Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation

Abstract

Alzheimers disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWAS) have led to a significant set of SNPs associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed with even the strongest associations in the GWAS, the lead SNPs have been historically the focus of the field, with the remaining associations inferred as redundant. Recent deep genome annotation tools enable the prediction of function from a segment of DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits on the chromatin functions, and whether it will be altered by the genomic context (i.e., alleles of neighborhood SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impact on the downstream functions. Although some GWAS lead SNPs showed dominating functional effect regardless of the neighborhood SNP alleles, several other ones do get enhanced loss or gain of function under certain genomic context, suggesting potential extra information hidden in the LD blocks.