A community-led initiative to de-risk and advance Parkinson's disease therapeutic targets.

Identifying effective therapeutic targets for Parkinson's disease (PD) is challenging, with no current disease-modifying therapies available. To address this, The Michael J. Fox Foundation for Parkinson's Research launched the Targets to Therapies (T2T) initiative, uniting experts to prioritize and validate promising targets.

Human genetic evidence enriched for side effects of approved drugs.

Safety failures are an important factor in low drug development success rates. Human genetic evidence can select drug targets causal in disease and enrich for successful programs. Here, we sought to determine whether human genetic evidence can also enrich for labeled side effects (SEs) of approved drugs.

Refining the impact of genetic evidence on clinical success.

The cost of drug discovery and development is driven primarily by failure, with only about 10% of clinical programmes eventually receiving approval. We previously estimated that human genetic evidence doubles the success rate from clinical development to approval. In this study we leverage the growth in genetic evidence over the past decade to better understand the characteristics that distinguish clinical success and failure.

Future prospects for human genetics and genomics in drug discovery.

Evidence from human genetics supporting the therapeutic hypothesis increases the likelihood that a drug will succeed in clinical trials. Rare and common disease genetics yield a wide array of alleles with a range of effect sizes that can proxy for the effect of a drug in disease. Recent advances in large scale population collections and whole genome sequencing approaches have provided a rich resource of human genetic evidence to support drug target selection.

Using human genetics to improve safety assessment of therapeutics.

Human genetics research has discovered thousands of proteins associated with complex and rare diseases. Genome-wide association studies (GWAS) and studies of Mendelian disease have resulted in an increased understanding of the role of gene function and regulation in human conditions. Although the application of human genetics has been explored primarily as a method to identify potential drug targets and support their relevance to disease in humans, there is increasing interest in using genetic data to identify potential safety liabilities of modulating a given target.

Exome sequencing and characterization of 49,960 individuals in the UK Biobank.

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%).

Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort.

Background: β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.

Objective: We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.

Methods: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics.

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization.

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions.

Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.

Predicting clinically promising therapeutic hypotheses using tensor factorization.

Background: Determining which target to pursue is a challenging and error-prone first step in developing a therapeutic treatment for a disease, where missteps are potentially very costly given the long-time frames and high expenses of drug development. With current informatics technology and machine learning algorithms, it is now possible to computationally discover therapeutic hypotheses by predicting clinically promising drug targets based on the evidence associating drug targets with disease indications. We have collected this evidence from Open Targets and additional databases that covers 17 sources of evidence for target-indication association and represented the data as a tensor of 21,437 × 2211 × 17.

A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury.

Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.

Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry.

Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles.

Some patients prescribed flucloxacillin (~ 0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI.

Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

A phenome-wide association study of variants in genes in the Th17 and IL-17 pathway was performed using self-reported phenotypes and genetic data from 521,000 research participants of 23andMe. Results replicated known associations with similar effect sizes for autoimmune traits illustrating self-reported traits can be a surrogate for clinically assessed conditions. Novel associations controlling for a false discovery rate of 5% included the association of the variant encoding p.

STOPGAP: a database for systematic target opportunity assessment by genetic association predictions.

Summary: We developed the STOPGAP (Systematic Target OPportunity assessment by Genetic Association Predictions) database, an extensive catalog of human genetic associations mapped to effector gene candidates. STOPGAP draws on a variety of publicly available GWAS associations, linkage disequilibrium (LD) measures, functional genomic and variant annotation sources. Algorithms were developed to merge the association data, partition associations into non-overlapping LD clusters, map variants to genes and produce a variant-to-gene score used to rank the relative confidence among potential effector genes.

Impact of genetically supported target selection on R&D productivity.

This corrects the article DOI: 10.1038/nrd.2016.

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.

Background: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Objectives: To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity.

Methods: A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensitive and 182 tolerant, HIV-infected Malawian adults.

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.

Background & Aims: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors.

Methods: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274).

Characterization of ADME gene variation in 21 populations by exome sequencing.

Objective: Proteins involving absorption, distribution, metabolism, and excretion (ADME) play a critical role in drug pharmacokinetics. The type and frequency of genetic variation in the ADME genes differ among populations. The aim of this study was to systematically investigate common and rare ADME coding variation in diverse ethnic populations by exome sequencing.

The genetics of drug efficacy: opportunities and challenges.

Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval.

HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury.

Objective: Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown.

GWASdb v2: an update database for human genetic variants identified by genome-wide association studies.

Genome-wide association studies (GWASs), now as a routine approach to study single-nucleotide polymorphism (SNP)-trait association, have uncovered over ten thousand significant trait/disease associated SNPs (TASs). Here, we updated GWASdb (GWASdb v2, http://jjwanglab.org/gwasdb) which provides comprehensive data curation and knowledge integration for GWAS TASs.

HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer.

Purpose: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury.

The support of human genetic evidence for approved drug indications.

Over a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions.

Improved genome inference in the MHC using a population reference graph.

Although much is known about human genetic variation, such information is typically ignored in assembling new genomes. Instead, reads are mapped to a single reference, which can lead to poor characterization of regions of high sequence or structural diversity. We introduce a population reference graph, which combines multiple reference sequences and catalogs of variation.