Interaction Analysis Reveals Complex Genetic Associations with Alzheimer's Disease in the and Gene Regions.

Sporadic Alzheimer's disease (AD) is a polygenic neurodegenerative disorder. Single-nucleotide polymorphisms (SNPs) in multiple genes (e.g., and ) have been associated with AD. However, none of them were characterized as causal variants that indicate the complex genetic architecture of AD, which is likely affected by individual variants and their interactions. We performed a meta-analysis of four independent cohorts to examine associations of 32 and 50 polymorphisms as well as their 496 and 1225 pair-wise interactions with AD. The single SNP analyses revealed that six and five SNPs were associated with AD. Ten of them were previously not reported. The interaction analyses identified AD-associated compound genotypes for 25 and 24 SNP pairs, whose comprising SNPs were not associated with AD individually. Three and one additional and pairs composed of the AD-associated SNPs showed partial interactions as the minor allele effect of one SNP in each pair was intensified in the absence of the minor allele of the other SNP. The interactions identified here may modulate associations of the and variants with AD. Our analyses highlight the importance of the roles of combinations of genetic variants in AD risk assessment.