Use of local genetic ancestry to assessTOMM40-523′ and risk for Alzheimer disease

Abstract

ObjectiveHere, we re-examineTOMM40-523′ as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) inApolipoprotein E(APOE) ε4 haplotypes.MethodsTheTOMM40-523′ size was determined by fragment analysis and whole genome sequencing in homozygousAPOE ε3 andAPOE ε4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size.ResultsTheTOMM40-523′ length did not modify risk for LOAD inAPOE ε4haplotypes with EUR or AF LGA. Increasing length ofTOMM40-523′ was associated with a significantly reduced risk for LOAD in EURAPOEε3 haplotypes.ConclusionsAdjustment for LGA confirms thatTOMM40-523′ cannot explain the strong differential risk for LOAD betweenAPOEε4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of theTOMM40-523′repeat is associated with decreased risk for LOAD in carriers of homozygousAPOEε3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGAAPOEε3 allele haplotype.