A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry
Authors: Rajabli Farid , Beecham Gary W. , Hendrie Hugh C. , Baiyewu Olusegun , Ogunniyi Adesola , Gao Sujuan , Kushch Nicholas A. , Lipkin-Vasquez Marina , Hamilton-Nelson Kara L. , Young Juan I. , Dykxhoorn Derek M. , Nuytemans Karen , Kunkle Brian W. , Wang Liyong , Jin Fulai , Liu Xiaoxiao , Feliciano-Astacio Briseida E. ,   Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Genetic Consortium, Schellenberg Gerard D. , Dalgard Clifton L. , Griswold Anthony J. , Byrd Goldie S. , Reitz Christiane , Cuccaro Michael L. , Haines Jonathan L. , Pericak-Vance Margaret A. , Vance Jeffery M. 
Published: July 2022

African descent populations have a lower Alzheimer disease risk fromApoEε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding theApoElocus (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 theApoEε4 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 theApoEε4 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 forApoEε4/ε4 carriers lacking the A allele to 2.1 forApoEε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of theApoElocus, 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 ofApoE ε4for developing Alzheimer disease. The mechanism of the interaction withApoEε4is not known but suggests a novel mechanism for reducing the risk forε4carriers opening the possibility for potential ancestry-specific therapeutic intervention.