Multi-omics Characterization of Epigenetic and Genetic Risk of Alzheimer Disease in Autopsied Brains from two Ethnic Groups

Background Both genetic variants and epigenetic features contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as the hub of both the genetic and epigenetic effects, in Hispanics decedents and generalized the findings to Non-Hispanic Whites (NHW) decedents. Methods First, we derived the dosage of the CpG site-creating allele of multiple CGSes in each 1 KB window across the genome and we conducted a sliding window association test with clinical diagnosis of AD in 7,155 Hispanics (3,194 cases and 3,961 controls) using generalized linear mixed models with the adjustment of age, sex, population structure, genomic relationship matrix, and genotyping batches. Next, using methylation and bulk RNA-sequencing data from the dorsolateral pre-frontal cortex in 150 Hispanics 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 checked their enriched pathways. Results We identified six genetic loci in Hispanics with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score=55.2, P= 4.06×10-8), between VRTN (Score=-19.6, P= 1.47×10-8) and SYNDIG1L (Score=-37.7, P= 2.25×10-9), SPG7 (16q24.3) (Score=40.5, 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 genome-wide significant in NHW. Except for ADAM20 , CGSes in all the other five loci were associated with Hispanic 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 all the other five loci affected downstream RNA expression in the Hispanics ( P <0.05), and methylation at VRTN and TOMM40 were also associated with RNA 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 synapse (FDR<0.05). Conclusions We identified six CpG associated genetic loci associated with AD in Hispanics, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Data collection and sharing for this project was supported by (WHICAP, R01 AG072474, RF1 AG066107) funded by the National Institute on Aging (NIA) and by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. Data collection for this project was supported by the Genetic Studies of Alzheimer disease in Caribbean Hispanics (EFIGA) funded by the National Institute on Aging (NIA) and by the National Institutes of Health (NIH) (R01 AG067501). The project was partially funded by the National Institute on Aging (NIA) of the National Institutes of Health (NIH) under Award Numbers R01AG062517, and P30AG072972, P30AG062429, NIA (P30 AG062677, P01 AG003949), Florida Department of Health, Ed and Ethel Moore Alzheimer Disease Research Program (20A22, 8AZ06), NIH P30AG072979, P01AG066597 and U19AG062418. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: An informed consent was signed by the participant and/or legal guardian of the individuals included into this study. IRB approval was approved by each institution. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors