Assessment of gene-by-sex interaction effect on bone mineral density.
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. © 2012 American Society for Bone and Mineral Research.
Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue CT3, Boston,MA 02118, USA. ctliu@bu.edu
Ching-Ti
CT
Liu
Karol
K
Estrada
Laura M
LM
Yerges-Armstrong
Najaf
N
Amin
Evangelos
E
Evangelou
Guo
G
Li
Ryan L
RL
Minster
Melanie A
MA
Carless
Candace M
CM
Kammerer
Ling
L
Oei
Yanhua
Y
Zhou
Nerea
N
Alonso
Zoe
Z
Dailiana
Joel
J
Eriksson
Natalia
N
García-Giralt
Sylvie
S
Giroux
Lise Bjerre
LB
Husted
Rita I
RI
Khusainova
Theodora
T
Koromila
Annie Waichee
AW
Kung
Joshua R
JR
Lewis
Laura
L
Masi
Simona
S
Mencej-Bedrac
Xavier
X
Nogues
Millan S
MS
Patel
Janez
J
Prezelj
J Brent
JB
Richards
Pak Chung
PC
Sham
Timothy
T
Spector
Liesbeth
L
Vandenput
Su-Mei
SM
Xiao
Hou-Feng
HF
Zheng
Kun
K
Zhu
Susana
S
Balcells
Maria Luisa
ML
Brandi
Morten
M
Frost
David
D
Goltzman
Jesús
J
González-Macías
Magnus
M
Karlsson
Elza K
EK
Khusnutdinova
Panagoula
P
Kollia
Bente Lomholt
BL
Langdahl
Osten
O
Ljunggren
Mattias
M
Lorentzon
Janja
J
Marc
Dan
D
Mellström
Claes
C
Ohlsson
José M
JM
Olmos
Stuart H
SH
Ralston
José A
JA
Riancho
François
F
Rousseau
Roser
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Urreizti
Wim
W
Van Hul
María T
MT
Zarrabeitia
Martha
M
Castano-Betancourt
Serkalem
S
Demissie
Elin
E
Grundberg
Lizbeth
L
Herrera
Tony
T
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Carolina
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Medina-Gómez
Tomi
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Pastinen
Gunnar
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Sigurdsson
Gudmar
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Thorleifsson
Joyce Bj
JB
Vanmeurs
John
J
Blangero
Albert
A
Hofman
Yongmei
Y
Liu
Braxton D
BD
Mitchell
Jeffrey R
JR
O'Connell
Ben A
BA
Oostra
Jerome I
JI
Rotter
Kari
K
Stefansson
Elizabeth A
EA
Streeten
Unnur
U
Styrkarsdottir
Unnur
U
Thorsteinsdottir
Frances A
FA
Tylavsky
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Uitterlinden
Jane A
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Cauley
Tamara B
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John Pa
JP
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Bruce M
BM
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John A
JA
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M Carola
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Cornelia M
CM
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D015519:Bone Density / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005796:Genes / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D015203:Reproducibility of Results; D012727:Sex Characteristics