A Novel Protective locus significantly reduces the ApoEε4 risk for Alzheimer's Disease in individuals of African Ancestry. (20th December 2022) - Vasquez, Marina Lipkin
Abstract: Background: African ancestry populations have a lower risk for developing Alzheimer disease (AD) from ApoE ε4 compared to other populations. Understanding this mechanism of protection could lead new therapeutic insights for AD. Our goal is to identify areas of the genome that interact with ApoE ε4 in African ancestry that result in the lowered risk for developing AD in this population. Methods: We performed association analyses using a logistic regression model with ApoE ε4 allele as an interaction term and adjusted for genome‐wide ancestry, age, and sex. Discovery analysis included imputed SNP data from 1, 850 African American (AA) individuals with AD and 4, 331 AA controls. We performed replication analysis on whole‐genome sequenced (WGS) data from 1) 63 Ibadan (Nigerian) AD individuals and 648 Ibadan controls; 2) WGS 273 Puerto Rican (PR) AD individuals and 275 PR controls; and 3) SNPs imputed from 8, 463 non‐Hispanic White (NHW) AD individuals and 11, 365 NHW controls. Results: We identified a significant interaction with the ApoE ε4 allele and the SNP rs10423769_A allele, that reduces the odds ratio for AD risk from 7.2 for ApoE ε4/ε4 without the A allele to 2.1 for allele ApoE ε4/ε4 carriers with at least one A allele. rs10423769 (frequency = 0.11 in AA, NHW= 0.003) is located approximately 2 megabases distal to ApoE, in a large cluster of pregnancy specific beta‐1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. rs10423769 is reported to be a splicing QTL (sQTL) for TMEM145, whose highest brain expression is in the cerebellum. This interaction analysis was identified in the discovery AA dataset (β=‐0.54, SE=0.12, p‐value=7.50x10 ‐6 ), and this finding was replicated in both the Ibadan (β = ‐1.32, SE = 0.52, p‐value = 1.15x10 ‐2 ) and PR (β=‐1.27, SE=0.64, p‐value=4.91x10 ‐2 ) datasets while it trended but was not significant in the NHW dataset. Conclusion: This study identified a new African‐ancestry specific locus that reduces the risk effect of ApoEε4 for developing AD by approximately 75%. The genes lying near this protective locus suggest potential new protective mechanisms for AD development.