Integrating transcriptome-wide association study and mRNA expression profiling identifies novel genes associated with bone mineral density

Ma, Mei; Huang, Dageng; Liang, Xiao; Zhang, L.; Cheng, Shiqiang; Cheng, Bolun; Qi, Xin; Li, P.; Du, Yanan; Liu, L.; Zhao, Yan; Ding, Miao; Wen, Yan; Guo, Xiong; Zhang, F.

doi:10.1007/s00198-019-04958-z

Cited by 13 publications

(4 citation statements)

References 42 publications

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“…Although several genome-wide association studies (GWAS) have confirmed the close association between βII spectrin and osteoporosis 12,[118][119][120][121][122] , the mechanism of its role in bone pathophysiology is unknown. Osteoporosis is a disease characterized by low bone mass and microstructural degradation of the bone tissue, resulting in an increased risk of fracture.…”

Section: βIi Spectrin In Osteoporosismentioning

confidence: 99%

βII spectrin (SPTBN1): biological function and clinical potential in cancer and other diseases

Yang¹,

Yang²,

Sun³

et al. 2021

Int. J. Biol. Sci.

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βII spectrin, the most common isoform of non-erythrocyte spectrin, is a cytoskeleton protein present in all nucleated cells. Interestingly, βII spectrin is essential for the development of various organs such as nerve, epithelium, inner ear, liver and heart. The functions of βII spectrin include not only establishing and maintaining the cell structure but also regulating a variety of cellular functions, such as cell apoptosis, cell adhesion, cell spreading and cell cycle regulation. Notably, βII spectrin dysfunction is associated with embryonic lethality and the DNA damage response. More recently, the detection of altered βII spectrin expression in tumors indicated that βII spectrin might be involved in the development and progression of cancer. Its mutations and disorders could result in developmental disabilities and various diseases. The versatile roles of βII spectrin in disease have been examined in an increasing number of studies; nonetheless, the exact mechanisms of βII spectrin are still poorly understood. Thus, we summarize the structural features and biological roles of βII spectrin and discuss its molecular mechanisms and functions in development, homeostasis, regeneration and differentiation. This review highlight the potential effects of βII spectrin dysfunction in cancer and other diseases, outstanding questions for the future investigation of therapeutic targets. The investigation of the regulatory mechanism of βII spectrin signal inactivation and recovery may bring hope for future therapy of related diseases.

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Section: βIi Spectrin In Osteoporosismentioning

confidence: 99%

βII spectrin (SPTBN1): biological function and clinical potential in cancer and other diseases

Yang¹,

Yang²,

Sun³

et al. 2021

Int. J. Biol. Sci.

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“…TBL1X mainly plays an important role in maintaining precursor adipocytes in an undifferentiated state by inhibiting adipogenesis ( 60 ). Ma et al ( 61 ) showed that TMTC4 is significantly related to the formation of human skeletal muscle. From the above elementary description of the candidate genes, we find some of them are more or less associated with muscle development and body weight in different species, which allows us to predict the genes might take part in similar processes in sheep genome.…”

Section: Discussionmentioning

confidence: 99%

Uncovering the candidate genes related to sheep body weight using multi-trait genome-wide association analysis

Li,

Yang,

Guo

et al. 2023

Front. Vet. Sci.

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In sheep, body weight is an economically important trait. This study sought to map genetic loci related to weaning weight and yearling weight. To this end, a single-trait and multi-trait genome-wide association study (GWAS) was performed using a high-density 600 K single nucleotide polymorphism (SNP) chip. The results showed that 43 and 56 SNPs were significantly associated with weaning weight and yearling weight, respectively. A region associated with both weaning and yearling traits (OARX: 6.74–7.04 Mb) was identified, suggesting that the same genes could play a role in regulating both these traits. This region was found to contain three genes (TBL1X, SHROOM2 and GPR143). The most significant SNP was Affx-281066395, located at 6.94 Mb (p = 1.70 × 10−17), corresponding to the SHROOM2 gene. We also identified 93 novel SNPs elated to sheep weight using multi-trait GWAS analysis. A new genomic region (OAR10: 76.04–77.23 Mb) with 22 significant SNPs were discovered. Combining transcriptomic data from multiple tissues and genomic data in sheep, we found the HINT1, ASB11 and GPR143 genes may involve in sheep body weight. So, multi-omic anlaysis is a valuable strategy identifying candidate genes related to body weight.

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“… 6 However, most of the genetic variants reported by GWASs are located in non-coding regions and have limited capacity for explanation at the level of gene expression. 8 Compared with single nucleotide polymorphism (SNP)-based GWASs studies, transcriptome-wide association studies (TWASs) can take into account regulatory genes in non-coding regions, and better determine gene-trait associations by integrating GWASs and gene expression datasets. 8 In addition, TWAS can drastically reduce the comparisons in statistical analysis and enhance the ability to detect the candidate genes of diseases with complex traits.…”

Section: Introductionmentioning

confidence: 99%

“… 8 Compared with single nucleotide polymorphism (SNP)-based GWASs studies, transcriptome-wide association studies (TWASs) can take into account regulatory genes in non-coding regions, and better determine gene-trait associations by integrating GWASs and gene expression datasets. 8 In addition, TWAS can drastically reduce the comparisons in statistical analysis and enhance the ability to detect the candidate genes of diseases with complex traits. 9 In recent years, TWAS has been widely used to identify risk genes in a variety of orthopaedic diseases.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome-wide association study reveals candidate causal genes for lumbar spinal stenosis

Zeng

et al. 2023

Bone Joint Res

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AimsLumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease.MethodsWe conducted a transcriptome-wide association study (TWAS) of spinal canal stenosis by integrating genome-wide association study summary statistics (including 661 cases and 178,065 controls) derived from Biobank Japan, and pre-computed gene expression weights of skeletal muscle and whole blood implemented in FUSION software. To verify the TWAS results, the candidate genes were furthered compared with messenger RNA (mRNA) expression profiles of LSS to screen for common genes. Finally, Metascape software was used to perform enrichment analysis of the candidate genes and common genes.ResultsTWAS identified 295 genes with permutation p-values < 0.05 for skeletal muscle and 79 genes associated for the whole blood, such as RCHY1 (PTWAS = 0.001). Those genes were enriched in 112 gene ontology (GO) terms and five Kyoto Encyclopedia of Genes and Genomes pathways, such as ‘chemical carcinogenesis - reactive oxygen species’ (LogP value = −2.139). Further comparing the TWAS significant genes with the differentially expressed genes identified by mRNA expression profiles of LSS found 18 overlapped genes, such as interleukin 15 receptor subunit alpha (IL15RA) (PTWAS = 0.040, PmRNA = 0.010). Moreover, 71 common GO terms were detected for the enrichment results of TWAS and mRNA expression profiles, such as negative regulation of cell differentiation (LogP value = −2.811).ConclusionThis study revealed the genetic mechanism behind the pathological changes in LSS, and may provide novel insights for the early diagnosis and intervention of LSS.Cite this article: Bone Joint Res 2023;12(6):387–396.

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Integrating transcriptome-wide association study and mRNA expression profiling identifies novel genes associated with bone mineral density

Cited by 13 publications

References 42 publications

βII spectrin (SPTBN1): biological function and clinical potential in cancer and other diseases

βII spectrin (SPTBN1): biological function and clinical potential in cancer and other diseases

Uncovering the candidate genes related to sheep body weight using multi-trait genome-wide association analysis

Transcriptome-wide association study reveals candidate causal genes for lumbar spinal stenosis

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