Abstract
Genome-wide association studies (GWASs) have identified many genetic variations associated with type 2 diabetes mellitus (T2DM) in Asians, but understanding the functional genetic variants that influence traits is often a complex process. In this study, fine mapping and other analytical strategies were performed to investigate the effects of G protein signaling modulator 1 (GPSM1) on insulin resistance in skeletal muscle. A total of 128 single-nucleotide polymorphisms (SNPs) within GPSM1 were analysed in 21,897 T2DM cases and 32,710 healthy controls from seven GWASs. The SNP rs28539249 in intron 9 of GPSM1 showed a nominally significant association with T2DM in Asians (OR = 1.07, 95% CI = 1.04–1.10, P < 10−4). The GPSM1 mRNA was increased in skeletal muscle and correlated with T2DM traits across obese mice model. An eQTL for the cis-acting regulation of GPSM1 expression in human skeletal muscle was identified for rs28539249, and the increased GPSM1 expression related with T2DM traits within GEO datasets. Another independent Asian cohort showed that rs28539249 is associated with the skeletal muscle expression of CACFD1, GTF3C5, SARDH, and FAM163B genes, which are functionally enriched for endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) pathways. Moreover, rs28539249 locus was predicted to disrupt regulatory regions in human skeletal muscle with enriched epigenetic marks and binding affinity for CTCF. Supershift EMSA assays followed luciferase assays demonstrated the CTCF specifically binding to rs28539249-C allele leading to decreased transcriptional activity. Thus, the post-GWAS annotation confirmed the Asian-specific association of genetic variant in GPSM1 with T2DM, suggesting a role for the variant in the regulation in skeletal muscle.
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Data availability
Summary statistics of two Japanese GWAS (study 1: 9817 cases, 6763 controls; study 2: 5646 cases, 19,420 controls) for directly genotyped data are available through the NBDC Human Database website (http://humandbs.biosciencedbc.jp/en/).
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Acknowledgements
We thank all the researchers for their contribution and support for making this study possible. In particular, we would like to thank Anne U. Jackson and Michael Boehnke for Finland GWAS data offered. This work was supported by grants from National Science Foundation of China (No. 181570714 and 8161113013).
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QD: Data extraction, data analysis, and interpretation and paper writing and figure preparation. ALMT: Experiment performance and data analysis, and interpretation and paper writing and figure preparation. EJP, MC, XS, YYT, JL and HA: Data provision and data interpretation. EP and EST: Study design, data interpretation, and paper writing. HC: Study design, data interpretation, manuscript writing, and drawing.
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Ding, Q., Tan, A.L.M., Parra, E.J. et al. Genome-wide meta-analysis associates GPSM1 with type 2 diabetes, a plausible gene involved in skeletal muscle function. J Hum Genet 65, 411–420 (2020). https://doi.org/10.1038/s10038-019-0720-3
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DOI: https://doi.org/10.1038/s10038-019-0720-3
