Polymorphism in the MAGI2 Gene Modifies the Effect of Amyloid β on Neurodegeneration

Introduction: A weak association between amyloid beta (A beta) deposition and neurodegeneration biomarkers, such as brain atrophy, has been repeatedly reported in a subset of patients with Alzheimer disease, suggesting individual differences in response to A beta deposition. Methods: Here, we performed a genome-wide interaction study to identify single-nucleotide polymorphism (SNP) that modify the effect of A beta (measured by F-18-florbetapir positron emission tomography) on brain atrophy (measured by cortical thickness using magnetic resonance imaging). We used magnetic resonance imaging, positron emission tomography, cerebrospinal fluid, and genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database [discovery cohort, ADNI-GO/2 (n=723) and replication cohort, ADNI-1 (n=129)]. Results: We identified a genome-wide suggestive interaction of rs3807779 SNP (beta=-0.14, SE=0.029, P=9.08x10(-7)) in the discovery cohort. The greater dosage of rs3807779 SNP increased the detrimental effect of A beta deposition on cortical thickness. In replication analyses, the congruent results were replicated to confirm our findings. Furthermore, rs3807779 SNP augmented the detrimental effect of A beta deposition on cognitive function. Genetic profiling showed that rs3807779 has chromatin interactions with the promoter region of MAGI2 gene, suggesting its association with MAGI2 expression. Conclusions: These findings demonstrate that subjects carrying the rs3807779 SNP are more susceptible to A beta-related neurodegeneration.