Refined QTLs of osteoporosis-related traits by linkage analysis with genome-wide SNPs: Framingham SHARe

Abstract

Genome-wide association studies (GWAS) using high-density array of single-nucleotide polymorphisms (SNPs) offer an unbiased strategy to identify new candidate genes for osteoporosis. We used a subset of autosomal SNPs from the Affymetrix 500K+50K SNP GeneChip marker set to examine genetic linkage with multiple highly heritable osteoporosis-related traits, including BMD of the hip and spine, heel ultrasound (attenuation and speed of sound), and geometric indices of the hip, in two generations from the Framingham Osteoporosis Study. Variance component linkage analysis was performed using normalized residuals (adjusted for age, height, BMI, and estrogen status in women). Multipoint linkage analyses produced LOD scores > or =3.0 for BMD on chromosomes (chr.) 9 and 11 and for ultrasound speed of sound on chr. 5. Hip geometric traits were linked with higher LOD scores, such as with shaft width on chr. 4 (LOD=3.9) and chr. 16 (LOD=3.8) and with shaft section modulus on chr. 22 (LOD=4.0). LOD score > or =5.0 was obtained for femoral neck width on chr. 7. In conclusion, with an SNP-based linkage approach, we identified several novel potential QTLs and confirmed previously identified chromosomal regions linked to bone mass and geometry. Subsequent focus on the spectrum of genetic polymorphisms in these refined regions may contribute to finding variants predisposing to osteoporosis.

Keywords: BMD; SNP array; bone geometry; osteoporosis; quantitative trait loci.

Figure 1

Linkage results on chromosome 7 (Neck Width) and 22 (ShaftZ), in men, women, and the combined sample. Multipoint LOD scores are displayed.

Figure 2

Linkage results of trochanter BMD on chromosome 11, in women: not conditional on SNPs in SOX6 (triangles) and conditional (crosses). Multipoint LOD scores are displayed.