New research published today by investigators from the Boston University School of Public Health (BUSPH) and the UTHealth Houston School of Public Health has identified 17 significant genetic variants in five genomic regions that are associated with Alzheimer’s disease (AD). The study, published in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, employed whole-genome sequencing which enabled researchers to pinpoint these rare and important genes and variants, and built upon existing data from genome-wide association studies (GWAS), which have focused on common variants and regions.
“Prior genome-wide association studies using common variants have identified regions of the genome, and sometimes genes, that are associated with Alzheimer’s disease,” said Anita DeStefano, PhD, professor of biostatistics at BUSPH co-senior author of the paper. “Whole genome sequence data interrogates every base pair in the human genome and can provide more information about which specific genetic change in a region may be contributing to Alzheimer’s disease risk or protection.”
For their work, the team used whole-genome sequencing data from the Alzheimer’s Disease Sequencing Project (ADSP), an NIH genetics project developed in 2012 as part of the National Alzheimer’s Project Act aimed at developing treatments and preventative measures for AD. Using these data the team conducted single variant association analysis and rare variant aggregation association tests.
Among the 17 variants discovered that are linked to AD, the KAT8 variants stood out as it was associated with AD in both the single variant and rare variant analyses. Other associations were found with several TREM2 variants.
According to co-lead author Chloé Sarnowski, PhD, assistant professor of epidemiology at UTHealth Houston School of Public Health, using whole-genome sequencing in a diverse sample, allowed for the identification of both novel genetic variants in known genomic regions of AD risk, but also characterized whether these newly found associations with AD are shared across populations.
This was possible because the ADSP includes data form an ethnically diverse groups of participants and the population-specific assessments focused on White/European-ancestry, Black/African-American, and Hispanic/Latino subgroups, as well as a multi-population meta-analysis.
“Including participants that represent diverse genetic ancestry and diverse environments in terms of social determinants of health is important to understanding the full spectrum of Alzheimer’s disease risk, as both the prevalence of the disease and the frequencies of genetic variants can differ among populations,” said DeStefano. While the sample sizes in the population-specific analyses were small, limiting the team’s ability to detect associations, DeStefano added: “we replicated known population differences for the APOE gene, which is one of the best-known and strongest risk genes for Alzheimer’s disease.”
Next steps in the research will be to examine the populations-specific variants the investigators identified in much larger samples size, while also looking to better understand if and how these variants affect biology.
