Genome-wide Association Study Of LncRNA Polymorphisms With Bone Mineral Density

Osteoporosis is a prevalent skeletal disorder characterized by excessive bone loss and skeletal fragility thus greatly increased risk of fractures,and it is increasingly becoming an important public health issue.With the natural aging process of the world’s population,osteoporosis is an increasingly common problem,imposed financial burden both to the patient and the society.Long noncoding RNAs（lncRNAs）,which are defined as non-coding RNAs（ncRNAs）with longer than 200nucleotides（nt.）were widely transcribed in the biotic genome,but their potential roles in genetic complexity of human disorders required further exploration.Nowadays, growing evidence showed that lncRNA polymorphisms played important roles in diverse cellular contexts and human diseases.The purpose of the present study was to explore genetic polymorphisms of lncRNAs associated with bone mineral density（BMD）and its potential value.Based on the lncRNASNP database,55906 lncSNPs were selected to conduct a genome-wide association study（GWAS）meta-analysis among 11140 individuals of 7independent studies for BMDs at the femoral neck（FNK）,lumbar spine（SPN）and total hip（HIP）.Interested results were replicated in the Genetic Factors for Osteoporosis consortium（GEFOS Sequencing,n=32965）.The identified polymorphism were corrected by Bonfferoni test,and the significance threshold is P<8.94×10^-7.RevMan was used to simply generate the forest plot,and Haploview was used for linkage disequilibrium analysis.Then,we explored the potential function of these interested lncRNA genes.A total of 39 SNPs in MEF2C-AS1 located at 5q14.3were significantly associated with FNK-BMD after Bonferroni correction,and the strongest association signal was detected at rs6894139(P=7.43×10^-7).MEF2C-AS1 rs6894139 was replicated in GEFOS Sequencing with a P value of 1.43×10^-23.LD analysis revealed that these 39 SNPs were in extremely strong LD（r2>0.8）and were located within the rightmost LD block approximately 55 kb.LOC100506136 rs6465531 located at7q21.3 showed significant association with HIP-BMD.Previous functional studies suggested MEF2C-AS1 rs6894139 may play an important role in bone formation and pathogenesis network of osteoporosis,but the mechanism of these two genes was not entirely clear.Our results illustrated the important role of polymorphisms in lncRNAs in determining variations of BMD and provided justification and evidence for subsequent functional studies,thus may provide a valuable target intervention and treatment of osteoporosis.