探索阿尔茨海默病的遗传异质性：遗传亚型的证据。

Exploring the Genetic Heterogeneity of Alzheimer's Disease: Evidence for Genetic Subtypes.

机构信息

Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA.

出版信息

J Alzheimers Dis. 2024;100(4):1209-1226. doi: 10.3233/JAD-231252.

DOI:10.3233/JAD-231252

PMID:38995775

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11636402/

Abstract

BACKGROUND

Alzheimer's disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins.

OBJECTIVE

We investigated genetic heterogeneity in AD risk through a multi-step analysis.

METHODS

We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases = 2,739, controls = 5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (AD cases = 500, controls = 470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n = 399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories.

RESULTS

PCA revealed three distinct clusters ("constellations") driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time.

CONCLUSIONS

This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time.

摘要

背景

阿尔茨海默病（AD）表现出相当大的表型异质性，提示可能存在亚型。AD 受大量遗传影响，因此识别遗传风险的系统变化可能有助于了解疾病的起源。

目的

我们通过多步骤分析研究 AD 风险的遗传异质性。

方法

我们对英国生物库中与 AD 相关的变异进行主成分分析（PCA），以评估结构遗传异质性。随后，双聚类算法在病例亚组中搜索特定疾病的遗传特征。使用阿尔茨海默病神经影像学倡议（ADNI）数据集（AD 病例=500，对照=470）进行复制测试。我们将 ADNI 中另一组轻度认知障碍（MCI；n=399）的个体分为遗传亚型，并检查认知、淀粉样蛋白和 tau 轨迹。

结果

PCA 显示了三个不同的聚类（“星座”），主要由 MAPT 基因座周围强连锁不平衡区域中不同的相关模式驱动。星座包含病例和对照的混合物，反映了与疾病相关但不是特定于疾病的结构。我们在 AD 病例中发现了两个特定于疾病的双聚类。通路分析将双聚类相关变体与神经元形态发生和生长联系起来。在 ADNI 中复制了与疾病相关和特定于疾病的结构，并且双聚类 2 随着时间的推移表现出脑脊液 p-tau 增加和认知下降。