Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study.
Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study.
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DOI：
10.1016/s1474-4422(17)30400-3
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发表时间：
2018-01
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影响因子：
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通讯作者：
Bras J
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作者：
Guerreiro R;Ross OA;Kun-Rodrigues C;Hernandez DG;Orme T;Eicher JD;Shepherd CE;Parkkinen L;Darwent L;Heckman MG;Scholz SW;Troncoso JC;Pletnikova O;Ansorge O;Clarimon J;Lleo A;Morenas-Rodriguez E;Clark L;Honig LS;Marder K;Lemstra A;Rogaeva E;St George-Hyslop P;Londos E;Zetterberg H;Barber I;Braae A;Brown K;Morgan K;Troakes C;Al-Sarraj S;Lashley T;Holton J;Compta Y;Van Deerlin V;Serrano GE;Beach TG;Lesage S;Galasko D;Masliah E;Santana I;Pastor P;Diez-Fairen M;Aguilar M;Tienari PJ;Myllykangas L;Oinas M;Revesz T;Lees A;Boeve BF;Petersen RC;Ferman TJ;Escott-Price V;Graff-Radford N;Cairns NJ;Morris JC;Pickering-Brown S;Mann D;Halliday GM;Hardy J;Trojanowski JQ;Dickson DW;Singleton A;Stone DJ;Bras J
路易体痴呆症是老年人中第二种最常见的痴呆症，但在研究领域一直被蒙上阴影，部分原因是路易体痴呆症，帕金森病和阿尔茨海默病之间的相似性。到目前为止，据我们所知，还没有对路易体痴呆症进行大规模的遗传学研究。为了更好地了解路易体痴呆症的遗传基础，我们进行了一项全基因组关联研究，旨在确定这种疾病的遗传风险因素。在这个两阶段的全基因组关联研究中，我们收集了来自欧洲血统的白色参与者的样本，这些参与者根据既定的临床或病理标准被诊断为路易体痴呆。在发现阶段（病例队列从10个国家的22个中心招募，对照来自美国基因型和表型研究的两个公开数据库[phs000404.v1.p1和phs000982.v1.p1]），我们进行了基因分型，并利用最近建立的单倍型参考联盟面板作为插补的基础。病理样本在每个脑库尸检后确定，而临床样本在参与者检查后收集。没有收集样本的具体时间表。我们对所有患有路易体痴呆的参与者进行了关联分析，并且仅对病理诊断的参与者进行了关联分析。在复制阶段，我们对发现阶段的重要和提示性结果进行基因分型。最后，我们在固定效应模型下对这两个阶段进行了荟萃分析，并使用逻辑回归来检验每个阶段的关联。这项研究包括1743例路易体痴呆患者（1324例病理诊断）和4454例对照（1216例路易体痴呆患者与3791例对照处于发现阶段; 527例与663例处于复制阶段）。结果证实了先前报道的相关性：APOE（rs 429358;比值比[OR] 2·40，95% CI 2·14-2·70; p=1·05 × 10−48），SNCA（rs7681440; OR 0·73，0·66-0·81; p=6·39 × 10−10）和GBA（rs35749011; OR 2·55，1·88-3·46; p=1·78 × 10−9）。他们还为一个新的候选基因座提供了一些证据，即CNTN 1（rs7314908; OR 1.51，1.27 - 1.79; p= 2.32 × 10−6）;进一步的复制将是重要的。此外，我们估计路易体痴呆的遗传成分约为36%。尽管全基因组关联研究的样本量很小，并承认从多个地点确定样本的潜在偏倚，但我们提出了迄今为止路易体痴呆症最全面和最有力的遗传研究。这些数据表明，常见的遗传变异性在疾病中起作用。
Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson’s disease, and Alzheimer’s disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), and GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.