RESUMO
Throughout the last 2 decades, several scholars observed that present day research into human genes rarely turns toward genes that had not already been extensively investigated in the past. Guided by hypotheses derived from studies of science and innovation, we present here a literature-wide data-driven meta-analysis to identify the specific scientific and organizational contexts that coincided with early-stage research into human genes throughout the past half century. We demonstrate that early-stage research into human genes differs in team size, citation impact, funding mechanisms, and publication outlet, but that generalized insights derived from studies of science and innovation only partially apply to early-stage research into human genes. Further, we demonstrate that, presently, genome biology accounts for most of the initial early-stage research, while subsequent early-stage research can engage other life sciences fields. We therefore anticipate that the specificity of our findings will enable scientists and policymakers to better promote early-stage research into human genes and increase overall innovation within the life sciences.
Assuntos
Genética Humana/história , Genética Humana/métodos , Genoma Humano , História do Século XX , História do Século XXI , Genética Humana/economia , HumanosRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a continuous progression of pathophysiologic stages that is challenging to diagnose due to its inherent heterogeneity and poor standardization across a wide variety of diagnostic measures. NAFLD is heritable, and several loci have been robustly associated with various stages of disease. In the past few years, larger genetic association studies using new methodology have identified novel genes associated with NAFLD, some of which have shown therapeutic promise. This mini-review provides an overview of the heterogeneity in NAFLD phenotypes and diagnostic methods, discusses genetic associations in relation to the specific stages for which they were identified, and offers a perspective on the design of future genetic mapping studies to accelerate therapeutic target identification.
Assuntos
Genética Populacional , Terapia de Alvo Molecular/métodos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/terapia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Técnicas de Diagnóstico Endócrino/tendências , Progressão da Doença , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genética Humana/métodos , Genética Humana/tendências , Humanos , Terapia de Alvo Molecular/tendências , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The goals of PhenX (consensus measures for Phenotypes and eXposures) are to promote the use of standard measurement protocols and to help investigators identify opportunities for collaborative research and cross-study analysis, thus increasing the impact of individual studies. The PhenX Toolkit (https://www.phenxtoolkit.org/) offers high-quality, well-established measurement protocols to assess phenotypes and exposures in studies with human participants. The Toolkit contains protocols representing 29 research domains and 6 specialty collections of protocols that add depth to the Toolkit in specific research areas (e.g., COVID-19, Social Determinants of Health [SDoH], Blood Sciences Research [BSR], Mental Health Research [MHR], Tobacco Regulatory Research [TRR], and Substance Abuse and Addiction [SAA]). Protocols are recommended for inclusion in the PhenX Toolkit by Working Groups of domain experts using a consensus process that includes input from the scientific community. For each PhenX protocol, the Toolkit provides a detailed description, the rationale for inclusion, and supporting documentation. Users can browse protocols in the Toolkit, search the Toolkit using keywords, or use Browse Protocols Tree to identify protocols of interest. The PhenX Toolkit provides data dictionaries compatible with the database of Genotypes and Phenotypes (dbGaP), Research Electronic Data Capture (REDCap) data submission compatibility, and data collection worksheets to help investigators incorporate PhenX protocols into their study design. The PhenX Toolkit provides resources to help users identify published studies that used PhenX protocols. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Using the PhenX Toolkit to support or extend study design.
Assuntos
Bases de Dados como Assunto , Estudo de Associação Genômica Ampla/métodos , Genética Humana/métodos , Pesquisa Interdisciplinar/métodos , Software/normas , Exposição Ambiental , Predisposição Genética para Doença , Humanos , FenótipoRESUMO
The melding of human genetics with clinical assisted reproduction, now all but self-evident, gave flight to diagnostic and therapeutic approaches previously deemed infeasible. Preimplantation genetic diagnosis, mitochondrial replacement techniques, and remedial germline editing are particularly noteworthy. Here we explore the relevant disruption brought forth by coalescence of these mutually enabling disciplines with the regulatory and legal implications thereof.
Assuntos
Genética Humana/métodos , Técnicas de Reprodução Assistida/ética , Técnicas de Reprodução Assistida/tendências , Feminino , Edição de Genes/métodos , Genética Médica/ética , Genética Médica/tendências , Células Germinativas , Humanos , Gravidez , Diagnóstico Pré-Implantação/métodos , Reprodução/genética , Reprodução/fisiologiaRESUMO
Canalization refers to the evolution of populations such that the number of individuals who deviate from the optimum trait, or experience disease, is minimized. In the presence of rapid cultural, environmental, or genetic change, the reverse process of decanalization may contribute to observed increases in disease prevalence. This review starts by defining relevant concepts, drawing distinctions between the canalization of populations and robustness of individuals. It then considers evidence pertaining to three continuous traits and six domains of disease. In each case, existing genetic evidence for genotype-by-environment interactions is insufficient to support a strong inference of decanalization, but we argue that the advent of genome-wide polygenic risk assessment now makes an empirical evaluation of the role of canalization in preventing disease possible. Finally, the contributions of both rare and common variants to congenital abnormality and adult onset disease are considered in light of a new kerplunk model of genetic effects.
Assuntos
Doenças Genéticas Inatas/genética , Genoma/genética , Genética Humana/métodos , Variação Genética/genética , Genótipo , Humanos , FilogeniaRESUMO
BACKGROUND: Human genetic resources are an important material component for life science research and have strategic significance for medical science and technological innovation. In this study, we employ frameworks from social psychology and the science of human behavior to study human genetic resource providers. AIMS: We used structural equation techniques to explain factors affecting the intention to provide human genetic resources and the mechanisms for providing such resources. METHODS: We conducted an online survey with respondents from ethnic minorities (n = 912). Our model integrates key variables informed by the theory of planned behavior (TPB), the theory of benefit and risk assessment (BRA), as well as variables that represent the policy and political system. RESULTS: Our results show that the factors affecting the intention to provide human genetic resources, ranked from highly influential to less influential, are perceived benefits, privacy risk, attitudes toward providing human genetic resources, perceived behavioral efficacy, psychological risk, subjective norms, and physical risk. The variables informed by the TPB all have a significant positive effect on the intention to provide human genetic resources. With the exception of physical risk, the variables informed by the theory of BRA have a significant effect on the intention to provide human genetic resources. Respondents with different health conditions have significantly different levels of physical risk. CONCLUSIONS: The results of our study provide insights into how to improve people's intention to provide human genetic resources. We also proposed ways to protect such resources globally.
Assuntos
Controle Comportamental , Genética Humana , Seleção de Pacientes/ética , Atitude , Controle Comportamental/métodos , Controle Comportamental/psicologia , Participação da Comunidade/psicologia , Genética Humana/ética , Genética Humana/métodos , Genética Humana/tendências , Humanos , Intenção , Teoria Psicológica , Pesquisa , Medição de RiscoRESUMO
Estimates of individual-level genomic ancestry are routinely used in human genetics, and related fields. The analysis of population structure and genomic ancestry can yield insights in terms of modern and ancient populations, allowing us to address questions regarding admixture, and the numbers and identities of the parental source populations. Unrecognized population structure is also an important confounder to correct for in genome-wide association studies. However, it remains challenging to work with heterogeneous datasets from multiple studies collected by different laboratories with diverse genotyping and imputation protocols. This work presents a new approach and an accompanying open-source toolbox that facilitates a robust integrative analysis for population structure and genomic ancestry estimates for heterogeneous datasets. We show robustness against individual outliers and different protocols for the projection of new samples into a reference ancestry space, and the ability to reveal and adjust for population structure in a simulated case-control admixed population. Given that visually evident and easily recognizable patterns of human facial characteristics co-vary with genomic ancestry, and based on the integration of three different sources of genome data, we generate average 3D faces to illustrate genomic ancestry variations within the 1,000 Genome project and for eight ancient-DNA profiles, respectively.
Assuntos
Identificação Biométrica/métodos , Face/anatomia & histologia , Genoma Humano , Genética Humana/métodos , Padrões de Herança , Modelos Estatísticos , Conjuntos de Dados como Assunto , Reconhecimento Facial/fisiologia , Feminino , Genética Populacional/métodos , Estudo de Associação Genômica Ampla , História do Século XXI , História Antiga , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Grupos Raciais/históriaRESUMO
Rising prices for new, transformative therapies are challenging health systems around the world, leading many payers and providers to begin rationing access to treatments, even in the countries that have been most resistant to doing so. This is the case for direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV). However, little attention has been paid to the increasing role that human genetics might play in rationing decisions. Researchers have already proposed that genetic markers associated with spontaneous HCV clearance could be used to restrict DAA access for some patients, although treatment would be medically beneficial for those patients. Would such forms of rationing present a form of genetic discrimination? And what of the public health implications of these approaches? Here we present an ethical analysis of such proposals for "precision rationing" and raise 4 key areas of concern. We argue that ethical issues arising in this area are not substantively different from the pressing ethical issues regarding rationing and discrimination more broadly, but provide important impetus for motivating broad public debate to find ethically sound ways of managing genomics and new expensive medications.
Assuntos
Fenômenos Genéticos , Hepatite C , Genética Humana , Seleção de Pacientes , Antivirais/economia , Antivirais/uso terapêutico , Testes Genéticos/métodos , Alocação de Recursos para a Atenção à Saúde/ética , Alocação de Recursos para a Atenção à Saúde/métodos , Acessibilidade aos Serviços de Saúde , Hepatite C/tratamento farmacológico , Hepatite C/economia , Hepatite C/genética , Genética Humana/métodos , Genética Humana/tendências , HumanosRESUMO
Social science genetics is concerned with understanding whether, how and why genetic differences between human beings are linked to differences in behaviours and socioeconomic outcomes. Our review discusses the goals, methods, challenges and implications of this research endeavour. We survey how the recent developments in genetics are beginning to provide social scientists with a powerful new toolbox they can use to better understand environmental effects, and we illustrate this with several substantive examples. Furthermore, we examine how medical research can benefit from genetic insights into social-scientific outcomes and vice versa. Finally, we discuss the ethical challenges of this work and clarify several common misunderstandings and misinterpretations of genetic research on individual differences.
Assuntos
Genética Humana , Ciências Sociais/métodos , Estudo de Associação Genômica Ampla , Genética Humana/métodos , Humanos , Herança Multifatorial , Psicologia Social , Mobilidade SocialRESUMO
Neuropsychiatric disorders are frequently complicated by aggressive behaviors. For some individuals, existing behavioral and psychopharmacological treatments are ineffective or confer significant side effects, necessitating development of new ways to treat patients with severe aggression. Nicotinic acetylcholine receptors (nAChRs) are a large and diverse family of ligand-gated ion channels expressed throughout the brain that influence behaviors highly relevant for neuropsychiatric disorders, including attention, mood, and impulsivity. Nicotine and other drugs targeting nAChRs can reduce aggression in animal models of offensive, defensive, and predatory aggression, as well as in human laboratory studies. Human genetic studies have suggested a relationship between the CHRNA7 gene encoding the alpha-7 nAChR and aggressive behavior, although these effects are heterogeneous and strongly influenced by genetic background and environment. Here we review animal, human genetic, and clinical studies supporting a consistent role of nicotine and nAChR signaling in modulation of aggressive behaviors. We integrate findings from recent studies of aggression neuroscience, discuss the circuitry that may be involved in these effects of nAChRs, and identify multiple key questions that must be answered prior to safe and effective translation for human patients. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Assuntos
Agressão/fisiologia , Ensaios Clínicos como Assunto/métodos , Genética Humana/métodos , Modelos Animais , Receptores Nicotínicos/fisiologia , Agressão/efeitos dos fármacos , Animais , Genética Humana/tendências , Humanos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologiaRESUMO
Pulmonary arterial hypertension (PAH) is an incurable disease characterized by disordered and dysfunctional angiogenesis leading to small-vessel loss and an obliterative vasculopathy. The pathogenesis of PAH is not fully understood, but multiple studies have demonstrated links between elevated angiostatic factors, disease severity, and adverse clinical outcomes. ES (endostatin), one such circulating angiostatic peptide, is the cleavage product of the proteoglycan COL18A1 (collagen α1[XVIII] chain). Elevated serum ES is associated with increased mortality and disease severity in PAH. A nonsynonymous variant of ES (aspartic acid-to-asparagine substitution at amino acid 104; p.D104N) is associated with differences in PAH survival. Although COL18A1/ES expression is markedly increased in remodeled pulmonary vessels in PAH, the impact of ES on pulmonary endothelial cell (PEC) biology and molecular contributions to PAH severity remain undetermined. In the present study, we characterized the effects of exogenous ES on human PEC biology and signaling. We demonstrated that ES inhibits PEC migration, proliferation, and cell survival, with significant differences between human variants, indicating that they are functional genetic variants. ES promotes proteasome-mediated degradation of the transcriptional repressor ID1, increasing expression and release of TSP-1 (thrombospondin 1). ES inhibits PEC migration via an ID1/TSP-1/CD36-dependent pathway, in contrast to proliferation and apoptosis, which require both CD36 and CD47. Collectively, the data implicate ES as a novel negative regulator of ID1 and an upstream propagator of an angiostatic signal cascade converging on CD36 and CD47, providing insight into the cellular and molecular effects of a functional genetic variant linked to altered outcomes in PAH.
Assuntos
Colágeno Tipo VIII/metabolismo , Endostatinas/metabolismo , Células Endoteliais/metabolismo , Endotélio/metabolismo , Hipertensão Pulmonar Primária Familiar/metabolismo , Pulmão/metabolismo , Apoptose/fisiologia , Linhagem Celular , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Colágeno Tipo XVIII/metabolismo , Genética Humana/métodos , Humanos , Transdução de Sinais/fisiologiaRESUMO
Drug repurposing has attracted increased attention, especially in the context of drug discovery rates that remain too low despite a recent wave of approvals for biological therapeutics (e.g. gene therapy). These new biological entities-based treatments have high costs that are difficult to justify for small markets that include rare diseases. Drug repurposing, involving the identification of single or combinations of existing drugs based on human genetics data and network biology approaches represents a next-generation approach that has the potential to increase the speed of drug discovery at a lower cost. This Pharmacological Perspective reviews progress and perspectives in combining human genetics, especially genome-wide association studies, with network biology to drive drug repurposing for rare and common diseases with monogenic or polygenic etiologies. Also, highlighted here are important features of this next generation approach to drug repurposing, which can be combined with machine learning methods to meet the challenges of personalized medicine.
Assuntos
Reposicionamento de Medicamentos/tendências , Redes Reguladoras de Genes/genética , Genética Humana/tendências , Aprendizado de Máquina/tendências , Animais , Reposicionamento de Medicamentos/métodos , Redes Reguladoras de Genes/efeitos dos fármacos , Terapia Genética/métodos , Terapia Genética/tendências , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/tendências , Genética Humana/métodos , HumanosRESUMO
Geographic patterns in human genetic diversity carry footprints of population history and provide insights for genetic medicine and its application across human populations. Summarizing and visually representing these patterns of diversity has been a persistent goal for human geneticists, and has revealed that genetic differentiation is frequently correlated with geographic distance. However, most analytical methods to represent population structure do not incorporate geography directly, and it must be considered post hoc alongside a visual summary of the genetic structure. Here, we estimate "effective migration" surfaces to visualize how human genetic diversity is geographically structured. The results reveal local patterns of differentiation in detail and emphasize that while genetic similarity generally decays with geographic distance, the relationship is often subtly distorted. Overall, the visualizations provide a new perspective on genetics and geography in humans and insight to the geographic distribution of human genetic variation.
Assuntos
Variação Genética , Genética Humana/métodos , Migração Humana , Geografia , HumanosRESUMO
Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Genética Humana/métodos , Confiabilidade dos Dados , Variação Genética , Genética Populacional/métodos , Genética Populacional/normas , Estudo de Associação Genômica Ampla/normas , Técnicas de Genotipagem/normas , Genética Humana/normas , Humanos , LinhagemRESUMO
Human average life expectancy in developed countries has increased dramatically in the last century, a phenomenon which is potentially accompanied by a significant rise in multi-morbidity and frailty among older individuals.[...].