evangelou, G (Guo) Li, RL Minster, MA Carless, CM Kammerer, Ling Oei - Oei, YH Zhou, N Alonso, Z Dailiana, J Eriksson, N Garcia-Giralt, S Giroux, LB Husted, RI Khusainova, T Koromila, AW KungJR Lewis, L Masi, S Mencej-Bedrac, X Nogues, MS Patel, J Prezelj, JB Richards, PC Sham, T Spector, L Vandenput, SM Xiao, HF Zheng, K Zhu, S Balcells, ML Brandi, M Frost, D Goltzman, J Gonzalez-Macias, M Karlsson, EK Khusnutdinova, P Kollia, BL Langdahl, O Ljunggren, M Lorentzon, J Marc, D Mellstroem, C Ohlsson, JM Olmos, SH Ralston, JA Riancho, F Rousseau, R Urreizti, W van Hul, MT Zarrabeitia, M Castano-Betancourt, S Demissie, E Grundberg, L Herrera, T Kwan, C Medina-Gomez, T Pastinen, G Sigurdsson, G Thorleifsson, JBJ VanMeurs, J Blangero, Bert Hofman, YM Liu, BD Mitchell, JR O'Connell, Ben Oostra, JI Rotter, K Stefansson, EA Streeten, U Styrkarsdottir, U Thorsteinsdottir, FA Tylavsky, André Uitterlinden, JA Cauley, TB Harris, JPA Ioannidis, BM Psaty, JA Robbins, M.C. Zillikens, CM VanDuijn, RL Prince, D Karasik, Fernando Rivadeneira, DP Kiel, LA Cupples, YH Hsu

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

42 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?X?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?X?10-5; female effect?=?-0.007 and p?=?3.3?X?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?X?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. (c) 2012 American Society for Bone and Mineral Research.

Original language	Undefined/Unknown
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
Publication status	Published - 2012

Research programs

EMC MGC-02-96-01
EMC MM-01-39-02
EMC MM-01-39-09-A
EMC NIHES-01-64-01

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10.1002/jbmr.1679

Cite this

Liu, CT., Estrada Gil, K., Yerges-Armstrong, LM., Amin, N., Evangelou, E., Li, G., Minster, RL., Carless, MA., Kammerer, CM., Oei - Oei, L., Zhou, YH., Alonso, N., Dailiana, Z., Eriksson, J., Garcia-Giralt, N., Giroux, S., Husted, LB., Khusainova, RI., Koromila, T., ... Hsu, YH. (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

@article{6207dbc5fd4049d2893c324361d36e7f,

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?X?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?X?10-5; female effect?=?-0.007 and p?=?3.3?X?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?X?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. (c) 2012 American Society for Bone and Mineral Research.",

author = "CT Liu and {Estrada Gil}, Karol and LM Yerges-Armstrong and Najaf Amin and E Evangelou and Li, {G (Guo)} and RL Minster and MA Carless and CM Kammerer and {Oei - Oei}, Ling and YH Zhou and N Alonso and Z Dailiana and J Eriksson and N Garcia-Giralt and S Giroux and LB Husted and RI Khusainova and T Koromila and AW Kung and JR Lewis and L Masi and S Mencej-Bedrac and X Nogues and MS Patel and J Prezelj and JB Richards and PC Sham and T Spector and L Vandenput and SM Xiao and HF Zheng and K Zhu and S Balcells and ML Brandi and M Frost and D Goltzman and J Gonzalez-Macias and M Karlsson and EK Khusnutdinova and P Kollia and BL Langdahl and O Ljunggren and M Lorentzon and J Marc and D Mellstroem and C Ohlsson and JM Olmos and SH Ralston and JA Riancho and F Rousseau and R Urreizti and {van Hul}, W and MT Zarrabeitia and M Castano-Betancourt and S Demissie and E Grundberg and L Herrera and T Kwan and C Medina-Gomez and T Pastinen and G Sigurdsson and G Thorleifsson and JBJ VanMeurs and J Blangero and Bert Hofman and YM Liu and BD Mitchell and JR O'Connell and Ben Oostra and JI Rotter and K Stefansson and EA Streeten and U Styrkarsdottir and U Thorsteinsdottir and FA Tylavsky and Andr{\'e} Uitterlinden and JA Cauley and TB Harris and JPA Ioannidis and BM Psaty and JA Robbins and M.C. Zillikens and CM VanDuijn and RL Prince and D Karasik and Fernando Rivadeneira and DP Kiel and LA Cupples and YH Hsu",

year = "2012",

doi = "10.1002/jbmr.1679",

language = "Undefined/Unknown",

volume = "27",

pages = "2051--2064",

journal = "Journal of Bone and Mineral Research",

issn = "0884-0431",

publisher = "Oxford University Press",

number = "10",

}

Liu, CT, Estrada Gil, K, Yerges-Armstrong, LM, Amin, N, Evangelou, E, Li, G, Minster, RL, Carless, MA, Kammerer, CM, Oei - Oei, L, Zhou, YH, Alonso, N, Dailiana, Z, Eriksson, J, Garcia-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, Gonzalez-Macias, J, Karlsson, M, Khusnutdinova, EK, Kollia, P, Langdahl, BL, Ljunggren, O, Lorentzon, M, Marc, J, Mellstroem, 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-Gomez, C, Pastinen, T, Sigurdsson, G, Thorleifsson, G, VanMeurs, JBJ, Blangero, J, Hofman, B, Liu, YM, Mitchell, BD, O'Connell, JR, Oostra, B, 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

TY - JOUR

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

AU - Liu, CT

AU - Estrada Gil, Karol

AU - Yerges-Armstrong, LM

AU - Amin, Najaf

AU - Evangelou, E

AU - Li, G (Guo)

AU - Minster, RL

AU - Carless, MA

AU - Kammerer, CM

AU - Oei - Oei, Ling

AU - Zhou, YH

AU - Alonso, N

AU - Dailiana, Z

AU - Eriksson, J

AU - Garcia-Giralt, N

AU - Giroux, S

AU - Husted, LB

AU - Khusainova, RI

AU - Koromila, T

AU - Kung, AW

AU - Lewis, JR

AU - Masi, L

AU - Mencej-Bedrac, S

AU - Nogues, X

AU - Patel, MS

AU - Prezelj, J

AU - Richards, JB

AU - Sham, PC

AU - Spector, T

AU - Vandenput, L

AU - Xiao, SM

AU - Zheng, HF

AU - Zhu, K

AU - Balcells, S

AU - Brandi, ML

AU - Frost, M

AU - Goltzman, D

AU - Gonzalez-Macias, J

AU - Karlsson, M

AU - Khusnutdinova, EK

AU - Kollia, P

AU - Langdahl, BL

AU - Ljunggren, O

AU - Lorentzon, M

AU - Marc, J

AU - Mellstroem, D

AU - Ohlsson, C

AU - Olmos, JM

AU - Ralston, SH

AU - Riancho, JA

AU - Rousseau, F

AU - Urreizti, R

AU - van Hul, W

AU - Zarrabeitia, MT

AU - Castano-Betancourt, M

AU - Demissie, S

AU - Grundberg, E

AU - Herrera, L

AU - Kwan, T

AU - Medina-Gomez, C

AU - Pastinen, T

AU - Sigurdsson, G

AU - Thorleifsson, G

AU - VanMeurs, JBJ

AU - Blangero, J

AU - Hofman, Bert

AU - Liu, YM

AU - Mitchell, BD

AU - O'Connell, JR

AU - Oostra, Ben

AU - Rotter, JI

AU - Stefansson, K

AU - Streeten, EA

AU - Styrkarsdottir, U

AU - Thorsteinsdottir, U

AU - Tylavsky, FA

AU - Uitterlinden, André

AU - Cauley, JA

AU - Harris, TB

AU - Ioannidis, JPA

AU - Psaty, BM

AU - Robbins, JA

AU - Zillikens, M.C.

AU - VanDuijn, CM

AU - Prince, RL

AU - Karasik, D

AU - Rivadeneira, Fernando

AU - Kiel, DP

AU - Cupples, LA

AU - Hsu, YH

PY - 2012

Y1 - 2012

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?X?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?X?10-5; female effect?=?-0.007 and p?=?3.3?X?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?X?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. (c) 2012 American Society for Bone and Mineral Research.

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?X?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?X?10-5; female effect?=?-0.007 and p?=?3.3?X?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?X?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. (c) 2012 American Society for Bone and Mineral Research.

U2 - 10.1002/jbmr.1679

DO - 10.1002/jbmr.1679

M3 - Article

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 -