Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel.

Cell-Free DNA Detection of Tumor Mutations in Heterogeneous, Localized Prostate Cancer Via Targeted, Multiregion Sequencing.

Unlabelled: Cell-free DNA (cfDNA) may allow for minimally invasive identification of biologically relevant genomic alterations and genetically distinct tumor subclones. Although existing biomarkers may detect localized prostate cancer, additional strategies interrogating genomic heterogeneity are necessary for identifying and monitoring aggressive disease. In this study, we aimed to evaluate whether circulating tumor DNA can detect genomic alterations present in multiple regions of localized prostate tumor tissue.

Cell-free DNA concentration and fragment size as a biomarker for prostate cancer.

Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer.

A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility.

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.

A machine learning approach to optimizing cell-free DNA sequencing panels: with an application to prostate cancer.

Background: Cell-free DNA's (cfDNA) use as a biomarker in cancer is challenging due to genetic heterogeneity of malignancies and rarity of tumor-derived molecules. Here we describe and demonstrate a novel machine-learning guided panel design strategy for improving the detection of tumor variants in cfDNA. Using this approach, we first generated a model to classify and score candidate variants for inclusion on a prostate cancer targeted sequencing panel.

Samasy: an automated system for sample selection and robotic transfer.

Sample automation and management is increasingly important as the number and size of population-scale and high-throughput projects grow. This is particularly the case in large-scale population studies where sample size is far outpacing the commonly used 96-well plate format. To facilitate management and transfer of samples in this format, we present Samasy, a web-based application for the construction of a sample database, intuitive display of sample and batch information, and facilitation of automated sample transfer or subset.

Orchid: a novel management, annotation and machine learning framework for analyzing cancer mutations.

Motivation: As whole-genome tumor sequence and biological annotation datasets grow in size, number and content, there is an increasing basic science and clinical need for efficient and accurate data management and analysis software. With the emergence of increasingly sophisticated data stores, execution environments and machine learning algorithms, there is also a need for the integration of functionality across frameworks.

Results: We present orchid, a python based software package for the management, annotation and machine learning of cancer mutations.

An open-source method to analyze optokinetic reflex responses in larval zebrafish.

Background: Optokinetic reflex (OKR) responses provide a convenient means to evaluate oculomotor, integrative and afferent visual function in larval zebrafish models, which are commonly used to elucidate molecular mechanisms underlying development, disease and repair of the vertebrate nervous system.

New Method: We developed an open-source MATLAB-based solution for automated quantitative analysis of OKR responses in larval zebrafish. The package includes applications to: (i) generate sinusoidally-transformed animated grating patterns suitable for projection onto a cylindrical screen to elicit the OKR; (ii) determine and record the angular orientations of the eyes in each frame of a video recording showing the OKR response; and (iii) analyze angular orientation data from the tracking program to yield a set of parameters that quantify essential elements of the OKR.

Mouse genome-wide association study identifies polymorphisms on chromosomes 4, 11, and 15 for age-related cardiac fibrosis.

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains.

Determination of ubiquitin fitness landscapes under different chemical stresses in a classroom setting.

Ubiquitin is essential for eukaryotic life and varies in only 3 amino acid positions between yeast and humans. However, recent deep sequencing studies indicate that ubiquitin is highly tolerant to single mutations. We hypothesized that this tolerance would be reduced by chemically induced physiologic perturbations.

A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences.

Unlabelled: A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.

Quantification of larval zebrafish motor function in multiwell plates using open-source MATLAB applications.

This article describes a method to quantify the movements of larval zebrafish in multiwell plates, using the open-source MATLAB applications LSRtrack and LSRanalyze. The protocol comprises four stages: generation of high-quality, flatly illuminated video recordings with exposure settings that facilitate object recognition; analysis of the resulting recordings using tools provided in LSRtrack to optimize tracking accuracy and motion detection; analysis of tracking data using LSRanalyze or custom MATLAB scripts; and implementation of validation controls. The method is reliable, automated and flexible, requires <1 h of hands-on work for completion once optimized and shows excellent signal:noise characteristics.

Functional genomic assessment of phosgene-induced acute lung injury in mice.

In this study, a genetically diverse panel of 43 mouse strains was exposed to phosgene and genome-wide association mapping performed using a high-density single nucleotide polymorphism (SNP) assembly. Transcriptomic analysis was also used to improve the genetic resolution in the identification of genetic determinants of phosgene-induced acute lung injury (ALI). We prioritized the identified genes based on whether the encoded protein was previously associated with lung injury or contained a nonsynonymous SNP within a functional domain.

Early gene expression differences in inbred mouse strains with susceptibility to pulmonary adenomas.

Lung cancer is the most common cause of cancer-related deaths in both men and women, and effective preventatives are rare due to the difficulty of early detection. Specific gene expression signatures have been identified in individuals that already developed lung cancer. To identify if gene expression differences could be detected in individuals before the onset of the disease, we obtained lung tissues for microarray analysis from young, healthy mice of 9 inbred strains with known differences in their susceptibility to spontaneous pulmonary adenomas when aged.

A major X-linked locus affects kidney function in mice.

Chronic kidney disease is a common disease with increasing prevalence in the western population. One common reason for chronic kidney failure is diabetic nephropathy. Diabetic nephropathy and hyperglycemia are characteristics of the mouse inbred strain KK/HlJ, which is predominantly used as a model for metabolic syndrome due to its inherited glucose intolerance and insulin resistance.

Identification of fat4 and tsc22d1 as novel candidate genes for spontaneous pulmonary adenomas.

Genetic influences that underlie spontaneous lung oncogenesis are poorly understood. The objective of this study was to determine the genetic influences on spontaneous pulmonary adenoma frequency and severity in 28 strains of mice as part of a large-scale aging study conducted at the Jackson Aging Center (http://agingmice.jax.

Automated measurement of zebrafish larval movement.

The zebrafish is a powerful vertebrate model that is readily amenable to genetic, pharmacological and environmental manipulations to elucidate the molecular and cellular basis of movement and behaviour. We report software enabling automated analysis of zebrafish movement from video recordings captured with cameras ranging from a basic camcorder to more specialized equipment. The software, which is provided as open-source MATLAB functions, can be freely modified and distributed, and is compatible with multiwell plates under a wide range of experimental conditions.