Genome-Wide Association Study Using Extreme Truncate Selection
Identifies Novel Genes Affecting Bone Mineral Density and Fracture
Risk
Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low
bone mineral density (BMD) is a major predisposing factor to fracture and is
known to be highly heritable. Site-, gender-, and age-specific genetic effects
on BMD are thought to be significant, but have largely not been considered in
the design of genome-wide association studies (GWAS) of BMD to date. We report
here a GWAS using a novel study design focusing on women of a specific age
(postmenopausal women, age 55–85 years), with either extreme high or low
hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0,
n = 1055, or −4.0 to −1.5,
n = 900), with replication in cohorts of women drawn from
the general population (n = 20,898). The study replicates
21 of 26 known BMD–associated genes. Additionally, we report suggestive
association of a further six new genetic associations in or around the genes
CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and
SOX4, with replication in two independent datasets. A novel
mouse model with a loss-of-function mutation in GALNT3 is also
reported, which has high bone mass, supporting the involvement of this gene in
BMD determination. In addition to identifying further genes associated with BMD,
this study confirms the efficiency of extreme-truncate selection designs for
quantitative trait association studies.
Vyšlo v časopise:
Genome-Wide Association Study Using Extreme Truncate Selection
Identifies Novel Genes Affecting Bone Mineral Density and Fracture
Risk. PLoS Genet 7(4): e32767. doi:10.1371/journal.pgen.1001372
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001372
Souhrn
Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low
bone mineral density (BMD) is a major predisposing factor to fracture and is
known to be highly heritable. Site-, gender-, and age-specific genetic effects
on BMD are thought to be significant, but have largely not been considered in
the design of genome-wide association studies (GWAS) of BMD to date. We report
here a GWAS using a novel study design focusing on women of a specific age
(postmenopausal women, age 55–85 years), with either extreme high or low
hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0,
n = 1055, or −4.0 to −1.5,
n = 900), with replication in cohorts of women drawn from
the general population (n = 20,898). The study replicates
21 of 26 known BMD–associated genes. Additionally, we report suggestive
association of a further six new genetic associations in or around the genes
CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and
SOX4, with replication in two independent datasets. A novel
mouse model with a loss-of-function mutation in GALNT3 is also
reported, which has high bone mass, supporting the involvement of this gene in
BMD determination. In addition to identifying further genes associated with BMD,
this study confirms the efficiency of extreme-truncate selection designs for
quantitative trait association studies.
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