Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer’s Disease

ABSTRACT Background The genetic component of early-onset Alzheimer’s disease (EOAD), accounting for ∼10% of all Alzheimer’s disease (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched for variants acting in the lipid pathway. Objective To examine the shared genetic heritability between EOAD and the lipid pathway by genome-wide multi-trait genetic covariance analyses. Methods Summary statistics were obtained from the GWAS meta-analyses of EOAD by the Alzheimer’s Disease Genetics Consortium ( n =19,668) and five blood lipid traits by the Global Lipids Genetics Consortium ( n =1,320,016), and genetic covariance analyses were performed via SUPERGNOVA. Genes in linkage disequilibrium (LD) with top EOAD hits in identified regions of covariance with lipid traits were scored and ranked for causality by combining evidence from gene-based analysis, AD-risk scores incorporating transcriptomic and proteomic evidence, eQTL data, eQTL colocalization analyses, DNA methylation data, and single-cell RNA sequencing analyses. Results Local genetic covariance analyses identified 3 regions of covariance between EOAD and at least one lipid trait. Gene prioritization nominated 3 likely causative genes at these loci: ANKDD1B , CUZD1 , and MS4A64 . Conclusion The current study identified genetic covariance between EOAD and lipids, providing further evidence of shared genetic architecture and mechanistic pathways between the two traits.