Campbell, H. | bioRxiv Science

bioRxiv2018

Defining the genetic control of human blood plasma N-glycome using genome-wide association study

Glycosylation is a common post-translational modification of proteins. It is known, that glycans are directly involved in the pathophysiology of every major disease. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here, we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people. We discovered and replicated twelve loci. This allowed us to demonstrate a clear overlap in genetic control between total plasma and IgG glycosylation. Majority of loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3, and MGAT5). We, however, also found loci that are likely to reflect other, more complex, aspects of plasma glycosylation process. Functional genomic annotation suggested the role of DERL3, which potentially highlights the role of glycoprotein degradation pathway, and such transcription factor as IKZF1.

genetics↗

bioRxiv2018

Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

genetics↗

bioRxiv2017

Novel Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk Of Coronary Artery Disease

Structural variation in retinal blood vessels is associated with global vascular health in humans and may provide a readily accessible indicator of several diseases of vascular origin. Increasing evidence suggests variation in retinal vasculature is highly heritable. This study aimed to identify genetic determinants of retinal vascular traits. We reported a meta-analysis of genome-wide association studies (GWAS) for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the Genetics of Diabetes Audit and Research in Tayside (GoDARTS) (n=1736) and the Orkney Complex Disease Study (ORCADES) (n=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these two loci were subsequently confirmed in three independent cohorts (n=1413). In the combined analysis in ACTN4/CAPN12 the lead single nucleotide polymorphism (SNP) was rs1808382 (n=4507; Beta=-0.109; standard error (SE) =0.015; P=2.39x10-13) and in COL4A2 it was rs7991229 (n=4507; Beta=0.103; SE=0.015; P=4.66x10-12). Notably, the ACTN4/CAPN12 locus associated with retinal TortV is also associated with coronary artery disease and heart rate. Our findings demonstrate the contribution of genetics in retinal tortuosity traits, and provide new insights into cardiovascular diseases.\n\nAuthor SummaryRetinal vascular features are associated with wide range of diseases related to vascular health and provide an opportunity to understand early structural changes in vasculature which may help to predict disease risk. Emerging evidence indicates that retinal tortuosity traits are both associated with vascular health and highly heritable. However, the genetic architecture of retinal vascular tortuosity has not been investigated. We therefore performed a genome-wide association study on retinal arteriolar tortuosity (TortA) and retinal venular tortuosity trait (TortV) using data from two independent discovery cohorts of 3094 individuals of European-heritage. We found a novel associations at 19q13 (ACTN4/CAPN12) for TortV, and one at 13q34 (COL4A2) for TortA at discovery stage and validated in three independent cohorts. A significant association was subsequently found between lead SNPs at 19q13 and coronary artery disease, cardiovascular vascular risk factors and heart rate. We also performed genome-wide association studies for retinal vascular calibres and optic disc radius (ODradius) and replicated previously reported locus at 10q21.3 for ODradius. Our findings highlight genetic impacts on retinal venular tortuosity and it is association with cardiovascular disease. This may provide a molecular pathophysiological foundation for use of retinal vascular traits as biomarkers for cardiovascular diseases.

genomics↗