ASHG Abstract Presented by Marlene Tejeda, Boston University School of Medicine, Boston, Massachusetts.
In their abstract, Tejeda and colleagues wrote the following:
Background: Multiple infectious agents have been identified as risk factors for Alzheimer’s disease (AD). Viruses can cause inflammatory damage and potentially increase the formation of the AD hallmark proteins amyloid-beta protein and hyperphosphorylated tau. We and others previously reported association between AD and the quantity of whole genome and whole exome sequence reads mapping to herpes simplex type 1 (HSV-1), human herpes virus 6B (HHV-6B), and human papilloma virus 71 (HPV-71). Here, we conducted GWAS using these viruses to identify genetic associations that (1) affect viral load and (2) modify the effect of viral load on AD risk.
Methods: DNA sequence reads that did not align to the human genome in whole exome and whole genome sequences generated by the Alzheimer Disease Sequencing Project from 57,000 AD cases and controls from multiple populations (European ancestry (EA), Caribbean Hispanic (CH), and African American) were mapped to 318 viral reference sequences and quantified. After quality control, there were 4,298 sequences derived from brain (AD cases= 3,404, controls= 894) and 40,156 sequences derived from blood (AD cases=15,612, controls=24,544). Two GWAS models for each virus were tested: (1) viral load ~ SNP + sex + age + tissue source and (2) AD ~ SNP + viral load + SNP*viral load + sex + age + tissue source.
Results: We observed genome-wide significant (GWS) associations between HSV-1 presence and HLA-DQA1 SNP rs28654242 (OR=3.01, P=2.15×10-8) with HPV-71, POTEE SNP rs199606922 (OR=2.03,P=1.91×10-8 ), and USP49 SNP rs201585090 (OR=0.26, P=1.28×10-8) , and between HHV-6B and CASS4 SNP rs6014724 (Beta=5.52, P=1.26×10-4) and rs16941239 near FOXF1 (Beta=6.93, P=5.95×10-4 ), all in CHs.
The CASS4 and FOXF1 SNPs were previously associated with AD risk. We also observed, in EAs, GWS interactions between HSV-1 presence and rs201217710 in ABCC2 (OR= 0.15, P=3.28×10-8 ), rs113432200 in KMT2C (OR=0.54, P=2.11×10 -8), and rs62345265 in FRG1 (OR=0.65, P=5.56×10-11) predicting AD risk.
Conclusions: These findings provide further evidence for the role of herpes viruses in the pathogenesis of AD and highlight the importance of genetic factors in modulating these associations.