Genome‐wide association study for Alzheimer disease in APOE ɛ4/ɛ4 carriers

Abstract

AbstractBackgroundThe APOE ɛ4/ɛ4 genotype has the greatest risk for late‐onset Alzheimer disease (AD). However, modifying effects of other genes on AD risk in APOE ɛ4 homozygotes are not fully understood.MethodsWe conducted a genome‐wide association study (GWAS) for AD among 1,223 non‐Hispanic White APOE ɛ4/ɛ4 carriers assembled by the Alzheimer’s Disease Genetics Consortium (ADGC). Expression of genes within 50 kb of suggestively associated single nucleotide polymorphisms (SNPs, P<10−6) were compared between AD and control brains from 576 Religious Orders Study and Memory and Aging Project (ROSMAP) subjects. We conducted survival analysis between carriers and non‐carriers of AD risk alleles for the suggestive SNPs in 4,287 Framingham Heart Study (FHS) participants. We compared expression of the top‐ranked genes between ɛ2/ɛ2 (APOE2) and ɛ4/ɛ4 (APOE4) human induced pluripotent stem cells (iPSC)‐derived neurons (iNeurons) and astrocytes (iAstrocytes) in a co‐culture system (Jun et al, 2022) and separately evaluated associations of their expression levels with neuropathological traits from 208 brains from FHS participants.ResultsWe identified association of AD with 11 SNPs at the suggestive level of which four near TRIB2, CTNNA2, ZNF443, and KLHL29 were genome‐wide significant (P<5×10−8). Rs75983775 near TRIB2, the most significant finding (P = 9.4×10−11), was associated with decreased risk of AD in ADGC APOE ɛ4 homozygotes (odds ratio = 0.12) and increased TRIB2 expression in ROSMAP ɛ4‐carrier brains (P = 0.02). TRIB2 expression was increased in APOE2 compared to APOE4 iAstrocytes (log2 fold change (log2FC) = 0.41, adjusted P (adjP) = 0.03) and iNeurons (log2FC = 0.31, adjP = 0.002) and elevated the Iba1 level in FHS brains (P = 0.03). Association with TENM3 SNP rs56035906 was suggestively associated with reduced AD risk in ADGC APOE ɛ4 homozygotes (odds ratio = 0.30, P = 4.3×10−7) and with lower incidence of AD among FHS ɛ4 carriers (P = 0.03). TENM3 expression was decreased in APOE2 compared to APOE4 iNeurons (log2FC = 0.59, adjP = 2.4×10−4) and associated with increasing phosphorylated tau 181 (P = 0.007) and C4a protein expression (P = 9.6×10−4) in FHS brains.ConclusionWe identified variants that may protect against AD risk among APOE ɛ4/ɛ4 carriers, delay disease onset, modulate expression of nearby genes in iAstrocytes and iNeurons, and are associated with measures of tau and neuroinflammation in autopsied brains.