Abstract:
Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Using whole-exome or whole-genome sequencing of 1,051 individuals with T1D, we aimed to find rare and low-frequency genomic variants associated with stroke in T1D. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and promoters. In addition, we attempted replication in T1D using a genome-wide association study (N = 3,945) and direct genotyping (N = 3,263), and in the general population from the large-scale population-wide FinnGen project and UK Biobank summary statistics. We identified a rare missense variant on SREBF1 exome-wide significantly associated with stroke (rs114001633, p.Pro227Leu, p-value = 7.30 × 10-8), which replicated for hemorrhagic stroke in T1D. Using gene aggregate analysis, we identified exome-wide significant genes: ANK1 and LRRN1 displayed replication evidence in T1D, and LRRN1, HAS1 and UACA in the general population (UK Biobank). Furthermore, we performed sliding-window analyses and identified 14 genome-wide significant windows for stroke on 4q33-34.1, of which two replicated in T1D, and a suggestive genomic window on LINC01500, which replicated in T1D. Finally, we identified a suggestively stroke-associated TRPM2-AS promoter (p-value = 5.78 × 10-6) with borderline significant replication in T1D, which we validated with an in vitro cell-based assay. Due to the rarity of the identified genetic variants, future replication of the genomic regions represented here is required with sequencing of individuals with T1D. Nevertheless, we here report the first genome-wide analysis on stroke in individuals with diabetes.
摘要:
1型糖尿病(T1D)患者卒中风险显著增加,与没有糖尿病的患者相比,具有明显的临床和神经影像学特征。使用1,051名患有T1D的个体的全外显子组或全基因组测序,我们旨在发现与T1D卒中相关的罕见且低频率的基因组变异.我们通过单变异分析全面分析了基因组,基因聚集分析,以及基因组窗口上的汇总分析,增强子和启动子。此外,我们尝试使用全基因组关联研究(N=3,945)和直接基因分型(N=3,263)在T1D中复制,以及在普通人群中来自大规模全人群FinnGen项目和UKBiobank汇总统计。我们在SREBF1外显子组上发现了一个罕见的错义变异,与卒中显著相关(rs114001633,p.Pro227Leu,p值=7.30×10-8),在T1D中复制出血性中风。使用基因聚集分析,我们确定了全外显子组的重要基因:ANK1和LRRN1在T1D中显示出复制证据,和LRRN1,HAS1和UACA在一般人群(英国生物银行)。此外,我们进行了滑动窗口分析,并在4q33-34.1上确定了14个基因组范围内中风的重要窗口,其中两个在T1D中复制,和LINC01500上的提示基因组窗口,在T1D中复制。最后,我们确定了一个提示卒中相关的TRPM2-AS启动子(p值=5.78×10-6),在T1D中具有临界显著复制,我们用体外细胞试验验证了这一点。由于确定的遗传变异的稀有性,对T1D患者进行测序时,需要对此处表示的基因组区域进行未来复制.然而,我们在这里报道了糖尿病患者卒中的首次全基因组分析.