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.

遗传变异和表观遗传特征都会增加患阿尔茨海默病 (AD) 的风险。我们研究了加勒比西班牙裔 (CH) 中 CpG 相关单核苷酸多态性 (CGS) 与 AD 的关联，CGS 充当遗传和表观遗传效应的中心，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 CH 和 1,283 名 NHW 参与者中进行了全基因组、基于滑动窗口的与 AD 关联。接下来，利用来自 179 个 CH 大脑背外侧前额叶皮层的数据，我们测试了 AD 相关 CGS 对大脑 DNA 甲基化到 mRNA 表达的顺式和反式影响。对于具有显着顺式和反式效应的基因，我们研究了它们的富集途径。我们在全基因组显着性水平上确定了 CH 中 CGS 剂量与 AD 相关的 6 个遗传位点： 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 （分数 = 75.12， P = 7.26 × 10 ^–26 ）。 PVRL2和APOE中的 CGS 在 NHW 中也很重要。除ADAM20外，其他 5 个位点中的 CGS 与 CH 脑甲基化水平 (mQTL) 相关， SPG7、PVRL2和APOE中的 CGS 也是 NHW 中的 mQTL。 SYNDIG1L除外（ P = 0。08），其他5个位点的脑甲基化水平影响CH下游mRNA表达（ P ％3C 0.05）， VRTN和TOMM40的甲基化也与NHW中的mRNA表达相关。这六个位点的基因表达也受到富含神经元投射和谷氨酸突触途径的基因中的 CpG 位点的调节 (FDR < 0.05)。所有六个位点的 DNA 甲基化以及SYNDIG1和TOMM40的 mRNA 表达与 CH 的 Braak 阶段显着相关。总之，我们在 CH 中鉴定了 6 个与 AD 相关的 CpG 相关基因位点，它们同时存在遗传和表观遗传风险。然而，它们对 mRNA 表达的下游影响可能是种族特异性的，并且与 NHW 不同。