Postmortem toxicology findings from the Camden Opioid Research Initiative.

The United States continues to be impacted by decades of an opioid misuse epidemic, worsened by the COVID-19 pandemic and by the growing prevalence of highly potent synthetic opioids (HPSO) such as fentanyl. In instances of a toxicity event, first-response administration of reversal medications such as naloxone can be insufficient to fully counteract the effects of HPSO, particularly when there is co-occurring substance use. In an effort to characterize and study this multi-faceted problem, the Camden Opioid Research Initiative (CORI) has been formed.

Patient Perceptions and Potential Utility of Pharmacogenetic Testing in Chronic Pain Management and Opioid Use Disorder in the Camden Opioid Research Initiative.

Pharmacogenetics (PGx) has the potential to improve opioid medication management. Here, we present patient perception data, pharmacogenetic data and medication management trends in patients with chronic pain (arm 1) and opioid use disorder (arm 2) treated at Cooper University Health Care in Camden City, NJ. Our results demonstrate that the majority of patients in both arms of the study (55% and 65%, respectively) are open to pharmacogenetic testing, and most (66% and 69%, respectively) believe that genetic testing has the potential to improve their medical care.

Pharmacogenomics: From Basic Research to Clinical Implementation.

The established contribution of genetic variation to drug response has the potential to improve drug efficacy and reduce drug toxicity [...

Common Treatment, Common Variant: Evolutionary Prediction of Functional Pharmacogenomic Variants.

Pharmacogenomics holds the promise of personalized drug efficacy optimization and drug toxicity minimization. Much of the research conducted to date, however, suffers from an ascertainment bias towards European participants. Here, we leverage publicly available, whole genome sequencing data collected from global populations, evolutionary characteristics, and annotated protein features to construct a new in silico machine learning pharmacogenetic identification method called XGB-PGX.

Testing a best practices risk result format to communicate genetic risks.

Objective: To investigate the effect of a genetic report format using risk communication "best-practices" on risk perceptions, in part to reduce risk overestimates.

Methods: Adults (N = 470) from the Coriell Personalized Medicine Collaborative (CPMC) were randomized to a 2 × 2 experimental design to receive a hypothetical "personalized" genetic risk result for leukemia (relative risk = 1.5 or 2.

Pharmacogenomic (PGx) Counseling: Exploring Participant Questions about PGx Test Results.

As pharmacogenomic (PGx) use in healthcare increases, a better understanding of patient needs will be necessary to guide PGx result delivery. The Coriell Personalized Medicine Collaborative (CPMC) is a prospective study investigating the utility of personalized medicine. Participants received online genetic risk reports for 27 potentially actionable complex diseases and 7 drug-gene pairs and could request free, telephone-based genetic counseling (GC).

Habitat-Specific Clock Variation and Its Consequence on Reproductive Fitness.

The circadian clock controls daily activities at the cellular and organismic level, allowing an organism to anticipate incoming stresses and to use resources accordingly. The circadian clock has therefore been considered a fitness trait in multiple organisms. However, the mechanism of how circadian clock variation influences organismal reproductive fitness is still not well understood.

rs11670527 Upstream of ZNF264 Associated with Body Mass Index in the Coriell Personalized Medicine Collaborative.

Introduction: the effects of obesity on health are a concern for the military as they affect the fitness to serve of active service members, increase costs to the Military Health System, and reduce quality of life for veterans and beneficiaries. Although obesity can be influenced by behavioral and environmental factors, it has also been shown to be associated with genetic risk factors that are not fully understood.

Materials And Methods: we performed a genome-wide association study of 5,251 participants in the Coriell Personalized Medicine Collaborative, which includes 2,111 Air Force participants.

Genomic evidence for shared common ancestry of East African hunting-gathering populations and insights into local adaptation.

Anatomically modern humans arose in Africa ∼300,000 years ago, but the demographic and adaptive histories of African populations are not well-characterized. Here, we have generated a genome-wide dataset from 840 Africans, residing in western, eastern, southern, and northern Africa, belonging to 50 ethnicities, and speaking languages belonging to four language families. In addition to agriculturalists and pastoralists, our study includes 16 populations that practice, or until recently have practiced, a hunting-gathering (HG) lifestyle.

Genetic and genomic stability across lymphoblastoid cell line expansions.

Objective: Lymphoblastoid cell lines are widely used in genetic and genomic studies. Previous work has characterized variant stability in transformed culture and across culture passages. Our objective was to extend this work to evaluate single nucleotide polymorphism and structural variation across cell line expansions, which are commonly used in biorepository distribution.

Adaptive Landscape of Protein Variation in Human Exomes.

The human genome contains hundreds of thousands of missense mutations. However, only a handful of these variants are known to be adaptive, which implies that adaptation through protein sequence change is an extremely rare phenomenon in human evolution. Alternatively, existing methods may lack the power to pinpoint adaptive variation.

Precision Military Medicine: Conducting a multi-site clinical utility study of genomic and lifestyle risk factors in the United States Air Force.

Following several years enrolling disease-specific and otherwise healthy cohorts into the Coriell Personalized Medicine Collaborative, a prospective study aimed at evaluating the clinical utility of personal genomic information for common complex disease and pharmacogenomics, the Coriell Personalized Medicine Collaborative expanded to create a military cohort, specifically, the United States Air Force. Initial recruitment focused on Air Force Medical Service personnel and later expanded to include all Active Duty Air Force members and beneficiaries. Now in its 6th year, the study has produced a wide variety of insights, including optimal study design for military-sponsored genomic research, and discussion on genetic information sharing between and amongst Air Force study participants, civilian and military researchers, and the United States Department of Defense.

e-GRASP: an integrated evolutionary and GRASP resource for exploring disease associations.

Background: Genome-wide association studies (GWAS) have become a mainstay of biological research concerned with discovering genetic variation linked to phenotypic traits and diseases. Both discrete and continuous traits can be analyzed in GWAS to discover associations between single nucleotide polymorphisms (SNPs) and traits of interest. Associations are typically determined by estimating the significance of the statistical relationship between genetic loci and the given trait.

Challenges in Translating GWAS Results to Clinical Care.

Clinical genetic testing for Mendelian disorders is standard of care in many cases; however, it is less clear to what extent and in which situations clinical genetic testing may improve preventive efforts, diagnosis and/or prognosis of complex disease. One challenge is that much of the reported research relies on tag single nucleotide polymorphisms (SNPs) to act as proxies for assumed underlying functional variants that are not yet known. Here we use coronary artery disease and melanoma as case studies to evaluate how well reported genetic risk variants tag surrounding variants across population samples in the 1000 Genomes Project Phase 3 data.

An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance.

Pharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process.

Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.

Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.

A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals.

Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not.

Using the Coriell Personalized Medicine Collaborative Data to conduct a genome-wide association study of sleep duration.

Sleep is critical to health and functionality, and several studies have investigated the inherited component of insomnia and other sleep disorders using genome-wide association studies (GWAS). However, genome-wide studies focused on sleep duration are less common. Here, we used data from participants in the Coriell Personalized Medicine Collaborative (CPMC) (n = 4,401) to examine putative associations between self-reported sleep duration, demographic and lifestyle variables, and genome-wide single nucleotide polymorphism (SNP) data to better understand genetic contributions to variation in sleep duration.

Common genetic risk for melanoma encourages preventive behavior change.

There is currently great interest in using genetic risk estimates for common disease in personalized healthcare. Here we assess melanoma risk-related preventive behavioral change in the context of the Coriell Personalized Medicine Collaborative (CPMC). As part of on-going reporting activities within the project, participants received a personalized risk assessment including information related to their own self-reported family history of melanoma and a genetic risk variant showing a moderate effect size (1.

Recent human adaptation: genomic approaches, interpretation and insights.

The recent availability of genomic data has spurred many genome-wide studies of human adaptation in different populations worldwide. Such studies have provided insights into novel candidate genes and pathways that are putatively involved in adaptation to different environments, diets and disease prevalence. However, much work is needed to translate these results into candidate adaptive variants that are biologically interpretable.

Patterns of ancestry, signatures of natural selection, and genetic association with stature in Western African pygmies.

African Pygmy groups show a distinctive pattern of phenotypic variation, including short stature, which is thought to reflect past adaptation to a tropical environment. Here, we analyze Illumina 1M SNP array data in three Western Pygmy populations from Cameroon and three neighboring Bantu-speaking agricultural populations with whom they have admixed. We infer genome-wide ancestry, scan for signals of positive selection, and perform targeted genetic association with measured height variation.

Clusters of adaptive evolution in the human genome.

Considerable work has been devoted to identifying regions of the human genome that have been subjected to recent positive selection. Although detailed follow-up studies of putatively selected regions are critical for a deeper understanding of human evolutionary history, such studies have received comparably less attention. Recently, we have shown that ALMS1 has been the target of recent positive selection acting on standing variation in Eurasian populations.

Genetic adaptation to high altitude in the Ethiopian highlands.

Background: Genomic analysis of high-altitude populations residing in the Andes and Tibet has revealed several candidate loci for involvement in high-altitude adaptation, a subset of which have also been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. Here, we have extended this work to high- and low-altitude populations living in Ethiopia, for which we have measured hemoglobin levels. We genotyped the Illumina 1M SNP array and employed several genome-wide scans for selection and targeted association with hemoglobin levels to identify genes that play a role in adaptation to high altitude.

Living the high life: high-altitude adaptation.

Genome-wide scans demonstrate that genetic variants associated with high-altitude adaptation in Tibetans and Andeans arose independently as a result of convergent adaptation.