Genome-wide association of polygenic risk extremes for Alzheimer's disease in the UK Biobank.
Genome-wide association of polygenic risk extremes for Alzheimer's disease in the UK Biobank.
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英国生物库中阿尔茨海默病多基因风险极端的全基因组关联
DOI：
10.1038/s41598-022-12391-2
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发表时间：
2022-05-19
影响因子：
4.6
通讯作者：
Bras J
中科院分区：
文献类型：
--
作者：
Gouveia C;Gibbons E;Dehghani N;Eapen J;Guerreiro R;Bras J
在短短十多年的时间里，全基因组关联研究（GWAS）的进展提供了一种根据疾病遗传风险对个体进行分层的方法。使用最近的阿尔茨海默病 (AD) GWAS 结果作为基础数据，我们确定了英国生物银行数据集中每个人的多基因风险评分 (PRS)。我们使用极端风险分布内的个体进行了 GWAS，该 GWAS 与 AD 表型无关，而是基于已知的疾病遗传风险。为了解释新风险因素的功能，我们进行了表型分析，包括全表型关联研究。我们确定了 246 个位点超过显着性阈值，其中 229 个位点未在基础 AD GWAS 中报告。其中包括在基础 GWAS 中显示出暗示关联水平的基因座以及之前未被怀疑与 AD 相关的基因座。其中，IL34 和 KANSL1 等基因座在最近的研究中已被证明与 AD 相关。我们还显示了与多种健康相关结果的高度显着的遗传相关性，这些结果提供了对前驱症状和合并症的见解。这是第一项在 AD 遗传学研究中利用 PRS 作为表型不可知群体分类的研究。我们确定了 AD 的潜在新位点，并对这些 PRS 极端情况进行了详细的表型分析。
In just over a decade, advances in genome-wide association studies (GWAS) have offered an approach to stratify individuals based on genetic risk for disease. Using recent Alzheimer's disease (AD) GWAS results as the base data, we determined each individual's polygenic risk score (PRS) in the UK Biobank dataset. Using individuals within the extreme risk distribution, we performed a GWAS that is agnostic of AD phenotype and is instead based on known genetic risk for disease. To interpret the functions of the new risk factors, we conducted phenotype analyses, including a phenome-wide association study. We identified 246 loci surpassing the significance threshold of which 229 were not reported in the base AD GWAS. These include loci that showed suggestive levels of association in the base GWAS and loci not previously suspected to be associated with AD. Among these, there are loci, such as IL34 and KANSL1, that have since been shown to be associated with AD in recent studies. We also show highly significant genetic correlations with multiple health-related outcomes that provide insights into prodromal symptoms and comorbidities. This is the first study to utilize PRS as a phenotype-agnostic group classification in AD genetic studies. We identify potential new loci for AD and detail phenotypic analysis of these PRS extremes.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
4.3
作者：
Logue MW;Lancour D;Farrell J;Simkina I;Fallin MD;Lunetta KL;Farrer LA
通讯作者：
Farrer LA
影响因子：
8.8
作者：
Lu, Tianyuan;Zhou, Sirui;Richards, J. Brent
通讯作者：
Richards, J. Brent
影响因子：
9.2
作者：
Choi, Shing Wan;O'Reilly, Paul F.
通讯作者：
O'Reilly, Paul F.