NEXT-GENERATION SEQUENCING OF THE BCHE LOCUS IDENTIFIES A FUNCTIONAL SNP ASSOCIATED WITH ALZHEIMER'S DISEASE BIOMARKERS AND AGE OF ONSET

Abstract

sphingolipid metabolism pathway was undertaken in the Australian Imaging, Biomarkers & Lifestyle (AIBL) Study of Aging cohort initially from DNA extracted at the 18-month time point. This data was investigated in relation to AD-risk and clinical phenotypes (i.e. neocortical amyloid burden, hippocampal volume, cognitive performance and lipid levels). Significantly associated variants from this first-pass analysis were taken forward for analysis across the extended AIBL cohort at the 72-month time point, which included the enrichment cohort and additional samples from the inception cohort. Results: Significant associations with AD risk in allelic, dominant and recessive models were observed for several variants within the sphingomyelin synthase 1 (SGMS1), sphingomyelin phosphodiesterase 3 (SMPD3; neutral sphingomyelinase 2) and prosaposin (PSAP) genes. Further, quantitative trait analysis revealed significant associations, with altered brain amyloid burden, for variants within SGMS1, PSAP and sphingomyelin phosphodiesterase 2 (SMPD2; neutral sphingomyelinase 1) genes. These SNPs, along with additional SNPs that approached significance were taken forward for analysis in the extended AIBL cohort with additional pathway analysis to determine gene-gene interactions. Conclusions: Data from this study suggests that genetic variations within constituents of the sphingolipid metabolism pathway modulate the risk towards developing AD and are associated with AD phenotypes. This project also supports the notion that alterations in lipid metabolism, specifically the synthesis of sphingolipids, in particular sphingomyelin and ceramides, play an important role in AD pathogenesis.