Association of ultra-rare coding variants with genetic generalized epilepsy: A case-control whole exome sequencing study.
Association of ultra-rare coding variants with genetic generalized epilepsy: A case-control whole exome sequencing study.
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DOI：
10.1111/epi.17166
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发表时间：
2022-03
期刊：
影响因子：
5.6
通讯作者：
EuroEPINOMICS-CoGIE Consortium
中科院分区：
文献类型：
--
作者：
Koko M;Motelow JE;Stanley KE;Bobbili DR;Dhindsa RS;May P;Canadian Epilepsy Network;Epi4K Consortium;Epilepsy Phenome/Genome Project;EpiPGX Consortium;EuroEPINOMICS-CoGIE Consortium
我们的目的是通过结合大量有阳性家族史的个体来鉴定与遗传性全身性癫痫（GGEs）相关的基因。其次，我们着手比较与家族性和散发性GGE相关的基因。我们在诊断为GGE的欧洲血统无关个体（先前通过多个国际合作招募和测序）和祖先匹配的对照中进行了病例对照全外显子组测序研究。在1，928名GGE患者（与8，578名对照）中检查了超罕见变异与癫痫（URV;在18，834个蛋白质编码基因中）的关联，然后分别在945名家族性GGE患者（与8，626名对照）中检查，最后在1，005名散发性GGE患者（与8，621名对照）中检查。我们还研究了URV与家族性和散发性GGE在两个对抑制性信号传导重要的基因组（19个编码GABAA受体的基因，113个代表GABA能途径的基因）中的关联。GABRG 2与GGE相关（p = 1.8x10−5），接近家族性GGE的研究范围内的显著性（p = 3.0x10−6），而没有基因接近与散发性GGE的显著关联。GABAA受体编码基因中最不耐受的亚基因区中的有害URV与家族性GGE相关（OR = 3.9，95% CI = 1.9 - 7.8，FDR调整的p = 0.0024），而其与散发性GGE的相关性具有略微较低的优势（OR = 3.1，95% CI = 1.3 - 6.7，FDR调整的p = 0.022）。GABA能通路基因中的URV与家族性GGE相关（OR = 1.8，95% CI = 1.3 - 2.5，FDR校正的p = 0.0024），但与散发性GGE无关（OR = 1.3，95% CI = 0.9 - 1.9，FDR校正的p = 0.19）。GABRG 2的URV可能是家族性GGE的重要危险因素。GABA能信号基因组与家族性GGE的相关性比与散发性GGE的相关性更显著。
We aimed to identify genes associated with genetic generalized epilepsy (GGEs) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. We performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants with epilepsy (URVs; in 18,834 protein coding genes) was examined in 1,928 individuals with GGE (vs. 8,578 controls), then separately in 945 individuals with familial GGE (vs. 8,626 controls), and finally in 1,005 individuals with sporadic GGE (vs. 8,621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding GABAA receptors, 113 genes representing the GABAergic pathway). GABRG2 was associated with GGE (p = 1.8x10−5), approaching study-wide significance in familial GGE (p = 3.0x10−6), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant sub-genic regions in genes encoding GABAA receptors were associated with familial GGE (OR = 3.9, 95% CI = 1.9 – 7.8, FDR-adjusted p = 0.0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3 – 6.7, FDR-adjusted p = 0.022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3 – 2.5, FDR-adjusted p = 0.0024) but not with sporadic GGE (OR = 1.3, 95% CI = 0.9 – 1.9, FDR-adjusted p = 0.19). URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.
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