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Identification of Genetic Factors for Bone Mineral Density through a Genome-Wide Association Study

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의과대학 의학과
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서울대학교 대학원
GWASosteoporosisbone mineral densitySNPgenetic study
학위논문 (박사)-- 서울대학교 대학원 : 의학과 분자유전체의학 전공, 2013. 2. 신찬수.
Introduction: Most large-scale genome-wide association studies of bone mineral density (BMD) have been focused on Caucasians. Caucasians and Asians are two distinct ethnic groups, with genetic background and osteoporosis phenotypes differences. To identify genetic variants that influence BMD in East Asians, we performed a quantitative trait analysis of lumbar spine, total hip and femoral neck BMD in a Korean population-based cohort and follow-up replication analysis.
Methods: We performed stage 1 discovery analysis of lumbar spine, total hip and femoral neck BMD in 2,729 unrelated subjects from a Korean population-based cohort (58.1% female). Stage 2 in silico replication was performed in a Chinese Han population and two Caucasian populations (1,547, 2,250 and 987 subjects, respectively).
Results: From stage 1 discovery analysis, 318 SNPs were selected for the stage 2 replication study. From the meta-analysis of the stage 1 discovery analysis and stage 2 replication analysis, we identified four BMD loci that reached genome-wide significance (P<5×10-7). One locus on 1q23 (UHMK1, rs16863247, P=4.1×10-7 for femoral neck BMD and P=3.2×10-6 for total hip BMD) was a novel BMD signal. Interestingly, variant rs16863247 was very rare in Caucasians (minor allele frequency<0.01), indicating that this association could be specific to East Asians. In gender specific analysis, one SNP (rs1160574) on 1q32 (KCNH1) was associated with femoral neck BMD (P=2.1×10-7) and total hip BMD (P=2.2×10-7) in female subjects. One SNP (rs9371538) in the known BMD region on 6q25 (ESR1
estrogen receptor 1) were associated with lumbar spine BMD (P=5.6×10-9 and P=9.4×10-9, respectively). One SNP (rs7776725) in the known BMD region on 7q31 (WTN16
wingless-type MMTV integration site family, member 16) was associated with total hip BMD (P=8.6×10-9) and femoral neck BMD (P=1.3×10-6). Endogenous UHMK1 expression was significantly increased during osteoblast differentiation and significantly decreased during osteoclast differentiation. Especially, osteoclast differentiation was significantly increased by UHMK1 knock down using shRNA plasmid.
Conclusions: In conclusion, our genome-wide association study identified the UHMK1 gene as a novel BMD locus specific to East Asians. Application of our findings could lead to new strategies for improving osteoporosis management.
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