Search

Major Depressive Disorder (MDD) remains inadequately treated by existing pharmacotherapies, with only a third of patients achieving remission with current antidepressants and a substantial proportion developing treatment resistance. This highlights the need for innovative approaches to discover novel drug targets. Large-scale human genetic studies, integrating genome-wide association studies (GWAS) and Mendelian randomisation (MR) methods with the druggable genome, offer opportunities to identify causal drug targets and repurposing candidates to aid efficient drug discovery research. Here, we implement cis-MR analyses using transcriptomic and proteomic data and the most recent Psychiatric Genomics Consortium (PGC) MDD GWAS meta-analysis to identify promising drug targets for MDD. For our outcome phenotype, we used summary statistics from the PGC MDD phase 3 GWAS meta-analysis in over 525,000 MDD cases and 3.36 million controls, primarily of European-associated genetic ancestry. Exposure data on protein and gene expression levels was derived from multiple quantitative trait loci (QTL) GWAS datasets measured in blood plasma, cerebrospinal fluid (CSF), and brain tissues. The druggable genome was curated from Open Targets, which included over 6,000 targets with evidence of druggability for approved drugs or clinical and experimental candidates across a range of therapeutic modalities. Our primary MR analysis was conducted using generalized least squares inverse-variance weighted modelling and heterogeneity-based pruning of variants. We employed three robust models for our sensitivity analyses to account for potential horizontal pleiotropy: MR-Egger, contamination mixture, and weighted median methods. In our preliminary analyses of nine proteomic datasets, we identified 104 potential drug targets for MDD after Bonferroni correction for multiple tests. All significant proteins were detected in blood plasma, with IL6R and BST1 overlapping in both blood and CSF. Regarding repurposing opportunities, 13 % of the identified proteins were targets of approved drugs, and 15 % were in clinical trial phases 1-3, including those for treating inflammatory disorders. In terms of potential novel therapeutic targets, 35 % of the identified targets causally linked with MDD had strong experimental evidence of druggability, and 37 % had moderate experimental evidence. These included potential targets for small molecule binding, proteolysis-targeting chimeras, and antibody-based therapy. Our study provides genetic evidence to prioritise promising drug targets for the treatment of MDD for further validation to progress into clinical practice. We will extend our analyses to eQTL GWAS meta-analysis datasets in brain tissues and blood plasma. Additionally, we will conduct follow-up analyses to identify high-confidence targets, triangulating multiple sources of evidence supporting potential therapeutic benefits. [ABSTRACT FROM AUTHOR]

The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral A β amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis -Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10 -3 ), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10 -5 ) and plasma tau concentration (0.06 log 2 (ng l -1 ) 95%CI 0.03; 0.08, p = 4.55 × 10 -6 ). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.