Varicose veins of lower extremities: Insights from the first large-scale genetic study.

Varicose veins of lower extremities (VVs) are a common multifactorial vascular disease. Genetic factors underlying VVs development remain largely unknown. Here we report the first large-scale study of VVs performed on a freely available genetic data of 408,455 European-ancestry individuals. We identified the 12 reliably associated loci that explain 13% of the SNP-based heritability, and prioritized the most likely causal genes CASZ1, PIEZO1, PPP3R1, EBF1, STIM2, HFE, GATA2, NFATC2, and SOX9. VVs-associated variants within these loci exhibited pleiotropic effects on several phenotypes including blood pressure/hypertension and blood cell traits. Gene set enrichment analysis revealed gene categories related to abnormal vasculogenesis. Genetic correlation analysis confirmed known epidemiological associations between VVs and deep venous thrombosis, weight, rough labor, and standing job, and found a genetic overlap with multiple traits that have not been previously suspected to share common genetic background with VVs. These traits included educational attainment, fluid intelligence and prospective memory scores, walking pace (negative correlation with VVs), smoking, height, number of operations, pain, and gonarthrosis (positive correlation with VVs). Finally, Mendelian randomization analysis provided evidence for causal effects of plasma levels of MICB and CD209 proteins, and anthropometric traits such as waist and hip circumference, height, weight, and both fat and fat-free mass. Our results provide novel insight into both VVs genetics and etiology. The revealed genes and proteins can be considered as good candidates for follow-up functional studies and might be of interest as potential drug targets

Mapping of the gene network that regulates glycan clock of ageing

Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.Pattern Recognition and Bioinformatic

Genetic architecture of glycomic and lipidomic phenotypes in isolated populations

This dataset contains the extended supplementary tables from the PhD thesis entitled "Genetic architecture of glycomic and lipidomic phenotypes in isolated populations" by Arianna Landini. Understanding how genetics contributes to the variation of complex traits and diseases is one of the key objectives of current medical studies. To date, a large portion of this genetic variation still needs to be identified, especially considering the contribution of low-frequency and rare variants. Omics data, such as proteomics and metabolomics, are extensively employed in genetic association studies as ‘proxies’ for traits or diseases of interest. They are regarded as “intermediate” traits: measurable manifestations of more complex phenotypes (e.g., cholesterol levels for cardiovascular diseases), often more strongly associated with genetic variation and having a clearer functional link than the endpoint or disease of interest. Accordingly, the genetics of omics have the potential to offer insights into relevant biological mechanisms and pathways and point to new drug targets or diagnostic biomarkers. The main goal of the related research is to expand the current knowledge about the genetic architecture of protein glycomics and bile acid lipidomics, two under-studied omic traits, but which are involved in several common diseases. In summary, in my thesis I describe the genetic architecture of the protein glycome and the bile acid lipidome: the former has a higher genetic component, while the latter is largely influenced by environmental factors (e.g., sex, diet, gut flora). Despite the limited sample size, we were able to describe rare variant associations, demonstrating that isolated populations represent a useful strategy to increase statistical power. However, additional statistical power is needed to identify the possible effect of protein glycome and bile acid lipidome on complex disease. A clearer understanding of the genetic architecture of omics traits is crucial to develop informed disease screening tests, to improve disease diagnosis and prognosis, and finally to design innovative and more customised treatment strategies to enhance human health