Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis
Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis
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DOI：
10.1136/jmedgenet-2020-106866
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发表时间：
2021-02-01
影响因子：
4
通讯作者：
Blair, Ian P.
中科院分区：
文献类型：
--
作者：
McCann, Emily P.;Henden, Lyndal;Blair, Ian P.
肌萎缩侧索硬化（Amyotrophiclateralsclerosis，ALS）是一种具有表型和遗传异质性的致死性神经退行性疾病.大约10%的病例是家族性的，而其余的病例被归类为散发性的。到目前为止，>30个基因和几百个遗传变异已牵连在ALS.MethodsSeven百和57散发性ALS病例从澳大利亚神经科诊所招募。分别从567例和616例病例中获得了详细的临床数据和全基因组测序（WGS）数据，其中426例病例两种数据集都可用。作为综合遗传分析的一部分，在散发性ALS WGS数据中询问了先前报告为ALS连锁突变或疾病相关等位基因的853种遗传变异。进行统计学分析以鉴定临床变量之间以及个体携带的表型和ALS相关变体数量之间的相关性。携带相同的变异个体之间的相关性进行了评估，使用身份的血统analysis.ResultsForty-three ALS牵连的18个基因，包括C9 orf 72，ATXN 2，TARDBP，SOD 1，SQSTM 1和SETX的变体，在澳大利亚散发性ALS病例。三分之一的病例携带至少一种变异，6.82%携带两种或两种以上变异，暗示ALS的潜在寡基因或多基因基础。在两个携带SOD 1 p.I114T突变的散发性ALS病例和三个携带SQSTM 1 p.K238E突变的病例之间检测到相关性。寡基因/多基因散发性ALS的情况下，表现出较早的发病年龄比那些没有报告的variant.ConclusionWe确认ALS病例之间的表型协会，并强调所有形式的ALS的遗传变异的贡献。
BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS.MethodsSeven hundred and fifty-seven sporadic ALS cases were recruited from Australian neurology clinics. Detailed clinical data and whole genome sequencing (WGS) data were available from 567 and 616 cases, respectively, of which 426 cases had both datasets available. As part of a comprehensive genetic analysis, 853 genetic variants previously reported as ALS-linked mutations or disease-associated alleles were interrogated in sporadic ALS WGS data. Statistical analyses were performed to identify correlation between clinical variables, and between phenotype and the number of ALS-implicated variants carried by an individual. Relatedness between individuals carrying identical variants was assessed using identity-by-descent analysis.ResultsForty-three ALS-implicated variants from 18 genes, including C9orf72, ATXN2, TARDBP, SOD1, SQSTM1 and SETX, were identified in Australian sporadic ALS cases. One-third of cases carried at least one variant and 6.82% carried two or more variants, implicating a potential oligogenic or polygenic basis of ALS. Relatedness was detected between two sporadic ALS cases carrying a SOD1 p.I114T mutation, and among three cases carrying a SQSTM1 p.K238E mutation. Oligogenic/polygenic sporadic ALS cases showed earlier age of onset than those with no reported variant.ConclusionWe confirm phenotypic associations among ALS cases, and highlight the contribution of genetic variation to all forms of ALS.