Frequency and phenotype associations of rare variants in five monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants with whole exome sequencing data
Frequency and phenotype associations of rare variants in five monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants with whole exome sequencing data
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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以及全外显子组测序数据
DOI：
10.1101/2021.11.17.21266447
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Ferguson A
中科院分区：
文献类型：
--
作者：
Ferguson A
根据以前的病例报告和基于疾病的队列，少数脑小血管疾病（cSVD）患者具有单基因病因，其中许多患者还表现出脑外表型。我们在UK Biobank （UKB）中调查了cSVD基因中罕见变异的频率、外显率和表型相关性，这是一项基于人群的大型研究。我们系统回顾了以往的文献和ClinVar，以确定推定的致病性罕见变异inCTSA， TREX1, HTRA1, COL4A1/2。我们将以前归因于这些变异的表型（感兴趣的表型）映射到UKB相关健康数据中使用的疾病编码系统，这些数据来自英国医院入院、死亡记录和初级保健。在199313名进行外显子组测序的UKB参与者中，我们评估了：携带≥1个变体的参与者比例；phenotype-of-interest外显率;使用二元（任何表型存在/不存在）和表型负担（参与者拥有的表型数量的线性评分）方法研究变异携带者状态与感兴趣表型之间的关系。在UKB参与者中，0.5%的研究基因有≥1个变异。根据住院和死亡记录，每个基因4-20%的变异携带者具有相关表型。当包括初级保健记录时，这一比例增加到7-55%。昂立col4a1变异携带者状态与具有≥1个感兴趣表型和较高表型评分显著相关（OR=1.29, p=0.006）。虽然在UKB人群中，单基因cSVD基因的推定致病性罕见变异发生率为1:20 00，但只有大约一半的变异携带者在相关的健康数据中记录了相关的疾病表型。我们无法复制大多数先前报道的基因表型关联，这表明较低的外显率，高估的致病性和/或有限的统计能力。
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 extra-cerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of rare variants in cSVD genes in UK Biobank (UKB), a large population-based study.We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants inCTSA, TREX1, HTRA1, COL4A1/2. We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in UKB’s linked health data from UK hospital admissions, death records and primary care. Among 199,313 exome-sequenced UKB participants, we assessed: 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.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. OnlyCOL4A1variant carrier-status was significantly associated with having ≥1 phenotype-of-interest and a higher phenotype score (OR=1.29, p=0.006).While putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only around 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.
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影响因子：
5.4
作者：
Hauer AJ;Ruigrok YM;Algra A;van Dijk EJ;Koudstaal PJ;Luijckx GJ;Nederkoorn PJ;van Oostenbrugge RJ;Visser MC;Wermer MJ;Kappelle LJ;Klijn CJM;Dutch Parelsnoer Institute‐Cerebrovascular Accident Study Group
通讯作者：
Dutch Parelsnoer Institute‐Cerebrovascular Accident Study Group
影响因子：
3.7
作者：
Kilarski LL;Rutten-Jacobs LC;Bevan S;Baker R;Hassan A;Hughes DA;Markus HS;UK Young Lacunar Stroke DNA Study
通讯作者：
UK Young Lacunar Stroke DNA Study
影响因子：
9.8
作者：
Jeanne, Marion;Labelle-Dumais, Cassandre;Gould, Douglas B.
通讯作者：
Gould, Douglas B.
影响因子：
3.7
作者：
Caciotti A;Catarzi S;Tonin R;Lugli L;Perez CR;Michelakakis H;Mavridou I;Donati MA;Guerrini R;d'Azzo A;Morrone A
通讯作者：
Morrone A
影响因子：
8.3
作者：
Marini, Sandro;Anderson, Christopher D.;Rosand, Jonathan
通讯作者：
Rosand, Jonathan