Genomics of severe and treatment-resistant obsessive–compulsive disorder treated with deep brain stimulation: A preliminary investigation

IF 1.6 3区 医学 Q3 GENETICS & HEREDITY
Long Long Chen, Matilda Naesström, Matthew Halvorsen, Anders Fytagoridis, Stephanie B. Crowley, David Mataix-Cols, Christian Rück, James J. Crowley, Diana Pascal
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Abstract

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 of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (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. This KCNB1 substitution (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.

Abstract Image

通过脑深部刺激治疗严重和耐药性强迫症的基因组学:初步调查
重度和难治性强迫症(trOCD)患者是一个人数不多但残疾严重的群体。由于有资格接受脑深部刺激(DBS)治疗的三重强迫症患者可能是强迫症谱系中最严重的一端,我们推测他们更有可能患有遗传性强迫症。因此,虽然全球接受脑深部刺激(DBS)治疗的病例可能很少(约 300 例),但用现代基因组学方法对这些人进行筛查可能会加速强迫症基因的发现。因此,我们已开始从符合 DBS 治疗条件的 trOCD 病例中收集 DNA,并在此报告对首批五例病例进行全外显子组测序和芯片基因分型的结果。所有参与者之前都接受过纹状体末端床核(BNST)的 DBS 治疗,其中两名患者对手术有反应,一名患者有部分反应。我们的分析重点是基因干扰性罕见变异(GDRVs;罕见的、预测的致死性单核苷酸变异或重叠蛋白编码基因的拷贝数变异)。五例病例中有三例携带 GDRV,包括 KCNB1 离子转运体结构域的错义变异、15q11.2 的缺失和 15q26.1 的重复。KCNB1 变体(hg19 chr20-47991077-C-T,NM_004975.3:c.1020G>A,p.Met340Ile)导致神经细胞钾电压门控离子通道 KV2.1 跨膜区的蛋氨酸被异亮氨酸取代。KCNB1 的这种置换(Met340Ile)位于蛋白质的一个高度受限区域,该区域中的其他罕见错义变异曾与神经发育障碍有关。携带 Met340Ile 变异的患者对 DBS 有反应,这表明遗传因素可能是预测 DBS 治疗强迫症反应的潜在因素。总之,我们已经制定了招募 trOCD 病例并对其进行基因组学鉴定的方案。初步结果表明,这将是发现强迫症风险基因的一种信息丰富的策略。
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来源期刊
CiteScore
5.90
自引率
7.10%
发文量
40
审稿时长
4-8 weeks
期刊介绍: Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.
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