Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation.
Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation.
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用深部脑刺激治疗的严重和难治性强迫症的基因组学：初步调查。
DOI：
10.1101/2023.04.15.23288623
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Pascal,Diana
中科院分区：
文献类型：
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作者：
Chen,LongLong;Naesström,Matilda;Halvorsen,Matthew;Fytagoridis,Anders;Mataix-Cols,David;Rück,Christian;Crowley,JamesJ;Pascal,Diana
患有重度和难治性强迫症（trOCD）的个体代表了一小部分但严重残疾的患者。由于适合脑深部电刺激（DBS）的trOCD病例可能是强迫症谱中最严重的一端，我们假设他们可能更有可能对他们的疾病有很强的遗传贡献。因此，虽然DBS治疗病例的全球人群可能很小（约300），但使用现代基因组方法筛选这些个体可能会加速OCD的基因发现。因此，我们已经开始从符合DBS条件的trOCD病例中收集DNA，在这里我们报告了前五例病例的全外显子组测序和微阵列基因分型结果。所有参与者之前都在终纹床核（BNST）中接受过DBS，其中2名患者对手术有反应，1名患者显示部分反应。我们的分析集中在基因破坏性罕见变异（GDRV;罕见的、预测有害的单核苷酸变异或与蛋白质编码基因重叠的拷贝数变异）。5例中有3例携带GDRV，包括KCNB 1离子转运域的错义变异、15q11.2的缺失和15q26.1的重复。KCNB 1变体（hg 19 chr 20 - 47991077-C-T，NM_004975.3：c.1020G>A，p. Met 340 Ile）导致神经元钾电压门控离子通道KV 2.1跨膜区的蛋氨酸取代异亮氨酸。ThisKCNB 1取代（Met 340 Ile）位于蛋白质的高度限制区域，其他罕见的错义变体先前与神经发育障碍有关。携带Met 340 Ile变异体的患者对DBS有反应，这表明遗传因素可能是DBS治疗OCD反应的预测因素。总之，我们已经建立了一个方案，招募和基因组特征trOCD的情况下。初步结果表明，这将是一个信息策略，发现风险基因在强迫症。
Individuals with severe and treatment‐resistant obsessive‐compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS‐treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene‐disruptive rare variants (GDRVs; rare, predicted‐deleterious single‐nucleotide variants or copy number variants overlapping protein‐coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain ofKCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. TheKCNB1variant (hg19 chr20‐47991077‐C‐T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans‐membrane region of neuronal potassium voltage‐gated ion channel KV2.1. ThisKCNB1substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.