Whole-genome sequencing reveals the impact of lipid pathway and APOE genotype on brain amyloidosis.

Amyloid-PET imaging tracks the accumulation of amyloid beta (Aβ) deposits in the brain. Amyloid plaques accumulation may begin 10 to 20 years before the individual experiences clinical symptoms associated with Alzheimer's diseases (ad). Recent large-scale genome-wide association studies reported common risk factors associated with brain amyloidosis, suggesting that this endophenotype is driven by genetic variants. However, these loci pinpoint to large genomic regions and the functional variants remain to be identified. To identify new risk factors associated with brain amyloid deposition, we performed whole-genome sequencing on a large cohort of European descent individuals with amyloid PET imaging data (n = 1,888). Gene-based analysis for coding variants was performed using SKAT-O for amyloid PET as a quantitative endophenotype that identified genome-wide significant association for APOE (P = 2.45 × 10-10), and 26 new candidate genes with suggestive significance association (P < 5. 0 × 10-03) including SCN7A (P = 7.31 × 10-05), SH3GL1 (P = 7.56 × 10-04), and MFSD12 (P = 8.51 × 10-04). Enrichment analysis highlighted the lipid binding pathways as associated with Aβ deposition in brain driven by PITPNM3 (P = 4.27 × 10-03), APOE (P = 2.45 × 10-10), AP2A2 (P = 1.06 × 10-03), and SH3GL1 (P = 7.56 × 10-04). Overall, our data strongly support a connection between lipid metabolism and the deposition of Aβ in the brain. Our study illuminates promising avenues for therapeutic interventions targeting lipid metabolism to address brain amyloidosis.