1. Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups
- Author
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Ma, Yiyi, Reyes-Dumeyer, Dolly, Piriz, Angel, Recio, Patricia, Mejia, Diones Rivera, Medrano, Martin, Lantigua, Rafael A, Vonsattel, Jean Paul G, Tosto, Giuseppe, Teich, Andrew F, Ciener, Benjamin, Leskinen, Sandra, Sivakumar, Sharanya, DeTure, Michael, Ranjan, Duara, Dickson, Dennis, Murray, Melissa, Lee, Edward, Wolk, David A, Jin, Lee-Way, Dugger, Brittany N, Hiniker, Annie, Rissman, Robert A, Mayeux, Richard, and Vardarajan, Badri N
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Dementia ,Human Genome ,Neurodegenerative ,Prevention ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease ,Brain Disorders ,Clinical Research ,Aging ,Acquired Cognitive Impairment ,Genetics ,Minority Health ,Health Disparities ,2.1 Biological and endogenous factors ,Neurological ,Aged ,Aged ,80 and over ,Female ,Humans ,Male ,Alzheimer Disease ,Autopsy ,Brain ,DNA Methylation ,Epigenesis ,Genetic ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Caribbean People ,White ,Alzheimer's disease ,Epigenetics ,Hispanics ,Non-Hispanic Whites ,CpG-related single nucleotide polymorphism ,Alzheimer’s disease ,Clinical Sciences ,Neurology & Neurosurgery - 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
- Published
- 2024