Multi-ancestry exome-wide study identifies variants associated with Alzheimer's disease protection

Area of Science:

• Genetics
• Neuroscience
• Population Health

Background:

• Previous genome-wide studies identified associations between rare variants and late-onset Alzheimer's disease (AD), but larger sample sizes are needed.
• The study addresses the need for expanded research into the genetic underpinnings of AD across diverse ancestral groups.

Purpose of the Study:

• To identify associations between rare coding variants and Alzheimer's disease (AD) risk.
• To analyze a large-scale, multi-ancestry exome-wide dataset for novel genetic associations with AD.

Main Methods:

• Combined whole exome and whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).
• Analyzed a sample of 34,202 individuals (≥60 years) across European, African American, Caribbean Hispanic, and Native American Hispanic populations.
• Utilized GENESIS for variant association testing and SAIGE for gene-based tests on predicted moderate and high-impact variants.

Main Results:

• Identified novel study-wide significant associations (p < 1.97×10⁻⁷) with variants in BTBD8, LINGO1, and KCNG2.
• Confirmed significant associations with APOE across all analyzed populations.
• Detected a significant association in Caribbean Hispanic individuals with the PSEN1 missense mutation G206A.

Conclusions:

• Identified rare variants in previously unrecognized genes associated with Alzheimer's disease risk.
• These findings contribute novel insights into the complex pathogenesis of Alzheimer's disease.
• The study underscores the importance of multi-ancestry analyses in uncovering AD genetic architecture.