200,000名英国生物银行参与者中5个单基因脑小血管疾病基因的罕见变异的频率和表型关联
Frequency and Phenotype Associations of Rare Variants in 5 Monogenic Cerebral Small Vessel Disease Genes in 200,000 UK Biobank Participants.
作者信息
Ferguson Amy Christina, Thrippleton Sophie, Henshall David, Whittaker Ed, Conway Bryan, MacLeod Malcolm, Malik Rainer, Rawlik Konrad, Tenesa Albert, Sudlow Cathie, Rannikmae Kristiina
机构信息
Centre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.
出版信息
Neurol Genet. 2022 Aug 24;8(5):e200015. doi: 10.1212/NXG.0000000000200015. eCollection 2022 Oct.
BACKGROUND AND OBJECTIVES
Based on previous case reports and disease-based cohorts, a minority of patients with cerebral small vessel disease (cSVD) have a monogenic cause, with many also manifesting extracerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of putative pathogenic variants in cSVD genes in the UK Biobank (UKB), a large population-based study.
METHODS
We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in , , , and . We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in the UKB's linked health data from UK hospital admissions, death records, and primary care. Among 199,313 exome-sequenced UKB participants, we assessed the following: the proportion of participants carrying ≥1 variant(s); phenotype-of-interest penetrance; and the association between variant carrier status and phenotypes-of-interest using a binary (any phenotype present/absent) and phenotype burden (linear score of the number of phenotypes a participant possessed) approach.
RESULTS
Among UKB participants, 0.5% had ≥1 variant(s) in studied genes. Using hospital admission and death records, 4%-20% of variant carriers per gene had an associated phenotype. This increased to 7%-55% when including primary care records. Only variant carrier status was significantly associated with having ≥1 phenotype-of-interest and a higher phenotype score (OR = 1.29, = 0.006).
DISCUSSION
While putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only approximately half of variant carriers have a relevant disease phenotype recorded in their linked health data. We could not replicate most previously reported gene-phenotype associations, suggesting lower penetrance rates, overestimated pathogenicity, and/or limited statistical power.
背景与目的
基于先前的病例报告和疾病队列研究，少数脑小血管病（cSVD）患者有单基因病因，许多患者还表现出脑外表型。我们在英国生物银行（UKB）这一大型基于人群的研究中，调查了cSVD基因中假定致病变异的频率、外显率及表型关联。
方法
我们对先前文献和临床变异数据库（ClinVar）进行系统回顾，以确定在[具体基因名称]、[具体基因名称]、[具体基因名称]和[具体基因名称]中的假定致病罕见变异。我们将先前归因于这些变异的表型（感兴趣的表型）映射到UKB从英国医院入院、死亡记录和初级保健中获取的关联健康数据所使用的疾病编码系统。在199313名进行了外显子测序的UKB参与者中，我们评估了以下内容：携带≥1个变异的参与者比例；感兴趣表型的外显率；以及使用二元法（存在/不存在任何表型）和表型负担法（参与者拥有的表型数量的线性评分）评估变异携带者状态与感兴趣表型之间的关联。
结果
在UKB参与者中，0.5%在研究基因中有≥1个变异。利用医院入院和死亡记录，每个基因4%-20%的变异携带者有相关表型。当纳入初级保健记录时，这一比例增至7%-55%。只有[具体基因名称]变异携带者状态与有≥1个感兴趣表型及更高的表型评分显著相关（优势比=1.29，P=0.006）。
讨论
虽然在UKB人群中，单基因cSVD基因中的假定致病罕见变异在每200人中出现1例，但在其关联健康数据中记录的变异携带者中，只有约一半有相关疾病表型。我们无法重现大多数先前报道的基因-表型关联，这表明外显率较低、致病性估计过高和/或统计效力有限。
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