Genome-wide association study of Alzheimer's disease

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Genome-wide association studies (GWASs) have identified several genes associated with late-onset Alzheimer's disease (LOAD) risk, including apolipoprotein E (APOE) and nine other loci.
• However, known genetic factors explain only about 50% of the heritability for LOAD, indicating the need to identify additional risk genes.

Purpose of the Study:

• To investigate the Alzheimer's disease (AD) risk associated with nine recently implicated gene regions using a new GWAS dataset.
• To perform a meta-analysis of top single-nucleotide polymorphisms (SNPs) across multiple datasets to identify novel AD loci.

Main Methods:

• Utilized a new GWAS dataset from the University of Pittsburgh (1291 cases, 938 controls) genotyped on the Illumina Omni1-Quad chip.
• Performed imputation of ~2.5 million markers.
• Conducted a meta-analysis of top 1% GWAS SNPs (P<0.01) combined with four independent datasets (2727 cases, 3336 controls).

Main Results:

• Observed nominal significant associations (P<0.05) near five genes: PICALM, BIN1, ABCA7, MS4A4/MS4A6E, and EPHA1.
• Identified significant signals outside four other genes: CD33, CLU, CD2AP, and CR1.
• Meta-analysis revealed a suggestive novel association with the PPP1R3B gene (rs3848140, P = 3.05E-07), with a consistent odds ratio of 2.43 across five samples.

Conclusions:

• PPP1R3B is a potential candidate gene for AD risk due to its expression in the brain and involvement in lipid metabolism.
• Further validation in additional samples is required to confirm the association of PPP1R3B with AD risk.