Genome-wide association of an integrated osteoporosis-related phenotype: Is there evidence for pleiotropic genes?

Abstract

Multiple musculoskeletal traits assessed by various methods at different skeletal sites serve as surrogates for osteoporosis risk. However, it is a challenge to select the most relevant phenotypes for genetic study of fractures. Principal component analyses (PCA) were conducted in participants of the Framingham Osteoporosis Study on 17 measures including BMD (hip and spine), heel ultrasound, leg lean mass (LLM), and hip geometric indices, adjusting for covariates (age, height, BMI), in a combined sample of 1,180 men and 1,758 women, as well as in each sex. Four principal components (PCs) jointly explained ~69% of the total variability of musculoskeletal traits. PC1, explaining ~33% of the total variance, was referred to as the component of “Bone strength”, since it included the hip and spine BMD as well as several hip cross-sectional properties. PC2 (20.5% variance) was labeled as “Femoral cross-sectional geometry“; PC3 (~8% variance) captured only ultrasound measures; PC4, explaining ~7% variance, was correlated with LLM and hip geometry. We then evaluated ~2,5 mil SNPs for association with PCs 1, 2, and 4. There were genome-wide significant associations (p < 5 × 10−8) between PC2 and HTR1E (that codes for one of the serotonin receptors) and PC4 with COL4A2 in women. In the sexes-combined sample, AKAP6 was associated with PC2 (p= 1.40 × 10−7). A SNP in HTR1E was also associated with the risk of non-vertebral fractures in women (p= 0.005). Functions of top associated genes were enriched for the skeletal and muscular system development (p < 0.05). In conclusion, multivariate combination provides genetic associations not identified in the analysis of primary phenotypes. Genome-wide screening for the linear combinations of multiple osteoporosis-related phenotypes suggests that there are variants with potentially pleiotropic effects in established and novel pathways to be followed up to provide further evidence of their functions.

Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing

“…Pathway analysis of these genes revealed that they are primarily involved in cell development, morphology, survival and death, cell-to-cell signalling and interaction, humoral immune response, inflammatory response, nervous system development and function, and tissue development. In support of this notion, analysis of the chromosomal location of the sequence variants found in the present study as putatively associated with SF pathogenesis (n = 146) showed that none co-localized with any of the SNPs or genes previously associated with metacarpal bone geometry (Karasik et al, 2008), trabecular and cortical volumetric bone mineral densities (Paternoster et al, 2010(Paternoster et al, , 2013, osteoporosis-related phenotype (Karasik et al, 2012), bone mass, hip geometry and fractures (Boudin et al, 2013;Garcia-Ibarbia et al, 2013), bone mineral density, cortical bone thickness and bone strength , bone mineral density loci and osteoporotic fracture (Duncan et al, 2011;Estrada et al, 2012), and femoral neck bone geometry (Zhao et al, 2010) (Supplemental Table 6), including the ones that were reviewed by Ralston & Uitterlinden (2010) (Supplemental Table 7). Noteworthy, some of these genes and pathways have not been considered 'classical SF candidate genes' and have never been reported to be analysed as candidate SF genes.…”

Association of the TREML2 and HTR1E Genetic Polymorphisms with Osteoporosis

“…The HTR1E gene locates on chromosome 6q14-q15 encoding '5-Hydroxytryptamine Receptor 1E, G protein-coupled'. One SNP of HTR1E were reported to have relation with osteoporosis according to a GWAS for osteoporosis showing risk of nonvertebral fractures in females (P=0.005) (Karasik et al, 2012). In our analyses, there was association between the SNP of HTR1E gene and osteoporosis in females, but only one SNP was statistically significant (P=0.044).…”

Metabolomic serum profiling after ACL injury in rats: A pilot study implicating inflammation and immune dysregulation in post‐traumatic osteoarthritis

“…Given the presently demonstrated reduction in tryptophan metabolites that could serve as AHR ligands in ACLR animals, we hypothesize that a pro‐inflammatory environment is favored in the acute period after injury. Furthermore, the tryptophan metabolite serotonin has been closely linked with bone mineral density in the setting of osteoporosis and with IL‐17‐associated osteoclastogenesis in autoimmune arthritis, indicating that serotonin may play a role in the subchondral and epiphyseal bone remodeling we have observed following ACL rupture in this model …”