不同的基因集负担模式是常见的全面性和局灶性癫痫的基础。

Distinct gene-set burden patterns underlie common generalized and focal epilepsies.

机构信息

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller Str. 27, Tübingen 72076, Germany.

Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue du Swing, Belvaux 4367, Luxembourg.

出版信息

EBioMedicine. 2021 Oct;72:103588. doi: 10.1016/j.ebiom.2021.103588. Epub 2021 Sep 24.

DOI:10.1016/j.ebiom.2021.103588

PMID:34571366

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8479647/

Abstract

BACKGROUND

Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis.

METHODS

The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls.

FINDINGS

Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE.

INTERPRETATION

Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies.

FUNDING

DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).

摘要

背景

对少数基因集的分析表明，它们有可能揭示关键的疾病关联。我们着手研究在一套全面的、假定与癫痫发生有关的生物学意义上的基因集中，超罕见变异（URV）的负担。

方法

使用欧洲血统的发育性和癫痫性脑病（DEE，n=1003）、遗传性全面性癫痫（GGE，n=3064）或非获得性局灶性癫痫（NAFE，n=3522）个体的全外显子组测序数据，通过 Epi25 合作研究收集，比较了 12 种 URV 类型在 92 个基因集中的负担，与 3962 名匹配的对照组进行比较。

结果

在高度约束区域的错义 URV 在神经元特异性和发育基因中富集，而在大脑中不表达的基因则不受影响。GGE 在来源于抑制性 vs. 兴奋性神经元或相关受体的基因集中的负担较高，而 NAFE 则相反，而 DEE 则在两者中都有负担。来自全基因组关联研究（GWAS）和来源于全面性 vs. 局灶性癫痫的基因集中的顶级易感基因的发现，揭示了 GGE 与 NAFE 相比 URV 的特定富集模式。