目的:蛛网膜下腔出血(SAH)后发生认知障碍的可能性很大,导致血管性痴呆.我们进行了一项新的纵向全基因组关联研究(GWAS),以在长期前瞻性队列研究中确定与SAH后认知障碍相关的遗传修饰。
方法:该GWAS涉及153例SAH患者,在高通量填补后共有5,971,372个标记。进行全基因组Cox比例风险回归测试以估计风险比(HR)和95%置信区间(CI)。随后,确定了加权多遗传风险评分(wPRS),基于GWAS驱动的基因座和风险分层。
结果:在平均37.7±12.4个月的随访中,65例患者(42.5%)出现认知障碍。五个全基因组信号,包括rs138753053(PDCD6IP-LOC101928135,HR=28.33,p=3.4×10-8),rs56823384(LINC00499,HR=12.47,p=2.8×10-9),rs145397166(CASC15,HR=11.16,p=1.7×10-8),rs10503670(LPL-SLC18A1,HR=2.88,p=4.0×10-8),rs76507772(IRS2,HR=5.99,p=3.5×10-8),与SAH后的认知障碍显着相关。此外,包含5个标志物的构建良好的wPRS显示出预测认知障碍的名义能力(AUROC=0.745,95%CI:0.667-0.824).Tertile分层在预测认知障碍方面显示出更高的有效性,尤其是那些结合珠蛋白2-1(HR=44.59,95%CI:8.61-231.08)。
结论:我们的研究揭示了新的认知障碍易感基因座,在SAH患者中进行纵向测量。这些基因座的临床效用将在进一步的后续研究中进行评估。
OBJECTIVE: The occurrence of cognitive deficits after subarachnoid hemorrhage (SAH) is highly possible, leading to vascular dementia. We performed a novel longitudinal genome-wide association study (GWAS) to identify genetic modifications associated with cognitive impairment following SAH in a long-term prospective cohort study.
METHODS: This GWAS involved 153 patients with SAH sharing 5,971,372 markers after high-throughput imputation. Genome-wide Cox proportional hazard regression testing was performed to estimate the hazard ratio (HR) and 95% confidence interval (CI). Subsequently, a weighted polygenetic risk score (wPRS) was determined, based on GWAS-driven loci and risk stratification.
RESULTS: Cognitive impairment was observed in 65 patients (42.5%) during a mean follow-up of 37.7 ± 12.4 months. Five genome-wide signals, including rs138753053 (PDCD6IP-LOC101928135, HR = 28.33, p = 3.4 × 10-8), rs56823384 (LINC00499, HR = 12.47, p = 2.8 × 10-9), rs145397166 (CASC15, HR = 11.16, p = 1.7 × 10-8), rs10503670 (LPL-SLC18A1, HR = 2.88, p = 4.0 × 10-8), and rs76507772 (IRS2, HR = 5.99, p = 3.5 × 10-8), were significantly associated with cognitive impairment following SAH. In addition, the well-constructed wPRS containing five markers showed nominal ability to predict cognitive impairment (AUROC = 0.745, 95% CI: 0.667-0.824). Tertile stratification showed a higher effectiveness in predicting cognitive impairment, especially in those with haptoglobin 2-1 (HR = 44.59, 95% CI: 8.61-231.08).
CONCLUSIONS: Our study revealed novel susceptible loci for cognitive impairment, longitudinally measured in patients with SAH. The clinical utility of these loci will be evaluated in further follow-up studies.