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Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Byline: D.. Chopade, Harish. Harde, Pallavi. Ugale, Sandesh. Chopade Rearrangements between homologous chromosomes are extremely rare and manifest mainly as monosomic or trisomic offsprings. There are remarkably few reports of [...]

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.