Papers by Paolo Di Domenico
Clinical implementation of new prediction models requires evaluation of their validity and utilit... more Clinical implementation of new prediction models requires evaluation of their validity and utility in a broad range of intended use populations. Here we outline the development and validation of multiple ancestry-specific Polygenic Risk Scores (PRSs) for Coronary Artery Disease (CAD) using a dataset comprising 29,389 individuals from multiple cohorts and diverse genetic ancestry groups. We leverage summary statistics from multiple genome-wide association studies comprising over 850,000 individuals to develop calibrated CAD PRSs with an average Odds Ratio per Standard Deviation (ORxSD) of 1.57 (SD = 0.14). Relative to competing scores, across major genetic ancestry groups these PRSs identify between 26 and 184 additional high risk individuals for every 1,000 people screened. We infer ancestry- specific high risk PRS thresholds and apply these to independent test datasets to identify between 12% and 24% of individuals who are at greater than twice the polygenic risk of CAD compared to...
European Heart Journal, 2020
Background Coronary artery disease (CAD) is a complex multifactorial disease leading cause of mor... more Background Coronary artery disease (CAD) is a complex multifactorial disease leading cause of morbidity and mortality worldwide. Identifying individuals at high risk is crucial to guide life-style and therapeutics interventions. Polygenic Risk Score (PRS) is a weighted sum of common genetic variants that showed to be able to identify a population at greater than threefold risk of CAD compared to the average. Notably, individuals at high genetic risk who adhere to a healthy lifestyle displayed between two and three-fold relative risk reduction, compared to individuals with a poor lifestyle. Despite such evidences, a systematic assessment of the interplay between PRS and CAD risk factors such as blood lipid levels in contributing to the overall CAD risk is still lacking. Methods We analysed in more than 130.0000 individuals of the UK Biobank the association of incident CAD with PRS and blood lipids (LDL, TC, HDL, TC:HDL, LDL:HDL) using a Cox Proportional Hazard Model. We defined three...
Nature
Data collection lead M. Arfan Ikram 75 Admin team lead Andre G. Uitterlinden 74,75 Estonian Bioba... more Data collection lead M. Arfan Ikram 75 Admin team lead Andre G. Uitterlinden 74,75 Estonian Biobank Analysis team lead Reedik Mägi 76 Data collection lead Lili Milani 76
Nature, 2022
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation i... more Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates ...
Cell Reports, 2021
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is par... more Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify four genomic loci with suggestive associations for SARS-CoV-2 susceptibility and nineteen for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. GWAS signals in eleven loci colocalize with eQTLs associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene) including lung, brain, heart, muscle, skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify ten GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome affecting gene expression levels in a wide variety of tissue types.
ABSTRACTThe genetic makeup of an individual contributes to susceptibility and response to viral i... more ABSTRACTThe genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising up to 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflamma...
Journal of the American Heart Association
Background Cardiovascular diseases are the leading cause of death in the United States, yet a sig... more Background Cardiovascular diseases are the leading cause of death in the United States, yet a significant proportion of adults at high risk remain undetected by standard screening practices. Polygenic risk score for coronary artery disease (CAD‐PRS) improves precision in determining the 10‐year risk of atherosclerotic cardiovascular disease but health benefits and health care costs associated with CAD‐PRS are unknown. We examined the cost‐effectiveness of including CAD‐PRS as a risk‐enhancing factor in the pooled cohort equation (PCE)—the standard of care for determining the risk of atherosclerotic cardiovascular disease—versus PCE alone. Methods and Results We applied a Markov model on a cohort of 40‐year‐old individuals with borderline or intermediate 10‐year risk (5% to <20%) for atherosclerotic cardiovascular disease to identify those in the top quintile of the CAD‐PRS distribution who are at high risk and eligible for statin prevention therapy. Health outcomes examined inclu...
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 2 Key Points Question: Is it cost-effective to use polygenic risk scores (PRS) for coronary artery disease (CAD) among individuals with borderline or intermediate risk of atherosclerotic cardiovascular disease (ASCVD) to inform preventive therapy decisions? Findings: We modeled a hypothetical cohort of individuals with borderline or intermediate risk of ASCVD who fall in the top quintile of the CAD-PRS distribution but not on preventive therapy. Integrating CAD-PRS in the pooled cohort equation improved quality-adjusted lifeyears, saved money and was cost-effective. Meaning: Integrating PRS as an enhancing factor in the pooled cohort equation risk assessment for ASCVD used in current clinical practice was cost-effective. .
Breast cancer is the most common cancer among women and is a leading cause of cancer mortality wo... more Breast cancer is the most common cancer among women and is a leading cause of cancer mortality worldwide. There is a significant genetic component to breast cancer risk which is the result of both rare pathogenic mutations and common genome-wide variation. However, the penetrance of pathogenic mutations varies widely and their frequency is low, both at a population level and amongst breast cancer cases. Polygenic risk scores, which aggregate the effect of hundreds to millions of common genome-wide variants offer a way to further understand the contribution of genetics to disease risk. Here we analyse genome-wide data from 221,479 women and 90,307 high coverage exomes to understand how rare and common variation affect lifetime breast cancer risk. We show that PRS strongly modulates the penetrance of mutations in 8 breast cancer susceptibility genes. For example, lifetime risk in BRCA1 carriers with low polygenic risk is almost one third that of carriers with high PRS (26% v 69% in th...
An individual's lifetime risk of Coronary Artery Disease (CAD) is determined by a combination... more An individual's lifetime risk of Coronary Artery Disease (CAD) is determined by a combination of genetic and lifestyle factors. Whilst adherence to a healthy lifestyle can help individuals with high genetic risk reduce their lifetime risk of CAD, the extent to which blood lipid levels affect CAD risk in individuals with varying genetic risk remains unknown. To explore how genetics, blood lipids and CAD risk interact, we derived a novel genome-wide polygenic risk score (PRS) for CAD. We then applied the PRS to individuals from the UK Biobank and divided them into Low PRS (bottom 10 percentiles of PRS distribution), Intermediate PRS (PRS in the 10th-90th percentiles), and High PRS (top 10 percentiles), and further stratified individuals by blood lipid levels. We found that the elevated CAD risk conferred by high low-density lipoprotein cholesterol (LDL-C) was modified by the interaction with PRS (P-value interaction: <0.005). Individuals with High PRS and whose LDL-C was Border...
In the last decade the scientific community witnessed a large increase in Genome-Wide Association... more In the last decade the scientific community witnessed a large increase in Genome-Wide Association Study sample size, in the availability of large Biobanks and in the improvements of statistical methods to model genomes features. This have paved the way for the development of new prediction medicine tools that use genomic data to estimate disease risk. One of these tools is the Polygenic Risk Score (PRS), a metric that estimates the genetic risk of an individual to develop a disease, based on a combination of a large number of genetic variants. Using the largest prospective genotyped cohort available to date, the UK Biobank, we built a new PRS for Coronary Artery Disease (CAD) and assessed its predictive performances along with two additional PRS for Breast Cancer (BC), and Prostate Cancer (PC). When compared with previously published PRS, the newly developed PRS for CAD displayed higher AUC and positive predictive value. PRSs were able to stratify disease risks from 1.34% to 25.7% (...
In the last decade the scientific community witnessed a large increase in Genome-Wide Association... more In the last decade the scientific community witnessed a large increase in Genome-Wide Association Study sample size, in the availability of large Biobanks and in the improvements of statistical methods to model genomes features. This have paved the way for the development of new prediction medicine tools that use genomic data to estimate disease risk. One of these tools is the Polygenic Risk Score (PRS), a metric that estimates the genetic risk of an individual to develop a disease, based on a combination of a large number of genetic variants. Using the largest prospective genotyped cohort available to date, the UK Biobank, we built a new PRS for Coronary Artery Disease (CAD) and assessed its predictive performances along with two additional PRS for Breast Cancer (BC), and Prostate Cancer (PC). When compared with previously published PRS, the newly developed PRS for CAD displayed higher AUC and positive predictive value. PRSs were able to stratify disease risks from 1.34% to 25.7% (...
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Papers by Paolo Di Domenico