Whole genome analysis in APOE4 homozygotes identifies the DAB1-RELN pathway in Alzheimer’s disease pathogenesis

The APOE -ε4 allele is known to predispose to amyloid deposition and consequently is strongly associated with Alzheimer’s disease (AD) risk. There is debate as to whether the APOE gene accounts for all genetic variation of the APOE locus. Another question which remains is whether APOE -ε4 carriers have other genetic factors influencing the progression of amyloid positive individuals to AD. We conducted a genome-wide association study in a sample of 5,390 APOE -ε4 homozygous (ε4ε4) individuals (288 cases and 5,102 controls) aged 65 or over in the UK Biobank. We found no significant associations of SNPs in the APOE locus with AD in the sample of ε4ε4 individuals. However, we identified a novel genome-wide significant locus associated to AD, mapping to DAB1 (rs112437613, OR=2.28, CI=1.73-3.01, p =5.4×10 −9 ). This identification of DAB1 led us to investigate other components of the DAB1-RELN pathway for association. Analysis of the DAB1-RELN pathway indicated that the pathway itself was associated with AD, therefore suggesting an epistatic interaction between the APOE locus and the DAB1-RELN pathway.