Biology subjects

Giedraitis, V.

Publications and source records attributed to Giedraitis, V..

5 recordsLinked to original sources

bioRxiv2020

Genomic evaluation of circulating proteins for drug target characterisation and precision medicine

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping using trans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.

genetics↗

bioRxiv2019

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

genetics↗

bioRxiv2019

Loss of Y in leukocytes, dysregulation of autosomal immune genes and disease risks

Mosaic loss of chromosome Y (LOY) in leukocytes has been associated with many diseases, yet it remains unclear whether this form of clonal mosaicism exerts a direct physiological effect. Here we perform single-cell and bulk RNA sequencing in leukocytes, observing considerable variation in the rate of LOY across individuals, cell types and disease state. Cells with LOY demonstrated a profound degree of transcriptional dysregulation impacting [~]500 autosomal genes. These genes are preferentially involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y challenging the view of it as a "genetic wasteland". Furthermore, they support the hypothesis that altered immune function in leukocytes is a mechanism directly linking LOY to disease.

immunology↗

bioRxiv2019

Intra-individual changes in the frequency of mosaic loss of chromosome Y over time estimated with a new method

BackgroundMosaic loss of chromosome Y (LOY) is the most common somatic mutation and is associated with all-cause mortality, non-haematological cancers and Alzheimers disease among other outcomes. The predominant method used for estimating LOY is the intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic scale. Here we describe a new way to convert the LOY mosaicism into a non-logarithmic scale, which instead represents the percentage of affected cells.\n\nMethodsWe compared three independent LOY readouts from matched samples, generated by SNP-array, whole genome sequencing and droplet digital PCR. The SNP-array standardization was derived from this comparison and was applied in analyses of serially collected samples from a large cohort of aging men. The sampling was performed up to five times, spanning up to 22 years.\n\nResultsWe observed a higher correlation between the LOY measurements from SNP-array and the two other readouts when using the standardized, instead of the logarithmic, SNP-array data. We also observed a pronounced intra-individual variation of changes in the frequency of LOY within individual males over time.\n\nConclusionsDescribing LOY measurements generated from SNP-arrays in percentage of cells without the Y chromosome makes comparisons to WGS and ddPCR measurements more precise and easier to interpret. This standardization could be applied to the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated disease and outcomes. Additionally, the frequency of LOY in this study changed profoundly within men over time, likely as a result of aberrant clonal expansions.

genetics↗

bioRxiv2018

Trans-ethnic genome-wide association study provides insight into effector genes and molecular mechanisms for kidney function and highlights a causal effect on kidney-specific disease aetiologies

Chronic kidney disease (CKD) affects [~]10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

genetics↗