RORB, an Alzheimer's disease susceptibility gene, is associated with viral encephalitis, an Alzheimer's disease risk factor

Abstract

Background: Viral encephalitis increases later-life risk of Alzheimer's disease (AD) by a factor of 31.

Methods: To further evaluate this finding, we examined the relationship of West Nile virus (WNV) to Alzheimer's disease in 50 US states. In addition, we performed a genome wide association study (GWAS) of viral encephalitis cases in UK Biobank (UKBB) to see if encephalitis genes might be related to AD.

Results: WNV was significantly associated with deaths from Alzheimer's disease in 50 US states (r = 0.806, p < 0.001). One gene, RORB-AS1, was most significantly related on GWAS to viral encephalitis. RORB-AS1 (RORB Antisense RNA 1) is an RNA gene. Diseases associated with RORB-AS1 include childhood epilepsy and idiopathic generalized epilepsy. The closely related RORB (Related Orphan Receptor B) is a marker of selectively AD vulnerable excitatory neurons in the entorhinal cortex; these neurons are depleted and susceptible to neurofibrillary inclusions during AD progression. RORB variants significantly decreased the risk of AD, independent of the significant effects of epilepsy, age, and years of education. The total effect size of variant RORB on AD prevalence is small, 0.19%, probably the reason RORB has not turned up on genome wide association studies of AD. But the decrease in effect size on AD, no variant versus varian is larger 0.20-0.16%. To produce the 31-fold increase in AD risk associated with viral encephalitis, non-variant RORB may need to interact with encephalitis virus.

Limitations: A weakness in our correlative analysis is possible confounding by the ecological fallacy (or ecological inference fallacy), a logical fallacy in the interpretation of statistical data where inferences about the nature of individuals are derived from inference for the group to which those individuals belong. In this case, inferences about individuals are being drawn from the characteristics of U.S. states where they reside, rather than from the individuals themselves. A weakness in our GWAS is that UK Biobank had only 18 cases of viral encephalitis and none of these had AD.

Conclusion: data presented here confirm the association of viral encephalitis with AD and suggest that WNV infection is a significant AD risk factor. In addition, GWAS suggests that the gene RORB, an AD vulnerability factor, is significantly related to viral encephalitis.

Future prospects: A human WNV vaccine could reduce Alzheimer's disease morbidity and mortality.

Keywords: Encephalitis; Genetics; Neurodegeneration; Virus.