Identification of genetic regulators of human metabolites in CSF

Background Brain metabolism perturbation in dementia is not well understood. Metabolite levels are quantitative traits that have been linked to genetic loci. Existing metabolite trait loci (MQTL) were found mostly using tissues other than cerebrospinal fluid (CSF) and brain, which being less ideal for studying neurodegenerative diseases. The first CSF MQTL study was published last year, but with limited power. Therefore, we hope expand our knowledge on the central nervous system better understand neurological disorders. Method We performed metabolome-wide genome-wide association (M-GWAS). More 400 metabolites passed QC from 2329 participants recruited five cohorts (CASTLE project). a three-stage design: discovery (1224 CASTLE participants), replication (meta-analysis of results 1087 291 (Panyard, D.J. et. al 2021)) meta-analyses. Linear regression model includes age, sex, genetics principal components, genotyping array, cohort information as covariates. defined an region be 1 Mb interval centered index SNP (lowest study-wide P value) by performing clumping signals plink1.9. merged regions if they share overlapping chromosome location identify locus associated level traits. Future plan including rare variants, functional annotation each locus, conditional analysis independent signals, identified M-GWAS metabolomics datasets (1169 samples total), comparing features associations amongst multi-tissue (CSF, brain blood) mashr R. In addition, colocalization Mendelian randomization will discover contributing Result preliminary jointing 165 125 90 Meta-analysis utilized downstream annotation, tissue comparison, disease mechanistic exploration. Conclusion present largest so far showed substantial number findings metabolites. only expect replicate studies blood tissues, also novel has potential unique CSF.