TY - JOUR
T1 - Genome-wide pleiotropy of osteoporosis-related phenotypes
T2 - The Framingham study
AU - Karasik, David
AU - Hsu, Yi Hsiang
AU - Zhou, Yanhua
AU - Cupples, L. Adrienne
AU - Kiel, Douglas P.
AU - Demissie, Serkalem
PY - 2010/7
Y1 - 2010/7
N2 - Genome-wide association studies offer an unbiased approach to identify new candidate genes for osteoporosis. We examined the Affymetrix 500K + 50K SNP GeneChip marker sets for associations with multiple osteoporosis-related traits at various skeletal sites, including bone mineral density (BMD, hip and spine), heel ultrasound, and hip geometric indices in the Framingham Osteoporosis Study. We evaluated 433,510 single-nucleotide polymorphisms (SNPs) in 2073 women (mean age 65 years), members of two-generational families. Variance components analysis was performed to estimate phenotypic, genetic, and environmental correlations (ρP, ρG, and ρE) among bone traits. Linear mixed-effects models were used to test associations between SNPs and multivariable-adjusted trait values. We evaluated the proportion of SNPs associated with pairs of the traits at a nominal significance threshold α=0.01. We found substantial correlation between the proportion of associated SNPs and the ρP and ρG (r=0.91 and 0.84, respectively) but much lower with ρE (r=0.38). Thus, for example, hip and spine BMD had 6.8% associated SNPs in common, corresponding to ρP=0.55 and ρG=0.66 between them. Fewer SNPs were associated with both BMD and any of the hip geometric traits (eg, femoral neck and shaft width, section moduli, neck shaft angle, and neck length); ρG between BMD and geometric traits ranged from -0.24 to +0.40. In conclusion, we examined relationships between osteoporosis-related traits based on genome-wide associations. Most of the similarity between the quantitative bone phenotypes may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in defining the best phenotypes to be used in genetic studies of osteoporosis.
AB - Genome-wide association studies offer an unbiased approach to identify new candidate genes for osteoporosis. We examined the Affymetrix 500K + 50K SNP GeneChip marker sets for associations with multiple osteoporosis-related traits at various skeletal sites, including bone mineral density (BMD, hip and spine), heel ultrasound, and hip geometric indices in the Framingham Osteoporosis Study. We evaluated 433,510 single-nucleotide polymorphisms (SNPs) in 2073 women (mean age 65 years), members of two-generational families. Variance components analysis was performed to estimate phenotypic, genetic, and environmental correlations (ρP, ρG, and ρE) among bone traits. Linear mixed-effects models were used to test associations between SNPs and multivariable-adjusted trait values. We evaluated the proportion of SNPs associated with pairs of the traits at a nominal significance threshold α=0.01. We found substantial correlation between the proportion of associated SNPs and the ρP and ρG (r=0.91 and 0.84, respectively) but much lower with ρE (r=0.38). Thus, for example, hip and spine BMD had 6.8% associated SNPs in common, corresponding to ρP=0.55 and ρG=0.66 between them. Fewer SNPs were associated with both BMD and any of the hip geometric traits (eg, femoral neck and shaft width, section moduli, neck shaft angle, and neck length); ρG between BMD and geometric traits ranged from -0.24 to +0.40. In conclusion, we examined relationships between osteoporosis-related traits based on genome-wide associations. Most of the similarity between the quantitative bone phenotypes may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in defining the best phenotypes to be used in genetic studies of osteoporosis.
KW - Bone mineral density
KW - Femoral geometry
KW - Genetic correlations
KW - Genome-wide association
KW - Pleiotropy
KW - Quantitative ultrasound
KW - Single-nucleotide polymorphisms
UR - http://www.scopus.com/inward/record.url?scp=77954717620&partnerID=8YFLogxK
U2 - 10.1002/jbmr.38
DO - 10.1002/jbmr.38
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C2 - 20200953
AN - SCOPUS:77954717620
SN - 0884-0431
VL - 25
SP - 1555
EP - 1563
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 7
ER -