Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits.
Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits.
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变异基因图谱分析揭示了胰岛细胞在赋予睡眠相关特征遗传易感性方面的作用。
DOI：
10.1093/sleep/zsac109
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发表时间：
2022
期刊：
影响因子：
5.6
通讯作者：
Grant,StruanFA
中科院分区：
文献类型：
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作者：
Lasconi,Chiara;Pahl,MatthewC;Pippin,JamesA;Su,Chun;Johnson,MatthewE;Chesi,Alessandra;Boehm,Keith;Manduchi,Elisabetta;Ou,Kristy;Golson,MariaL;Wells,AndrewD;Kaestner,KlausH;Grant,StruanFA
鉴于睡眠障碍和代谢紊乱（包括2型糖尿病和肥胖）涉及多基因贡献和复杂的相互作用，我们研究了睡眠性状相关遗传位点在通过胰腺α细胞和β细胞赋予其一定程度的影响方面的潜在作用。我们确定了睡眠和代谢障碍之间的遗传共性，并利用公开的GWAS汇总统计数据进行了连锁不平衡遗传相关分析。然后，我们研究了α和β细胞内启动子相互作用开放染色质区域中睡眠性状相关SNP的可能富集，将公共GWAS报告与我们自己的ATAC-seq和高分辨率启动子聚焦捕获C数据交叉，这些数据来自分选的人类α细胞和已建立的人类β细胞系（EndoC-βH1）。最后，我们通过变体-基因图谱鉴定了与α-和EndoC-β H1细胞中睡眠性状相关变体物理相互作用的推定效应基因，并建立了这些基因显着参与的途径。我们观察到，失眠、睡眠时间短或长与2型糖尿病、肥胖和其他代谢特征显著相关，但不包括早晨。EndoC-βH1和α细胞都富集了失眠位点（p= 0.01;p= 0.0076）、短睡眠位点（p= 0.017;p= 0.022）和晨起位点（p= 2.2 × 10−7;p= 0.0016），而α细胞也富集了长睡眠位点（p= 0.034）。利用我们的启动子接触数据，我们在EndoC-βH1中鉴定了63个推定的效应基因，在α细胞中鉴定了76个推定的效应基因，这些基因在有机氮和有机磷生物合成、磷脂酰肌醇和磷酸化、细胞内转运和信号传导、应激反应和细胞分化中显示出显著富集。我们的数据表明，睡眠相关基因座的一个子集赋予他们的影响，通过胰岛细胞。
We investigated the potential role of sleep-trait associated genetic loci in conferring a degree of their effect via pancreatic α- and β-cells, given that both sleep disturbances and metabolic disorders, including type 2 diabetes and obesity, involve polygenic contributions and complex interactions. We determined genetic commonalities between sleep and metabolic disorders, conducting linkage disequilibrium genetic correlation analyses with publicly available GWAS summary statistics. Then we investigated possible enrichment of sleep-trait associated SNPs in promoter-interacting open chromatin regions within α- and β-cells, intersecting public GWAS reports with our own ATAC-seq and high-resolution promoter-focused Capture C data generated from both sorted human α-cells and an established human beta-cell line (EndoC-βH1). Finally, we identified putative effector genes physically interacting with sleep-trait associated variants in α- and EndoC-βH1cells running variant-to-gene mapping and establish pathways in which these genes are significantly involved. We observed that insomnia, short and long sleep—but not morningness—were significantly correlated with type 2 diabetes, obesity and other metabolic traits. Both the EndoC-βH1 and α-cells were enriched for insomnia loci (p= .01;p= .0076), short sleep loci (p= .017;p= .022) and morningness loci (p= 2.2 × 10−7;p= .0016), while the α-cells were also enriched for long sleep loci (p= .034). Utilizing our promoter contact data, we identified 63 putative effector genes in EndoC-βH1 and 76 putative effector genes in α-cells, with these genes showing significant enrichment for organonitrogen and organophosphate biosynthesis, phosphatidylinositol and phosphorylation, intracellular transport and signaling, stress responses and cell differentiation. Our data suggest that a subset of sleep-related loci confer their effects via cells in pancreatic islets.