多血统荟萃分析在已知和新发现的基因座上鉴定出阿尔茨海默病发病年龄的基因修饰因子。
Multi-ancestry meta-analysis identifies genetic modifiers of age-at-onset of Alzheimer's disease at known and novel loci.
作者信息
Blue Elizabeth E, Broome Jai, Xue Diane, Kingston Hanley, Chapman Nicola H, Gogarten Stephanie, Naj Adam C, Wijsman Ellen M
机构信息
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA.
Institute for Public Health Genetics, University of Washington, Seattle, Washington, USA.
出版信息
Alzheimers Dement. 2025 Sep;21(9):e70489. doi: 10.1002/alz.70489.
INTRODUCTION
Much of Alzheimer's disease (AD) risk is explained by age, apolipoprotein E (APOE) genotype, and sex. We sought to identify genetic modifiers of age at onset (AAO) of AD while probing the influence of sex and APOE among those with diverse ancestry.
METHODS
We performed genome-wide association studies (GWASs) of AAO in two diverse samples followed by meta-analysis, contrasting results with and without adjustment for sex and APOE. Genome-wide significance was set to p < 5×10.
RESULTS
GWASs adjusting for sex, APOE, population structure, and relatedness revealed 17 significant loci including independent associations at AD risk loci and four novel signals. APOE adjustment influenced GWAS effect sizes across the genome while sex adjustment had minimal effect.
DISCUSSION
We identified association signals within a diverse but relatively small sample, replicating loci recently discovered in large European ancestry-only GWASs, and illustrated the power of using a quantitative trait like AAO over a binary diagnosis trait.
HIGHLIGHTS
Survival analysis approach identified known and novel genetic modifiers of Alzheimer's disease (AD). Multi-ancestry analyses revealed independent signals at known AD loci. Apolipoprotein E adjustment influenced variant effects across the genome.
引言
阿尔茨海默病（AD）的许多风险可由年龄、载脂蛋白E（APOE）基因型和性别来解释。我们试图识别AD发病年龄（AAO）的基因修饰因子，同时探究性别和APOE在不同血统人群中的影响。
方法
我们在两个不同的样本中对AAO进行全基因组关联研究（GWAS），随后进行荟萃分析，对比了对性别和APOE进行调整与未调整的结果。全基因组显著性设定为p < 5×10⁻⁸。
结果
对性别、APOE、群体结构和相关性进行调整的GWAS揭示了17个显著位点，包括AD风险位点的独立关联以及四个新信号。APOE调整影响了全基因组的GWAS效应大小，而性别调整的影响最小。
讨论
我们在一个多样但相对较小的样本中识别出关联信号，复制了最近在仅具有欧洲血统的大型GWAS中发现的位点，并说明了使用像AAO这样的定量性状而非二元诊断性状的优势。
要点
生存分析方法识别出了阿尔茨海默病（AD）已知和新的基因修饰因子。多血统分析在已知的AD位点揭示了独立信号。载脂蛋白E调整影响了全基因组的变异效应。
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