# Genetic Interactions Explain Variance in Cingulate Amyloid Burden: An AV-45 PET Genome-Wide Association and Interaction Study in the ADNI Cohort

## TL;DR

This study explores how gene interactions influence amyloid buildup in the brain, a key sign of Alzheimer's disease, using brain imaging and genetic data from patients.

## Contribution

The study introduces a novel approach combining genome-wide association and interaction analyses to uncover gene interactions linked to amyloid burden in Alzheimer's.

## Key findings

- Genetic main effects near APOE, APOC1, and TOMM40 were confirmed as significant.
- Eight novel SNP-SNP interactions were identified that could explain amyloid burden variability.
- The findings suggest that gene interactions may help explain missing heritability in Alzheimer's.

## Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Using discrete disease status as the phenotype and computing statistics at the single marker level may not be able to address the underlying biological interactions that contribute to disease mechanism and may contribute to the issue of “missing heritability.” We performed a genome-wide association study (GWAS) and a genome-wide interaction study (GWIS) of an amyloid imaging phenotype, using the data from Alzheimer's Disease Neuroimaging Initiative. We investigated the genetic main effects and interaction effects on cingulate amyloid-beta (Aβ) load in an effort to better understand the genetic etiology of Aβ deposition that is a widely studied AD biomarker. PLINK was used in the single marker GWAS, and INTERSNP was used to perform the two-marker GWIS, focusing only on SNPs with p ≤ 0.01 for the GWAS analysis. Age, sex, and diagnosis were used as covariates in both analyses. Corrected p values using the Bonferroni method were reported. The GWAS analysis revealed significant hits within or proximal to APOE, APOC1, and TOMM40 genes, which were previously implicated in AD. The GWIS analysis yielded 8 novel SNP-SNP interaction findings that warrant replication and further investigation.