Lack of Epistatic Interaction ofSNCAwithAPOEin Synucleinopathies

Abstract

AbstractTwo recent studies suggested that theAPOEε4 haplotype was associated with increased α-synuclein pathology in cell and mouse models. Genetic variants in theSNCAregion have strong association with Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), and idiopathic REM Sleep Behavior Disorder (iRBD), whileAPOEis a genetic risk determinant for only DLB. To determine if genetic-level interactions betweenSNCAandAPOEexists that can explain the protein-level association, we investigated the genotypic interaction ofAPOEandSNCAin cohorts of PD, DLB, and iRBD. We analyzed genome-wide association study (GWAS) data from 5,229 PD patients and 5,480 controls, 2,610 DLB patients and 1,920 controls, and 1,055 iRBD patients and 3,667 controls. We used logistic regression interaction models across all 3 cohorts independently between the 1) top GWAS signals ofSNCASNPs andAPOEhaplotypes, 2) SNP x SNP and 3-way SNP interaction across the entire coding region plus 200kb flanking each gene. No significant interactions were found to be associated with any of the synucleinopathies after correction for multiple testing. Our results do not support a role for genetic interactions betweenAPOEandSNCAacross PD, DLB, and iRBD. Since the tested genetic variants affect the expression and function of these proteins, it is likely that any interactions between them does not affect the risk of PD, DLB and iRBD.