Novel Findings From Whole-Genome Sequence Analysis Of The Nimh Ad Initiative Study Families

Objectives: Over 200 rare and highly penetrant pathogenic variants in APP, PSEN1 and PSEN2 cause a subset of early-onset familial Alzheimer's disease (AD), while APOE-e4 and close to 60 other genomic loci are associated with late-onset forms of AD. In this study we performed a comprehensive and systematic analysis of whole genome sequencing data from 1440 subjects from 452 multiplex NIMH AD families. Methods: WGS data was generated using the Illumina HiSeq 2500 platform. The genotypes were called using Freebayes; ultimately, a single large annotated GEMINI database was created for the purpose of downstream analysis. We used a multi-pronged approach to identify both, rare, highly penetrant functional variants, as well as, more frequently occurring functional variants acting as genetic risk-factors for AD. Results: In addition to confirming previously known variants in the NIMH families, our analyses revealed several novel functional variants, comprised of both single nucleotide variants (SNVs) and insertion-deletion (Indels). Furthermore, our analyses have revealed several SVs showing association with AD risk. Conclusions: Our WGS analysis approach yielded several novel genetic functional variants influencing risk for AD. These variants are predicted to significantly alter normal gene function, and associated molecular pathways. To our knowledge, this is the first WGS study reporting novel functional genetic variants influencing risk for AD.