A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry

Abstract

African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the “protective” direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

Interaction analysis of ancestry-enriched variants with APOE-ɛ4 on MCI in the Study of Latinos-Investigation of Neurocognitive Aging

“…Both variants were assessed in Europeans, due to the paucity of variant carriers in non-European ancestries. Another recent study identified a variant proximal to the APOE region, reducing the APOE -ε4 risk for AD in African Ancestry 9 .…”

Note the Nuance—Examining the Association of Alzheimer-Protective APOE Variation With Risk for Age-Related Macular Degeneration

“…3 An important caveat to broad interpretation of this work is that AD and AMD risk vary across ancestry, as does APOE-specific AD risk. 6,7 In AD and AMD, studies in recent years have expanded focus beyond samples of primarily European descent to examine more diverse populations and have found major differences in wellknown disease-associated variants. A notable example of the importance of diversity was recently reported, in which the effect of the APOE ε4 allele in a population sample of primarily African ancestry was seemingly modified by a second locus (rs10423769), upstream of APOE.…”

“…Although the population sample evaluated was large (>100 000), all participants were of European descent, despite the fact that the rare variant motivating the work was discovered in a Colombian sample . An important caveat to broad interpretation of this work is that AD and AMD risk vary across ancestry, as does APOE -specific AD risk . In AD and AMD, studies in recent years have expanded focus beyond samples of primarily European descent to examine more diverse populations and have found major differences in well-known disease-associated variants.…”

“…In AD and AMD, studies in recent years have expanded focus beyond samples of primarily European descent to examine more diverse populations and have found major differences in well-known disease-associated variants. A notable example of the importance of diversity was recently reported, in which the effect of the APOE ε4 allele in a population sample of primarily African ancestry was seemingly modified by a second locus (rs10423769), upstream of APOE . The minor (A) allele of rs10423769 in the presence of the ε4/ε4 risk haplotype reduced the AD odds ratio (OR) from 7.2 to 2.1 in carriers of the minor allele; a less dramatic effect (OR reduction from 2.6-1.1) was noted in the presence of ε4/ε3.…”

“…Given the role of APOE in AD, AMD, and other diseases, the detection of an APOE -modifying variation in populations that are not primarily of European descent emphasizes the necessity of expanding many complex disease studies to include more globally diverse samples. In AMD, the largest and most recent study included the largest-ever evaluation of AMD in a population sample of primarily African ancestry .…”