Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data

Area of Science:

• Genetics
• Neuroscience
• Genomics

Background:

• Genome-wide association studies (GWAS) have identified Alzheimer's disease (AD) loci but not causal variants.
• Whole genome sequencing (WGS) can identify rare variations and causal variants within these loci.

Purpose of the Study:

• To identify causal variants within AD-associated loci using WGS data.
• To leverage WGS data to gain insights into genetic risk factors for Alzheimer's disease.

Main Methods:

• Performed single common variant and rare variant aggregate analyses on WGS data from the Alzheimer's Disease Sequencing Project (ADSP).
• Focused analyses on variants within 100 kb of 83 previously identified GWAS lead variants.
• Utilized a pooled population (N cases=2184, N controls=2383) and subpopulations for targeted analyses.

Main Results:

• Identified seventeen variants significantly associated with AD within five genomic regions.
• Implicated genes OARD1/NFYA/TREML1, JAZF1, FERMT2, SLC24A4, and KAT8.
• KAT8 was implicated by both single variant and rare variant aggregate analyses.

Conclusions:

• Demonstrated the utility of WGS in identifying causal variants within GWAS loci for Alzheimer's disease.
• Provided insights into the genetic architecture of Alzheimer's disease by fine-mapping GWAS regions.