Polygenic risk scores as a marker for epilepsy risk across lifetime and after unspecified seizure events.
Polygenic risk scores as a marker for epilepsy risk across lifetime and after unspecified seizure events.
复制标题
多基因风险评分作为一生中和未特指癫痫发作事件后癫痫风险的标志。
DOI：
10.1101/2023.11.27.23297542
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Daly,MarkJ
中科院分区：
文献类型：
--
作者：
Heyne,HenrikeO;Pajuste,Fanny-Dhelia;Wanner,Julian;Onwuchekwa,JenniferIDaniel;Mägi,Reedik;Palotie,Aarno;FinnGen,EstonianBiobankresearchteam;Kälviainen,Reetta;Daly,MarkJ
癫痫的诊断对个人有重大影响，但在临床实践中往往具有挑战性。因此，非常需要新的生物标志物。在这里，我们调查了常见的遗传因素（癫痫多基因风险评分，[PRS]）如何影响癫痫风险的详细纵向电子健康记录（EHR）> 36万芬兰人跨越长达50年的个人生活。FinnGen中具有高遗传性全身性癫痫PRS（PRSGGE）的个体在其一生中和未指明的癫痫发作事件后发生遗传性全身性癫痫（GGE）的风险增加（风险比[HR] 1.55/PRSGGE标准差[SD]）。癫痫PRS的效应量与支持我们EHR衍生癫痫诊断的临床策划数据的效应量相当。在未指明的癫痫发作后10年内，当PRSGGE > 2 SD时，GGE率为37%，而当PRSGGE <-2 SD时，GGE率为5.6%。PRSGGE对特发性全身性癫痫（IGE）的GGE亚型的影响甚至更大（HR 2.1/SD PRSGGE）。我们进一步报告了PRSGGE对女性和年轻年龄组癫痫的显著更大影响。类似地，我们发现与非获得性局灶性癫痫（NAFE）相关的局灶性癫痫PRS负担显着但更温和。我们发现，与>2000种独立疾病相比，PRSGGE与GGE特异性相关，而PRSNAFE也与NAFE以外的其他疾病如背痛相关。在这里，我们表明癫痫特异性PRS在第一次癫痫发作事件后具有良好的辨别能力，即在癫痫的先验概率很高的情况下，概述了作为癫痫诊断生物标志物的潜力。
A diagnosis of epilepsy has significant consequences for an individual but is often challenging in clinical practice. Novel biomarkers are thus greatly needed. Here, we investigated how common genetic factors (epilepsy polygenic risk scores, [PRSs]) influence epilepsy risk in detailed longitudinal electronic health records (EHRs) of > 360k Finns spanning up to 50 years of individuals’ lifetimes. Individuals with a high genetic generalized epilepsy PRS (PRSGGE) in FinnGen had an increased risk for genetic generalized epilepsy (GGE) (hazard ratio [HR] 1.55 per PRSGGE standard deviation [SD]) across their lifetime and after unspecified seizure events. Effect sizes of epilepsy PRSs were comparable to effect sizes in clinically curated data supporting our EHR-derived epilepsy diagnoses. Within 10 years after an unspecified seizure, the GGE rate was 37% when PRSGGE > 2 SD compared to 5.6% when PRSGGE < −2 SD. The effect of PRSGGE was even larger on GGE subtypes of idiopathic generalized epilepsy (IGE) (HR 2.1 per SD PRSGGE). We further report significantly larger effects of PRSGGE on epilepsy in females and in younger age groups. Analogously, we found significant but more modest focal epilepsy PRS burden associated with non-acquired focal epilepsy (NAFE). We found PRSGGE specifically associated with GGE in comparison with >2000 independent diseases while PRSNAFE was also associated with other diseases than NAFE such as back pain. Here, we show that epilepsy specific PRSs have good discriminative ability after a first seizure event i.e. in circumstances where the prior probability of epilepsy is high outlining a potential to serve as biomarkers for an epilepsy diagnosis.