Genome-wide association with bone mass and geometry in the Framingham Heart Study
Date
2007
DOI
Authors
Kiel, Douglas
Demissie, Serkalem
Dupuis, Josée
Lunetta, Kathryn
Murabito, Joanne
Karasik, David
Version
OA Version
Citation
2007. "Genome-wide association with bone mass and geometry in the
Framingham Heart Study," BMC Medical Genetics. vol. 8 issue. Suppl 1 .
Abstract
BACKGROUND:Osteoporosis is characterized by low bone mass and
compromised bone structure, heritable traits that contribute to fracture risk. There have
been no genome-wide association and linkage studies for these traits using high-density
genotyping platforms.METHODS:We used the Affymetrix 100K SNP GeneChip marker set in the
Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative
traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip.
To test associations with multivariable-adjusted residual trait values, we used additive
generalized estimating equation (GEE) and family-based association tests (FBAT) models
within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic
call rates [greater than or equal to]80%, HWE p [greater than or equal to] 0.001, and MAF
[greater than or equal to]10% in up to 1141 phenotyped individuals (495 men and 646 women,
mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200
markers.RESULTS:Heritability estimates for all bone phenotypes were 30-66%. LOD scores
[greater than or equal to]3.0 were found on chromosomes 15 (1.5 LOD confidence interval:
51,336,679-58,934,236 bp) and 22 (35,890,398-48,603,847 bp) for femoral shaft section
modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p
< 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most
significant p-values for GEE and FBAT were all less than 3.5 x 10-6 and 2.5 x 10-5,
respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD
traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were
in or near genes that have not previously been studied for osteoporosis. Notably,
pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for
association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes
for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in
LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as
SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT
and linkage results are provided as an open-access results resource at
http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:The FHS
100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and
to replicate previously suggested candidate genes for osteoporosis.