Biological Pathway-based Genome-wide Association Study For Bone Geometry In Chinese Population

Femoral neck (FN) bone geometry parameters are an important predictor of bone strength and fracture risk. However, the majority of the underlying genetic factors remain to be identified. Femoral Neck bone geometry parameters play an important role in the prediction of Osteoporosis. These bone geometry parameters, including CSA (Cross Sectional Area), CT (Cortical Thickness), ED (Endosteal Diameter), Z (Section Modulus) and BR (Buckling Ratio), are under strong genetic control.In this study, we performed pathway-based genome-wide association analysis in a cohort of1627unrelated Chinese adults (males:802; females:825) to search for genes underlying variation in FN bone geometry parameters. For a total of1627unrelated Chinese subjects, Bone Mineral Density (BMD, g/cm2) values and bone size values at femoral neck was measured by a Hologic QDR4500dual-energy X-ray absorptiometry (DXA) scanner. We performed further calculation with these measured values for bone geometry parameters. Our study used the Genome-Wide Human SNP Array6.0to genotype these subjects.The pathway-based analysis method used in this study is a modification of the Gene Set Enrichment Algorithm. As a complementary method to single-point genome-wide association studies (GWAS), biological pathway-based genome-wide association study (GWAS) has an advantage of considering potential biological interplay of the tested single-nucleotide polymorphism (SNPs) or genes instead of only focusing on individual SNPs or genes for related phenotypes.A total of1007pathways extracted from the BioCarta, KEGG, Ambion GeneAssist and Gene Ontology databases were analyzed. We performed association analysis in the total sample and males and females, separately. We did not find significant associated pathways with FN bone geometry parameters in the total sample and females. However, in the males, the Inflammatory Response pathway was the most strongly associated with FN CSA even after multiple testing adjustments (p=0.001, qfdr=0.004, pfwer=0.004), and the GPCR Pathway was the second strongly associated with FN CSA even after multiple testing adjustments (p=0.001, qfdr=0.012, pfwer=0.024). FN CSA refers to the area with mineralized bone tissue excluding bone marrow space. It is an important parameter assessing hip bone strength. The Inflammatory Response pathway is involved in regulating inflammatory response. Some of the genes in the Inflammatory Response (IR) pathway (e.g., CD40, TNFRSF1B, COL1A1) are major candidate genes tested for association with osteoporosis-related phenotypes. And in the G-protein Coupled Receptors (GPCR) Pathway, we also found some genes (eg, CALM1, NFATC1) related with osteoblastogenesis or osteoclastogenesis.In summary, our study suggests the importance of the Inflammatory Response pathway and GPCR Pathway on variation in FN bone geometry parameters in males. The result palys a vital role in the prediction of bone strength and fracture risk in males, and then provides the further effects in preventing and treating of Osteoporosis.