Genome-Wide Association Study Identifies ALDH7A1 as a Novel Susceptibility Gene for Osteoporosis

Guo, Yan; Tan, Lijun; Lei, Shu‐Feng; Yang, Tie‐Lin; Chen, Xiang-Ding; Zhang, Feng; Chen, Yuan; Pan, Feng; Yan, Han; Liu, Xiaogang; Tian, Qing; Zhang, Zhixin; Zhou, Qi; Qiu, Chuan; Dong, Shanshan; Xu, Xianghong; Guo, Yan-Fang; Zhu, Xinyao; Liu, Shanlin; Wang, Xiang-Li; Li, Xi; Luo, Yi; Zhang, Li-Shu; Li, Meng; Wang, Jintang; Wen, Ting; Drees, Betty M.; Hamilton, James A.; Papasian, Christopher J.; Recker, Robert R.; Song, Xiaoping; Cheng, Jing; Deng, Hong‐Wen

doi:10.1371/journal.pgen.1000806

Cited by 101 publications

(83 citation statements)

References 34 publications

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“…Covariates, including age, age 2 , menopause status (for the females only), height, weight, and PC1-10 generated by EIGENSTRAT[29], were tested for their significance of effect on hip BMD. Significant covariates were then used to adjust raw BMD values [30]. PLINK [31, 32] was used to perform genotypic association analyses by comparing mean hip BMD values among carriers of different genotypes at each SNP site.…”

Section: Methodsmentioning

confidence: 99%

Is GSN significant for hip BMD in female Caucasians?

Deng¹,

Zhu²,

Zeng³

et al. 2014

Bone

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Low bone mineral density (BMD) is a risk factor of osteoporosis. Osteoporosis is more prevalent in the females than the males. So far, the pathophysiological mechanisms underlying osteoporosis are unclear. Peripheral blood monocytes (PBM) are precursors of bone-resorbing osteoclasts. This study aims to identify PBM-expressed proteins (genes) influencing hip BMD in humans. We utilized three independent study cohorts (N=34, 29, 40), including premenopausal Caucasians with discordant hip BMD. We studied PBM proteome-wide protein expression profiles in Cohort 1 and identified 57 differentially expressed proteins (DEPs) between low vs. high BMD subjects. One protein gelsolin (GSN), after validation by Western blotting, was subject to follow-up. We compared GSN mRNA level in PBM between low vs. high BMD subjects in Cohorts 2 and 3. We genotyped SNPs across GSN in 2,286 unrelated Caucasians (Cohort 4) and 1,627 Chinese (Cohort 5), and tested association with hip BMD in the females and males, respectively. We discovered and validated that GSN protein expression level in PBM was down-regulated 3.0-fold in low vs. high BMD subjects (P<0.05). Down-regulation of GSN in PBM in low BMD subjects was also observed at mRNA level in both Cohorts 2 and 3. We identified that SNP rs767770 was significantly associated with hip BMD in female Caucasians (P=0.0003) only. Integrating analyses of the datasets at DNA, RNA, and protein levels from female Caucasians substantiated that GSN is highly significant for hip BMD (P=0.0001). We conclude that GSN is a significant gene influencing hip BMD in female Caucasians.

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Section: Methodsmentioning

confidence: 99%

Is GSN significant for hip BMD in female Caucasians?

Deng¹,

Zhu²,

Zeng³

et al. 2014

Bone

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“…[37] A novel gene, aldehyde dehydrogenase 7 family, member A1 ( ALDH7A1 ), was identified to be significant for hip OF. Further analyses confirmed its relevance to hip BMD in both Chinese (sample size, 2,955) and Caucasian (sample size, 7,007) populations.…”

Section: Gwass and Meta-analysis On Osteoporosis And Ofmentioning

confidence: 99%

Genome-wide Association Studies for Osteoporosis: A 2013 Update

et al. 2014

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In the past few years, the bone field has witnessed great advances in genome-wide association studies (GWASs) of osteoporosis, with a number of promising genes identified. In particular, meta-analysis of GWASs, aimed at increasing the power of studies by combining the results from different study populations, have led to the identification of novel associations that would not otherwise have been identified in individual GWASs. Recently, the first whole genome sequencing study for osteoporosis and fractures was published, reporting a novel rare nonsense mutation. This review summarizes the important and representative findings published by December 2013. Comments are made on the notable findings and representative studies for their potential influence and implications on our present understanding of the genetics of osteoporosis. Potential limitations of GWASs and their meta-analyses are evaluated, with an emphasis on understanding the reasons for inconsistent results between different studies and clarification of misinterpretation of GWAS meta-analysis results. Implications and challenges of GWAS are also discussed, including the need for multi- and inter-disciplinary studies.

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“…62). SNP rs13182402 within the ALDH7A1 (aldehyde dehydrogenase seven family, member A1) gene on chromosome 5q31 was strongly associated with OFs (P = 2.08 × 10 −9 , odds ratio = 2.25).…”

Section: Aldh7a1mentioning

confidence: 99%

Insights into the genetics of osteoporosis from recent genome-wide association studies

Zheng

Spector

Richards

2011

Expert Rev. Mol. Med.

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Osteoporosis, which is characterised by reduced bone mineral density (BMD) and an increased risk of fragility fractures, is the result of a complex interaction between environmental factors and genetic variants that confer susceptibility. Heritability studies have shown that BMD and other osteoporosis-related traits such as ultrasound properties of bone, skeletal geometry and bone turnover have significant inheritable components. Although previous linkage and candidate gene studies have provided few replicated loci for osteoporosis, genome-wide association approaches have produced clear and reproducible findings. To date, 20 genome-wide association studies (GWASs) for osteoporosis and related traits have been conducted, identifying dozens of genes. Further meta-analyses of GWAS data and deep resequencing of rare variants will uncover more novel susceptibility loci and ultimately provide possible therapeutic targets for fracture prevention.

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Genome-Wide Association Study Identifies ALDH7A1 as a Novel Susceptibility Gene for Osteoporosis

Cited by 101 publications

References 34 publications

Is GSN significant for hip BMD in female Caucasians?

Is GSN significant for hip BMD in female Caucasians?

Genome-wide Association Studies for Osteoporosis: A 2013 Update

Insights into the genetics of osteoporosis from recent genome-wide association studies

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