Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains.
Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains.
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DOI：
10.1136/jnnp-2017-317234
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Chinnery PF
中科院分区：
文献类型：
--
作者：
Keogh MJ;Wei W;Aryaman J;Wilson I;Talbot K;Turner MR;McKenzie CA;Troakes C;Attems J;Smith C;Al Sarraj S;Morris CM;Ansorge O;Pickering-Brown S;Jones N;Ironside JW;Chinnery PF
一些研究表明，导致单基因形式的神经退行性疾病的基因中的多种罕见遗传变异协同作用，以增加疾病风险或降低发病年龄，但这些研究尚未在大型散发病例系列中得到验证。我们分析了980例具有神经病理学特征的阿尔茨海默病（AD）、帕金森病-路易体痴呆（PD-DLB）、额颞叶痴呆-肌萎缩侧索硬化（FTD-ALS）和年龄匹配的对照组人脑。使用美国医学遗传学学会致病性标准评估遗传变异。在相关疾病基因组中具有两个或更多个变体的个体被定义为“寡基因”。大多数寡基因变异组合由一个高度外显的等位基因或已知的危险因素与另一个罕见但可能是良性的等位基因组合组成。寡基因变异的存在并不影响发病年龄或疾病严重程度。在控制了单个已知的主要风险等位基因后，病例组和对照组之间的寡基因变异频率没有差异。先验地，患有AD、PD-DLB和FTD-ALS的个体更可能具有已知的遗传风险因素，并且这些变体与罕见的良性等位基因组合的负担可能是导致一些寡基因关联的原因。在研究神经退行性疾病中寡基因变异的潜在作用时，控制这种偏倚是必不可少的。
Several studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series. We analysed 980 neuropathologically characterised human brains with Alzheimer’s disease (AD), Parkinson’s disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity. Individuals with two or more variants within a relevant disease gene panel were defined as ‘oligogenic’. The majority of oligogenic variant combinations consisted of a highly penetrant allele or known risk factor in combination with another rare but likely benign allele. The presence of oligogenic variants did not influence the age of onset or disease severity. After controlling for the single known major risk allele, the frequency of oligogenic variants was no different between cases and controls. A priori, individuals with AD, PD-DLB and FTD-ALS are more likely to harbour a known genetic risk factor, and it is the burden of these variants in combination with rare benign alleles that is likely to be responsible for some oligogenic associations. Controlling for this bias is essential in studies investigating a potential role for oligogenic variation in neurodegenerative diseases.
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影响因子：
16.2
作者：
Singleton A;Hardy J
通讯作者：
Hardy J
影响因子：
7
作者：
Keogh MJ;Wei W;Wilson I;Coxhead J;Ryan S;Rollinson S;Griffin H;Kurzawa-Akanbi M;Santibanez-Koref M;Talbot K;Turner MR;McKenzie CA;Troakes C;Attems J;Smith C;Al Sarraj S;Morris CM;Ansorge O;Pickering-Brown S;Ironside JW;Chinnery PF
通讯作者：
Chinnery PF
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
3.5
作者：
Tsuji S
通讯作者：
Tsuji S
影响因子：
3.5
作者：
Lubbe SJ;Escott-Price V;Gibbs JR;Nalls MA;Bras J;Price TR;Nicolas A;Jansen IE;Mok KY;Pittman AM;Tomkins JE;Lewis PA;Noyce AJ;Lesage S;Sharma M;Schiff ER;Levine AP;Brice A;Gasser T;Hardy J;Heutink P;Wood NW;Singleton AB;Williams NM;Morris HR;for International Parkinson’s Disease Genomics Consortium
通讯作者：
for International Parkinson’s Disease Genomics Consortium