Unique genetic architecture of CSF and brain metabolites pinpoints the novel targets for the traits of human wellness

Abstract

Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson’s Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions.

A 3’UTR Insertion Is a Candidate Causal Variant at theTMEM106BLocus Associated with Increased Risk for FTLD-TDP

“…To expand beyond these eQTL and pQTL results from publicly available databases, we tested the association between rs1990622 and TMEM106B expression, TMEM106B protein levels, and GRN protein levels in the WUSTL Neurogenomics dataset 36,37,38 . First, we examined GRN and TMEM106B protein levels in a group of 11 carriers of FTLD-TDP-causing progranulin ( PGRN ) mutations.…”

Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways

“…To further elucidate potential latent pathways associated with EOAD, we also tested for complex gene interaction and if any modi able risk factors are associated with our prioritized genes and with AD. To support this direction, we look at results from trans-pQTL colocalization, GWAS catalog associations with AD risk factors, and metabolite QTL (metabQTL 54 ) colocalization.…”

“…Additional cis-eQTL data was downloaded from the most recent MetaBrain analysis from the MetaBrain website (https://www.metabrain.nl) on downloaded February 24, 2023. CSF metabQTL data was generated using metabolite levels measure by Metabolon for 1,224+1,087 (discovery and replication) participants from ve dementia relevant cohorts, while brain metabQTLs are generated using parietal, prefrontal cortex, and temporal cortex post-mortem brain biopsies from 1,172 participants from four dementia-relevant cohorts 54 . CSF metabQTLs analysis is run separately in the discovery and replication sets, then meta-analyzed for the nal summary statistics.…”

“…CSF metabQTLs analysis is run separately in the discovery and replication sets, then meta-analyzed for the nal summary statistics. Further information on pQTL methods can be found in the source material Western et al, 30 and metabQTL methods can be found in source material from Wang et al, 54 .…”