A Genome-Wide Association Study and Rare Variant Analysis for Dupuytren Disease in a North American Population.

Purpose: Although European genome-wide association studies (GWAS) have aided in defining genetic associations in Dupuytren disease (DD), North American populations have been infrequently analyzed. Additionally, there are a paucity of rare variant analyses (RVA) for DD, which can help define both trait variability and risk for low-frequency variants. Our purpose was to perform a GWAS and RVA for DD using a North American database.

Genomic ascertainment of -related cancer predisposition.

Purpose: There is clear evidence that deleterious germline variants in increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk in germline pathogenic variant heterozygotes.

Patients And Methods: Germline variants were extracted from two exome-sequenced biobanks linked to the electronic health record: UK Biobank (n= 469,765) and Geisinger MyCode (n=170,503).

A genome-first approach to characterize DICER1 pathogenic variant prevalence, penetrance and cancer, thyroid, and other phenotypes in 2 population-scale cohorts.

Purpose: Population-scale, exome-sequenced cohorts with linked electronic health records (EHR) permit genome-first exploration of phenotype. Phenotype and cancer risk are well-characterized in children with a pathogenic (HGNC ID:17098) variant. Here, the prevalence, penetrance and phenotype of pathogenic germline variants in adults was investigated in two population-scale cohorts.

Development of a Polygenic Risk Score to Predict Diverticulitis.

Background: Despite its prevalence and associated morbidity, we remain limited in our ability to predict the course of a patient with diverticular disease. Although several clinical and genetic risk factors have been identified, we do not know how these factors relate to one another.

Objective: Our aim was to determine whether a polygenic risk score could improve risk prediction for diverticulitis and recurrent diverticulitis compared with a model using only clinical factors.

Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants.

Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis.

Association of varicose veins with rare protein-truncating variants in PIEZO1 identified by exome sequencing of a large clinical population.

Objective: The present study sought to determine whether protein-truncating variants (PTVs) in PIEZO1 and CASZ1 genes, previously shown to be associated with varicose veins, were associated with an altered risk of varicose veins.

Methods: An exome sequence database of 131,918 participants from the Geisinger MyCode Community Health Initiative was used to identify individuals with genetic variants in the PIEZO1 or CASZ1 gene. Clinical phenotypes, including varicose vein diagnoses, were determined by analysis of the electronic health record data.

Do Hernias Contribute to Increased Severity of Aneurysmal Disease among Abdominal Aortic Aneurysm Patients?

Background:  Connective tissue disorders could contribute to the pathogenesis of both abdominal aortic aneurysms (AAA) and hernias. We tested the hypothesis that hernias in AAA patients contribute to increased severity of the aneurysmal disease.

Methods:  A questionnaire was used to collect information from 195 AAA patients divided into four groups: (1) survivors ( = 22) of ruptured AAA, (2) patients ( = 90) after elective open repair, (3) patients ( = 43) after elective endovascular repair (EVAR), and (4) patients ( = 40) under surveillance of AAA.

Genome-wide association study of neck circumference identifies sex-specific loci independent of generalized adiposity.

Background/objectives: Neck circumference, an index of upper airway fat, has been suggested to be an important measure of body-fat distribution with unique associations with health outcomes such as obstructive sleep apnea and metabolic disease. This study aims to study the genetic bases of neck circumference.

Methods: We conducted a multi-ethnic genome-wide association study of neck circumference, adjusted and unadjusted for BMI, in up to 15,090 European Ancestry (EA) and African American (AA) individuals.

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.

The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system.

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls.

Rare-variant pathogenicity triage and inclusion of synonymous variants improves analysis of disease associations of orphan G protein-coupled receptors.

The pace of deorphanization of G protein-coupled receptors (GPCRs) has slowed, and new approaches are required. Small molecule targeting of orphan GPCRs can potentially be of clinical benefit even if the endogenous receptor ligand has not been identified. Many GPCRs lack common variants that lead to reproducible genome-wide disease associations, and rare-variant approaches have emerged as a viable alternative to identify disease associations for such genes.

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood.

Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF.

Genetic risk models: Influence of model size on risk estimates and precision.

Disease risk estimation plays an important role in disease prevention. Many studies have found that the ability to predict risk improves as the number of risk single-nucleotide polymorphisms (SNPs) in the risk model increases. However, the width of the confidence interval of the risk estimate is often not considered in the evaluation of the risk model.

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA.

Objective: To identify additional AAA risk loci using data from all available genome-wide association studies.

ePhenotyping for Abdominal Aortic Aneurysm in the Electronic Medical Records and Genomics (eMERGE) Network: Algorithm Development and Konstanz Information Miner Workflow.

Background And Objective: We designed an algorithm to identify abdominal aortic aneurysm cases and controls from electronic health records to be shared and executed within the "electronic Medical Records and Genomics" (eMERGE) Network.

Materials And Methods: Structured Query Language, was used to script the algorithm utilizing "Current Procedural Terminology" and "International Classification of Diseases" codes, with demographic and encounter data to classify individuals as case, control, or excluded. The algorithm was validated using blinded manual chart review at three eMERGE Network sites and one non-eMERGE Network site.

The Geisinger MyCode community health initiative: an electronic health record-linked biobank for precision medicine research.

Purpose: Geisinger Health System (GHS) provides an ideal platform for Precision Medicine. Key elements are the integrated health system, stable patient population, and electronic health record (EHR) infrastructure. In 2007, Geisinger launched MyCode, a system-wide biobanking program to link samples and EHR data for broad research use.

Population risk factor estimates for abdominal aortic aneurysm from electronic medical records: a case control study.

Background: Using abdominal aortic aneurysm (AAA) as a model, this case-control study used electronic medical record (EMR) data to assess known risk factors and identify new associations.

Methods: The study population consisted of cases with AAA (n =888) and controls (n =10,523) from the Geisinger Health System EMR in Central and Northeastern Pennsylvania. We extracted all clinical and diagnostic data for these patients from January 2004 to December 2009 from the EMR.

Genetic-based prediction of disease traits: prediction is very difficult, especially about the future.

Translation of results from genetic findings to inform medical practice is a highly anticipated goal of human genetics. The aim of this paper is to review and discuss the role of genetics in medically-relevant prediction. Germline genetics presages disease onset and therefore can contribute prognostic signals that augment laboratory tests and clinical features.

Update on abdominal aortic aneurysm research: from clinical to genetic studies.

An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta with a diameter of at least 3.0 cm. AAAs are often asymptomatic and are discovered as incidental findings in imaging studies or when the AAA ruptures leading to a medical emergency.