Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups

IF 9.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2024-08-23 DOI:10.1007/s00401-024-02778-y

Yiyi Ma, Dolly Reyes-Dumeyer, Angel Piriz, Patricia Recio, Diones Rivera Mejia, Martin Medrano, Rafael A. Lantigua, Jean Paul G. Vonsattel, Giuseppe Tosto, Andrew F. Teich, Benjamin Ciener, Sandra Leskinen, Sharanya Sivakumar, Michael DeTure, Duara Ranjan, Dennis Dickson, Melissa Murray, Edward Lee, David A. Wolk, Lee-Way Jin, Brittany N. Dugger, Annie Hiniker, Robert A. Rissman, Richard Mayeux, Badri N. Vardarajan

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Abstract

Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10^–8), the intergenic region between VRTN and SYNDIG1L (Score = − 37.67, P = 2.25 × 10^–9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10^–8), PVRL2 (Score = 125.86, P = 1.64 × 10^–9), TOMM40 (Score = − 18.58, P = 4.61 × 10^–8), and APOE (Score = 75.12, P = 7.26 × 10^–26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.

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从两个种族群体的尸检大脑看阿尔茨海默病的表观遗传和遗传风险。

遗传变异和表观遗传特征都会增加阿尔茨海默病（AD）的患病风险。CpG 相关单核苷酸多态性（CGS）是遗传和表观遗传效应的枢纽，我们研究了加勒比海西班牙裔人（CH）中 CpG 相关单核苷酸多态性与老年痴呆症的关联，并将研究结果推广到非西班牙裔白人（NHW）。首先，我们在 7,155 名加勒比海西班牙裔人和 1,283 名非西班牙裔白人中进行了基于滑动窗口的全基因组AD关联研究。接着，我们利用 179 名 CH 大脑背外侧前额叶皮层的数据，测试了与 AD 相关的 CGS 对大脑 DNA 甲基化和 mRNA 表达的顺式和反式影响。对于具有显著顺式和反式效应的基因，我们研究了其富集通路。我们在CGS剂量与AD相关的CH中发现了6个具有全基因组显著性水平的基因位点：ADAM20（得分 = 55.19，P = 4.06 × 10-8）、VRTN 和 SYNDIG1L 之间的基因间区域（得分 = - 37.67，P = 2.25 × 10-9）、SPG7（16q24.3）（得分 = 40.51，P = 2.23 × 10-8）、PVRL2（得分 = 125.86，P = 1.64 × 10-9）、TOMM40（得分 = - 18.58，P = 4.61 × 10-8）和 APOE（得分 = 75.12，P = 7.26 × 10-26）。在 NHW 中，PVRL2 和 APOE 的 CGS 也很显著。除 ADAM20 外，其他五个位点的 CGS 与 CH 脑甲基化水平相关（mQTLs），SPG7、PVRL2 和 APOE 的 CGS 也是 NHW 的 mQTLs。除 SYNDIG1L 外（P = 0.08），其他五个基因位点的脑甲基化水平均影响 CH 的下游 mRNA 表达（P = 0.05）。

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.