Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders.
Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders.
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DOI：
10.1093/brain/awad038
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发表时间：
2023-08-01
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精神障碍和常见癫痫是遗传性疾病，具有高度共病和症状重叠的特点。然而，这种关系背后的因果机制却鲜为人知。在这里，我们的目的是确定癫痫和精神障碍之间的重叠基因座，以更好地了解它们的共病和共同的临床特征。我们分析了所有癫痫(n=44 889)、遗传性全面性癫痫(n=33 446)、局灶性癫痫(n=39 348)、精神分裂症(n=77 096)、双相情感障碍(n=406 405)、抑郁症(n=500 199)、注意力缺陷多动障碍(n=53 293)和自闭症谱系障碍(n=46 350)的全基因组关联研究数据。首先，我们应用MIXER工具估计了影响疾病的因果变量的总数。接下来，我们使用合取错误发现率统计框架来提高发现共享基因组基因座的能力。此外，我们评估了这些发现在独立队列中的有效性，并从功能上表征了已识别的基因座。癫痫表型(1.0K~3.4K原因变异)明显低于精神疾病(5.6K~13.9K原因变异)，局灶性癫痫多基因最少(1.0K变异)，抑郁症多基因最高(13.9K变异)。我们观察到遗传性全面性癫痫和所有精神障碍之间，以及所有癫痫和精神分裂症和抑郁症之间的跨性状遗传丰富。利用关联误发率分析，我们确定了40个与癫痫和精神障碍相关的不同基因座，其中4个与所有癫痫相关，39个与遗传性全面性癫痫相关。癫痫危险部位多为精神分裂症(n=31)。在已鉴定的基因座中，32个为遗传性全面性癫痫的新基因，2个为所有癫痫的新基因。在共有的基因座上存在协调和不协调的等位基因效应。发现的变异与所有疾病的独立数据集之间的符号一致性高度一致，支持了研究结果的有效性。精神分裂症和遗传性全身性癫痫之间共有基因座的基因组分析涉及与细胞周期调节、蛋白磷酸酶活性、膜和囊泡功能相关的生物学过程；其他基因座的基因组分析缺乏说服力。精神障碍和常见癫痫之间广泛的遗传重叠和混合作用方向表明这些疾病之间存在复杂的遗传关系，符合它们的双向关系，并表明重叠的遗传风险可能有助于癫痫和精神疾病之间的共同病理生理和临床特征。Karadag等人。在一项全基因组关联研究中，确定了与常见癫痫和精神疾病相关的40个不同的基因座。广泛的遗传重叠和混合效应方向表明这些疾病之间存在复杂的遗传关系。
Psychiatric disorders and common epilepsies are heritable disorders with a high comorbidity and overlapping symptoms. However, the causative mechanisms underlying this relationship are poorly understood. Here we aimed to identify overlapping genetic loci between epilepsy and psychiatric disorders to gain a better understanding of their comorbidity and shared clinical features. We analysed genome-wide association study data for all epilepsies (n = 44 889), genetic generalized epilepsy (n = 33 446), focal epilepsy (n = 39 348), schizophrenia (n = 77 096), bipolar disorder (n = 406 405), depression (n = 500 199), attention deficit hyperactivity disorder (n = 53 293) and autism spectrum disorder (n = 46 350). First, we applied the MiXeR tool to estimate the total number of causal variants influencing the disorders. Next, we used the conjunctional false discovery rate statistical framework to improve power to discover shared genomic loci. Additionally, we assessed the validity of the findings in independent cohorts, and functionally characterized the identified loci. The epilepsy phenotypes were considerably less polygenic (1.0 K to 3.4 K causal variants) than the psychiatric disorders (5.6 K to 13.9 K causal variants), with focal epilepsy being the least polygenic (1.0 K variants), and depression having the highest polygenicity (13.9 K variants). We observed cross-trait genetic enrichment between genetic generalized epilepsy and all psychiatric disorders and between all epilepsies and schizophrenia and depression. Using conjunctional false discovery rate analysis, we identified 40 distinct loci jointly associated with epilepsies and psychiatric disorders at conjunctional false discovery rate <0.05, four of which were associated with all epilepsies and 39 with genetic generalized epilepsy. Most epilepsy risk loci were shared with schizophrenia (n = 31). Among the identified loci, 32 were novel for genetic generalized epilepsy, and two were novel for all epilepsies. There was a mixture of concordant and discordant allelic effects in the shared loci. The sign concordance of the identified variants was highly consistent between the discovery and independent datasets for all disorders, supporting the validity of the findings. Gene-set analysis for the shared loci between schizophrenia and genetic generalized epilepsy implicated biological processes related to cell cycle regulation, protein phosphatase activity, and membrane and vesicle function; the gene-set analyses for the other loci were underpowered. The extensive genetic overlap with mixed effect directions between psychiatric disorders and common epilepsies demonstrates a complex genetic relationship between these disorders, in line with their bi-directional relationship, and indicates that overlapping genetic risk may contribute to shared pathophysiological and clinical features between epilepsy and psychiatric disorders. Karadag et al. identify 40 distinct loci jointly associated with common epilepsies and psychiatric disorders in a genome-wide association study. The extensive genetic overlap with mixed effect directions points to a complex genetic relationship between these conditions.
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