小柯机器人

美国哥伦比亚大学医学中心David B. Goldstein和美国约翰霍普金斯大学医学院Gerald Nestadt合作取得最新进展。他们利用强迫症 (OCD)外显子组测序技术揭示罕见的破坏性编码变异负荷。2021年6月28日出版的《自然-神经科学》杂志发表了这项成果。

他们在迄今为止最大的 OCD 队列中进行了外显子组测序（总共 1,313 个病例，包括 587 个三突变、41 个四突变和 644 个单突变的受影响个体），并描述了罕见的破坏性编码变异对疾病风险的贡献。在病例对照分析中 (n = 1,263/11,580)，在 SLITRK5 中观察到最显著的单基因结果（优势比 (OR) = 8.8，95% 置信区间 3.4-22.5，P = 2.3 −6 1）。在整个外显子组中，特别是在 LoF 不耐受基因（OR = 1.33，P = 0.01）内，存在过多的功能丧失（LoF）变异。

在对三突变的分析中，他们观察到相对于对照有过多的从头错义预测的破坏性变异（OR = 1.22，P = 0.02），同时在 LoF 不耐受基因中有过多的从头 LoF 突变（OR = 2.55，P = 7.33 × 10−3)。这些数据支持罕见的编码变异对强迫症遗传风险的贡献。

据了解，OCD影响 1-2% 的群体，并且与其他复杂的神经精神疾病一样，人们认为罕见的变异会导致其遗传风险。

附：英文原文

Title: Exome sequencing in obsessive–compulsive disorder reveals a burden of rare damaging coding variants

Author: Mathew Halvorsen, Jack Samuels, Ying Wang, Benjamin D. Greenberg, Abby J. Fyer, James T. McCracken, Daniel A. Geller, James A. Knowles, Anthony W. Zoghbi, Tess D. Pottinger, Marco A. Grados, Mark A. Riddle, O. Joseph Bienvenu, Paul S. Nestadt, Janice Krasnow, Fernando S. Goes, Brion Maher, Gerald Nestadt, David B. Goldstein

Issue&Volume: 2021-06-28

Abstract: Obsessive–compulsive disorder (OCD) affects 1–2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case–control analyses (n=1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR)=8.8, 95% confidence interval 3.4–22.5, P=2.3×106). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR=1.33, P=0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR=1.22, P=0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR=2.55, P=7.33×103). These data support a contribution of rare coding variants to OCD genetic risk.

DOI: 10.1038/s41593-021-00876-8

Source: https://www.nature.com/articles/s41593-021-00876-8

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex