Use of Diagnostic Codes for Primary Open-Angle Glaucoma Polygenic Risk Score Construction in Electronic Health Record-Linked Biobanks.

Purpose: Polygenic risk scores (PRSs) likely predict risk and prognosis of glaucoma. We compared the PRS performance for primary open-angle glaucoma (POAG), defined using International Classification of Diseases (ICD) codes vs manual medical record review.

Design: Retrospective cohort study.

Muesli Intake May Protect Against Coronary Artery Disease: Mendelian Randomization on 13 Dietary Traits.

Background: Diet is a key modifiable risk factor of coronary artery disease (CAD). However, the causal effects of specific dietary traits on CAD risk remain unclear. With the expansion of dietary data in population biobanks, Mendelian randomization (MR) could help enable the efficient estimation of causality in diet-disease associations.

A deep learning transformer model predicts high rates of undiagnosed rare disease in large electronic health systems.

It is estimated that as many as 1 in 16 people worldwide suffer from rare diseases. Rare disease patients face difficulty finding diagnosis and treatment for their conditions, including long diagnostic odysseys, multiple incorrect diagnoses, and unavailable or prohibitively expensive treatments. As a result, it is likely that large electronic health record (EHR) systems include high numbers of participants suffering from undiagnosed rare disease.

Development of a human genetics-guided priority score for 19,365 genes and 399 drug indications.

Studies have shown that drug targets with human genetic support are more likely to succeed in clinical trials. Hence, a tool integrating genetic evidence to prioritize drug target genes is beneficial for drug discovery. We built a genetic priority score (GPS) by integrating eight genetic features with drug indications from the Open Targets and SIDER databases.

Polygenic prediction of preeclampsia and gestational hypertension.

Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis.

Quantitative prediction of right ventricular and size and function from the electrocardiogram.

Background: Right ventricular ejection fraction (RVEF) and end-diastolic volume (RVEDV) are not readily assessed through traditional modalities. Deep-learning enabled 12-lead electrocardiogram analysis (DL-ECG) for estimation of RV size or function is unexplored.

Methods: We trained a DL-ECG model to predict RV dilation (RVEDV>120 mL/m), RV dysfunction (RVEF≤40%), and numerical RVEDV/RVEF from 12-lead ECG paired with reference-standard cardiac MRI (cMRI) volumetric measurements in UK biobank (UKBB; n=42,938).

Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits.

Background: Causality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH, and REDUCE-IT. Further unclear is the association between TG levels and non-atherosclerotic diseases across organ systems.

Methods: Here, we conducted a phenome-wide, two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) regression to systematically infer the causal effects of plasma TG levels on 2600 disease traits in the European ancestry population of UK Biobank.

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease.

More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci.

Population-Based Penetrance of Deleterious Clinical Variants.

Importance: Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches.

Objective: To evaluate the population-based disease risk of clinical variants in known disease predisposition genes.

Design, Setting, And Participants: This cohort study included 72 434 individuals with 37 780 clinical variants who were enrolled in the BioMe Biobank from 2007 onwards with follow-up until December 2020 and the UK Biobank from 2006 to 2010 with follow-up until June 2020.

Genetic pleiotropy of ERCC6 loss-of-function and deleterious missense variants links retinal dystrophy, arrhythmia, and immunodeficiency in diverse ancestries.

Biobanks with exomes linked to electronic health records (EHRs) enable the study of genetic pleiotropy between rare variants and seemingly disparate diseases. We performed robust clinical phenotyping of rare, putatively deleterious variants (loss-of-function [LoF] and deleterious missense variants) in ERCC6, a gene implicated in inherited retinal disease. We analyzed 213,084 exomes, along with a targeted set of retinal, cardiac, and immune phenotypes from two large-scale EHR-linked biobanks.

Molecular Analysis of the Kidney From a Patient With COVID-19-Associated Collapsing Glomerulopathy.

Recent case reports suggest that coronavirus disease 2019 (COVID-19) is associated with collapsing glomerulopathy in African Americans with apolipoprotein L1 gene () risk alleles; however, it is unclear whether disease pathogenesis is similar to HIV-associated nephropathy. RNA sequencing analysis of a kidney biopsy specimen from a patient with COVID-19-associated collapsing glomerulopathy and risk alleles (G1/G1) revealed similar levels of and angiotensin-converting enzyme 2 () messenger RNA transcripts as compared with 12 control kidney samples downloaded from the GTEx (Genotype-Tissue Expression) Portal. Whole-genome sequencing of the COVID-19-associated collapsing glomerulopathy kidney sample identified 4 indel gene variants, 3 of which are of unknown significance with respect to chronic kidney disease and/or focal segmental glomerulosclerosis.

Genome-wide polygenic risk score for retinopathy of type 2 diabetes.

Diabetic retinopathy (DR) is a common consequence in type 2 diabetes (T2D) and a leading cause of blindness in working-age adults. Yet, its genetic predisposition is largely unknown. Here, we examined the polygenic architecture underlying DR by deriving and assessing a genome-wide polygenic risk score (PRS) for DR.