👤 Tom Schipper

Investigating the genetic underpinnings of functional brain connectivity is essential to understand how genetic variation influences brain health and disease. Here, a mass-univariate approach was adopted to study the genetic architecture of functional brain circuitry (N Show less

Many drug targets in ongoing Parkinson's disease (PD) clinical trials have strong genetic links. While genome-wide association studies (GWAS) nominate regions associated with disease, pinpointing causal genes is challenging. Our aim was to prioritize additional druggable genes underlying PD GWAS signals. The polygenic priority score (PoPS) integrates genome-wide information from MAGMA gene-level associations and over 57,000 gene-level features. We applied PoPS to East Asian and European PD GWAS data and prioritized genes based on PoPS, distance to the GWAS signal, and non-synonymous credible set variants. We prioritized 46 genes, including well-established PD genes (SNCA, LRRK2, GBA1, TMEM175, VPS13C), genes with strong literature evidence supporting a mechanistic link to PD (RIT2, BAG3, SCARB2, FYN, DYRK1A, NOD2, CTSB, SV2C, ITPKB), and genes relatively unexplored in PD. Many hold potential for drug repurposing or development. We prioritized high-confidence genes with strong links to PD pathogenesis that may represent our next-best candidates for developing disease-modifying therapeutics. Show less

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initially responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis. Show less

Recent advancements in Parkinson's disease (PD) drug development have been significantly driven by genetic research. Importantly, drugs supported by genetic evidence are more likely to be approved. While genome-wide association studies (GWAS) are a powerful tool to nominate genomic regions associated with certain traits or diseases, pinpointing the causal biologically relevant gene is often challenging. Our aim was to prioritize genes underlying PD GWAS signals. The polygenic priority score (PoPS) is a similarity-based gene prioritization method that integrates genome-wide information from MAGMA gene-level association tests and more than 57,000 gene-level features, including gene expression, biological pathways, and protein-protein interactions. We applied PoPS to data from the largest published PD GWAS in East Asian- and European-ancestries. We identified 120 independent associations with Show less

Hypertrophic cardiomyopathy (HCM) is the most common inherited human heart disease. The same disease has a high prevalence in cats, where it is also suspected to be inherited. More than 1500 variants in MYBPC3, MYH7 and other sarcomeric genes are associated with human HCM, while in cats, only two causative variants in MYBPC3 are currently known. Here, we describe an adult Domestic Shorthair cat with arterial thromboembolism and heart failure that was diagnosed with HCM on necropsy. Sequencing of the coding regions of MYBPC3 and MYH7 revealed 21 variants, of which the MYH7 c.5647G>A (p.(Glu1883Lys)) variant was further analysed, because its orthologous variant had already been reported in a human patient with HCM, but with limited causal evidence. This variant affects the highly conserved assembly competence domain, is predicted in silico to be damaging and was found only once in population databases. Recently, functional studies have confirmed its predicted damaging effect and a paralogous variant in MYH6 has been associated with cardiac disease in humans as well. This report of an orthologous variant in a cat with HCM and its absence in 200 additional cats provides further evidence for its disease-causing nature. As the first report of feline HCM caused by a variant in MYH7, this study also emphasises this gene as a candidate gene for future studies in cats and highlights the similarity between human and feline HCM. Show less