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.

中文翻译：

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全基因组的荟萃分析将GPSM1与2型糖尿病相关联，这是一种与骨骼肌功能有关的合理基因。

全基因组关联研究（GWAS）已经确定了亚洲人与2型糖尿病（T2DM）相关的许多遗传变异，但是了解影响特质的功能遗传变异通常是一个复杂的过程。在这项研究中，进行了精细映射和其他分析策略，以研究G蛋白信号调节剂1（GPSM1）对骨骼肌胰岛素抵抗的影响。在来自7个GWAS的21,897例T2DM病例和32,710例健康对照中分析了GPSM1中的总共128个单核苷酸多态性（SNP）。GPSM1内含子9中的SNP rs28539249在亚洲人中显示出与T2DM的名义上显着相关（OR = 1.07，95％CI = 1.04-1.10，P <10-4）。在肥胖小鼠模型中，GPSM1 mRNA在骨骼肌中增加，并与T2DM性状相关。rs28539249鉴定了一个用于人类骨骼肌中GPSM1表达顺式调节的eQTL，且GPSM1表达增加与GEO数据集中的T2DM性状有关。另一个独立的亚洲队列研究表明，rs28539249与CACFD1，GTF3C5，SARDH和FAM163B基因的骨骼肌表达相关，这些基因在功能上丰富了内质网应激（ERS）和未折叠的蛋白应答（UPR）途径。此外，预计rs28539249基因座会破坏人类骨骼肌的调节区，并具有丰富的表观遗传标记和对CTCF的结合亲和力。Supershift EMSA分析和荧光素酶分析表明CTCF与rs28539249-C等​​位基因特异性结合，导致转录活性降低。从而，