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Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
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COVID-19 , Estado Terminal , Genoma Humano , Interações Hospedeiro-Patógeno , Sequenciamento Completo do Genoma , Transportadores de Cassetes de Ligação de ATP , COVID-19/genética , COVID-19/mortalidade , COVID-19/patologia , COVID-19/virologia , Moléculas de Adesão Celular , Cuidados Críticos , Estado Terminal/mortalidade , Selectina E , Fator VIII , Fucosiltransferases , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno/genética , Humanos , Subunidade beta de Receptor de Interleucina-10 , Lectinas Tipo C , Mucina-1 , Proteínas do Tecido Nervoso , Proteínas de Transferência de Fosfolipídeos , Receptores de Superfície Celular , Proteínas Repressoras , SARS-CoV-2/patogenicidade , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison. This paper presents results from a very large public survey on attitudes toward genomic data sharing. Data from 36,268 individuals across 22 countries (gathered in 15 languages) are presented. In general, publics across the world do not appear to be aware of, nor familiar with, the concepts of DNA, genetics, and genomics. Willingness to donate one's DNA and health data for research is relatively low, and trust in the process of data's being shared with multiple users (e.g., doctors, researchers, governments) is also low. Participants were most willing to donate DNA or health information for research when the recipient was specified as a medical doctor and least willing to donate when the recipient was a for-profit researcher. Those who were familiar with genetics and who were trusting of the users asking for data were more likely to be willing to donate. However, less than half of participants trusted more than one potential user of data, although this varied across countries. Genetic information was not uniformly seen as different from other forms of health information, but there was an association between seeing genetic information as special in some way compared to other health data and increased willingness to donate. The global perspective provided by our "Your DNA, Your Say" study is valuable for informing the development of international policy and practice for sharing genomic data. It highlights that the research community not only needs to be worthy of trust by the public, but also urgent steps need to be taken to authentically communicate why genomic research is necessary and how data donation, and subsequent sharing, is integral to this.
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Genoma Humano , Genômica/ética , Disseminação de Informação/ética , Análise de Sequência de DNA/ética , Confiança/psicologia , Adulto , América , Ásia , Austrália , Europa (Continente) , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Saúde Pública/ética , Inquéritos e QuestionáriosRESUMO
We conducted an exploratory survey of genetic counselors internationally to assess similarities and differences in reported practice activities. Between November 2018 and January 2020 we conducted a mass emailing to an estimated 5600 genetic counselors in different countries and regions. We obtained 189 useable responses representing 22 countries, which are included in an aggregate manner. Data from countries with 10 or more responses, comprising 82% of the total (N = 156), are the primary focus of this report: Australia (13), Canada (26), USA (59), UK (17), France (12), Japan (19) and India (10). Twenty activities were identified as common (≥74%) across these countries, encompassing most subcategories of genetic counseling activity. Activities with most frequent endorsement include: reviewing referrals and medical records and identifying genetic testing options as part of case preparation; taking family and medical histories; performing and sharing risk assessment; and educating clients about basic genetic information, test options, outcomes and implications, including management recommendations on the basis of the test results. Genetic counselors also consistently establish rapport, tailor the educational process, facilitate informed decision making and recognize factors that may impact the counseling interaction. The least endorsed activities were in the Medical History category. Notable differences between countries were observed in the endorsement of 33 activities, primarily in the Contracting and Establishing Rapport, Family History, Medical History, Assessing Patients Psychosocially and Providing Psychosocial Support categories. Generalizations about international practice patterns are limited by the low response rate. However, this study is, to our knowledge, the first to systematically compare the clinical practice and specific activities of genetic counselors working in different countries.
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PURPOSE: The purpose of this study was to assess decisions, attitudes, and understanding of participants (patients, parents, relatives) having genome sequencing for rare disease diagnosis. METHODS: This study involved a cross-sectional observational survey with participants in the 100,000 Genomes Project. RESULTS: Survey response rate was 51% (504/978). Most participants self-reported that they had decided to undergo genome sequencing (94%) and that this was an informed decision (84%) with low decisional conflict (95%). Most self-reported that they had chosen to receive additional findings (88%) and that this was an informed decision (89%) with low decisional conflict (95%). Participants were motivated more by the desire to help others via research than by the belief it would help them obtain a diagnosis (Z = 14.23, P = 5.75 × 10-46), although both motivations were high. Concerns were relatively few but, where expressed, were more about the potential psychological impact of results than data sharing/access (Z = 9.61, P = 7.65 × 10-22). Concerns were higher among male, Asian or Asian British, and more religious participants. General and context-specific understanding of genome sequencing were both moderately high (means 5.2/9.0 and 22.5/28.0, respectively). CONCLUSION: These findings are useful to inform consent guidelines and clinical implementation of genome sequencing.
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Atitude , Pais , Estudos Transversais , Tomada de Decisões , Humanos , Masculino , Motivação , Pais/psicologia , Inquéritos e QuestionáriosRESUMO
PURPOSE: The aim of this study was to determine how attitudes toward the return of genomic research results vary internationally. METHODS: We analyzed the "Your DNA, Your Say" online survey of public perspectives on genomic data sharing including responses from 36,268 individuals across 22 low-, middle-, and high-income countries, and these were gathered in 15 languages. We analyzed how participants responded when asked whether return of results (RoR) would motivate their decision to donate DNA or health data. We examined variation across the study countries and compared the responses of participants from other countries with those from the United States, which has been the subject of the majority of research on return of genomic results to date. RESULTS: There was substantial variation in the extent to which respondents reported being influenced by RoR. However, only respondents from Russia were more influenced than those from the United States, and respondents from 20 countries had lower odds of being partially or wholly influenced than those from the United States. CONCLUSION: There is substantial international variation in the extent to which the RoR may motivate people's intent to donate DNA or health data. The United States may not be a clear indicator of global attitudes. Participants' preferences for return of genomic results globally should be considered.
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Atitude , Genômica , DNA , Genômica/métodos , Humanos , Intenção , Inquéritos e Questionários , Estados UnidosRESUMO
AIMS: Neuromuscular diseases are rare conditions that present with progressive muscular weakness. As affected children transition into adulthood, they become more physically dependent on their families for support. There is little evidence on the family transition experience, which this study explored to identify experiences, challenges, and strategies of coping. DESIGN: Informed by family systems theory, a constructivist grounded theory study was conducted (2014-2017). METHODS: Data were collected by one-on-one interviews with a purposive sample of affected Swiss individuals and their families from 2015 to 2016. Data analysis used coding, memo writing, theoretical sampling, and constant comparison techniques. RESULTS: The analysis of 31 interviews with 10 affected individuals and 21 family members resulted in an interpretive theory constituted of four categories: (a) living with physical dependence, while striving for independence; (b) balancing proximity; (c) conforming and challenging social standards and expectations; and (d) grieving for loss, while joining forces for life. CONCLUSION: Family functioning and well-being were threatened by recurring tension from stress, physical and emotional difficulties, strained relationships, and conflict. The families' strategies of coping and adaptation and their relationships and communication shaped their transition experience. IMPACT: Families that experience threats to their well-being and functioning would benefit from: needs assessment and monitoring; planning of appropriate family interventions; support of family relationships and communication, effective coping, and mastery; and positive adaptation to change.
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Família , Doenças Neuromusculares , Adaptação Psicológica , Adulto , Criança , Teoria Fundamentada , Humanos , Relações Profissional-FamíliaRESUMO
PURPOSE: The changes needed to accelerate integration of genomics across nursing are complex, with significant challenges faced globally. Common themes lend themselves to a coordinated and collaborative strategic approach to sustained change. We aim to synthesize the outputs of a research program to present a roadmap for nursing leadership to guide integration of genomics across practice. DESIGN: Mixed methods involving a purposive sample of global nursing leaders and nursing organizations in a sustained, highly interactive program. METHODS: Experts in nursing, health care and healthcare services, policy, and leadership were recruited. Online surveys preceded a 3-day residential meeting utilizing participatory methods and techniques to gain consensus on the essential elements of a roadmap to promote genomics integration. FINDINGS: Twenty-three leaders representing 19 countries and seven organizations participated overall. Data on the scope and status of nursing, genomics health care, and resources have been synthesized. Participants identified 117 facilitators to genomics integration across diverse sources. Barriers and priorities identified were mapped to the constructs of the Consolidated Framework for Implementation Research. The roadmap is underpinned by a maturity matrix created by participants to guide and benchmark progress in genomics integration. CONCLUSIONS: Nurse leaders seeking to accelerate change can access practical guidance with the roadmap, underpinned by support through the Global Genomics Nursing Alliance and its strategic priorities. CLINICAL RELEVANCE: Genomics is shaping the future of healthcare, but change is needed for integration across nursing. This practical roadmap, adaptable to local health systems and clinical and educational contexts, is relevant to nurse leaders aiming to accelerate change.
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Genômica/organização & administração , Enfermagem/organização & administração , Humanos , Internacionalidade , LiderançaRESUMO
PURPOSE: Nurse leaders driving strategic integration of genomics across nursing need tools and resources to evaluate their environment, guide strategies to address deficits, and benchmark progress. We describe the development and pilot testing of a self-assessment maturity matrix (MM) that enables users to benchmark the current state of nursing genomic competency and integration for their country or nursing group; guides the development of a strategic course for improvement and implementation; and assesses change over time. DESIGN: Mixed-methods participatory research and self-assessment. METHODS: During a 3-day workshop involving nursing experts in health care and genomics, a genomic integration MM grid was built by consensus using iterative participatory methods. Data were analyzed using descriptive techniques. This work built on an online survey involving the same participants to identify the critical elements needed for "effective nursing which promotes health outcomes globally through genomics." FINDINGS: Experts from 19 countries across six continents and seven organizations participated in item development. The Assessment of Strategic Integration of Genomics across Nursing (ASIGN) MM incorporates 55 outcome-focused items serving as subscales for six critical success factors (CSFs): education and workforce; effective nursing practice; infrastructure and resources; collaboration and communication; public/patient involvement; policy and leadership. Users select their current circumstances for each item against a 5-point ordinal scale (precontemplation to leading). Nurses representing 17 countries undertook matrix pilot testing. Results demonstrate variation across CSFs, with many countries at the earliest stages of implementation. CONCLUSIONS: The MM has the potential to guide the strategic integration of genomics across nursing and enables additional assessments within and between countries to be made. CLINICAL RELEVANCE: Nurse leadership and direction are essential to accelerate integration of genomics across nursing practice and education. The MM helps nurse leaders to benchmark progress and guide strategic planning to build global genomic nursing capacity.
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Benchmarking/métodos , Atenção à Saúde/organização & administração , Genômica , Política de Saúde , Enfermeiros Administradores/psicologia , Genômica/educação , HumanosRESUMO
PURPOSE: Little is known about how health-care professionals communicate with patients about consenting to genome sequencing. We therefore examined what topics health-care professionals covered and what questions patients asked during consent conversations. METHODS: Twenty-one genome sequencing consent appointments were audio recorded and analyzed. Participants were 35 individuals being invited to participate in the 100,000 Genomes Project (14 participants with rare diseases, 21 relatives), and 10 health-care professionals ("consenters"). RESULTS: Two-thirds of participants' questions were substantive (e.g., genetics and inheritance); one-third administrative (e.g., filling in the consent form). Consenters usually (19/21) emphasized participant choice about secondary findings, but less often (13/21) emphasized the uncertainty about associated disease risks. Consenters primarily used passive statements and closed-ended, rather than open-ended, questions to invite participants' questions and concerns. In two appointments, one parent expressed negative or uncertain views about secondary findings, but after discussion with the other parent opted to receive them. CONCLUSION: Health-care professionals need to be prepared to answer patients' questions about genetics to facilitate genome sequencing consent. Health-care professionals' education also needs to address how to effectively listen and elicit each patient's questions and views, and how to discuss uncertainty around the disease risks associated with secondary findings.
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Consentimento Livre e Esclarecido/ética , Sequenciamento Completo do Genoma/ética , Adulto , Idoso , Comunicação , Termos de Consentimento/ética , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde , Humanos , Consentimento Livre e Esclarecido/normas , Masculino , Pessoa de Meia-Idade , Pais , Pacientes , Sequenciamento Completo do Genoma/métodosRESUMO
Genome sequencing (GS) is increasingly being used to diagnose rare diseases in paediatric patients; however, no measures exist to evaluate their knowledge of this technology. We aimed to develop a robust measure of knowledge of GS (the kids-KOGS') suitable for use in the paediatric setting as well as for general public education. The target age was 11 to 15 year olds. An iterative process involving six sequential stages was conducted to develop a set of draft true/false items. These were then administered to 539 target-age school pupils (mean 12.8; SD ± 1.3), from the United Kingdom. Item-response theory was used to confirm the psychometric suitability of the candidate items. None of the Items was identified as misfits. All 10 items performed well under the two-parameter logistic model. The internal consistency of the test was 0.84 (Cronbach alpha value) indicating excellent reliability. The mean kids-KOGS score in the sample overall was 4.24 (SD; 2.49), where 0 = low knowledge and 10 = high knowledge. Age was positively associated with score in a multivariate linear regression. The kids-KOGS is a short and reliable tool that can be used by researchers and healthcare professionals offering GS to paediatric patients. Further validation in a clinical setting is required.
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Pediatria , Doenças Raras/genética , Sequenciamento Completo do Genoma , Adolescente , Criança , Feminino , Humanos , Modelos Lineares , Masculino , Análise Multivariada , Doenças Raras/diagnóstico , Doenças Raras/epidemiologia , Doenças Raras/patologia , Reino Unido/epidemiologiaRESUMO
Background: Genomic technology can now deliver cost effective, targeted diagnosis and treatment for patients. Genetic counselling is a communication process empowering patients and families to make autonomous decisions and effectively use new genetic information. The skills of genetic counselling and expertise of genetic counsellors are integral to the effective implementation of genomic medicine. Sources of data: Original papers, reviews, guidelines, policy papers and web-resources. Areas of agreement: An international consensus on the definition of genetic counselling. Genetic counselling is necessary for implementation of genomic medicine. Areas of controversy: Models of genetic counselling. Growing points: Genomic medicine is a growing and strategic priority for many health care systems. Genetic counselling is part of this. Areas timely for developing research: An evidence base is necessary, incorporating implementation and outcome research, to enable health care systems, practitioners, patients and families to maximize the utility (medically and psychologically) of the new genomic possibilities.
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Aconselhamento Genético , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Pesquisa Biomédica , Tomada de Decisões , Aconselhamento Genético/métodos , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/psicologia , Humanos , Educação de Pacientes como AssuntoRESUMO
BACKGROUND: An increasing number of genetic causes of intellectual disabilities (ID) are identifiable by clinical genetic testing, offering the prospect of bespoke patient management. However, little is known about the practices of psychiatrists and their views on genetic testing. METHOD: We undertook an online survey of 215 psychiatrists, who were contacted via the Royal College of Psychiatrist's Child and Adolescent and Intellectual Disability Psychiatry mailing lists. RESULTS: In comparison with child and adolescent psychiatrists, intellectual disability psychiatrists ordered more genetic tests, referred more patients to genetic services, and were overall more confident in the genetic testing process. Respondents tended to agree that genetic diagnoses can help patient management; however, management changes were infrequently found in clinical practice. CONCLUSIONS: Differences are apparent in the existing views and practices of child and adolescent and intellectual disability psychiatrists. Developing training and collaboration with colleagues working in genetic services could help to reduce discrepancies and improve clinical practice.
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Atitude do Pessoal de Saúde , Testes Genéticos , Deficiência Intelectual/diagnóstico , Padrões de Prática Médica , Adolescente , Criança , Pesquisas sobre Atenção à Saúde , Humanos , Deficiência Intelectual/genética , Psiquiatria , Reino UnidoRESUMO
Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.
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Cromossomos Humanos Par 2/genética , Deficiências do Desenvolvimento/genética , Transtornos Mentais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Duplicação Cromossômica , Variações do Número de Cópias de DNA/genética , Feminino , Duplicação Gênica/genética , Humanos , Deficiência Intelectual/genética , Masculino , Fenótipo , Reino UnidoRESUMO
Innovations in clinical genetics have increased diagnosis, treatment and prognosis of inherited genetic conditions (IGCs). This has led to an increased number of families seeking genetic testing and / or genetic counselling and increased the clinical load for genetic counsellors (GCs). Keeping pace with biomedical discoveries, interventions are required to support families to understand, communicate and cope with their Inherited Genetic Condition. The Socio-Psychological Research in Genomics (SPRinG) collaborative have developed a new intervention, based on multi-family discussion groups (MFDGs), to support families affected by IGCs and train GCs in its delivery. A potential challenge to implementing the intervention was whether GCs were willing and able to undergo the training to deliver the MFDG. In analysing three multi-perspective interviews with GCs, this paper evaluates the training received. Findings suggests that MFDGs are a potential valuable resource in supporting families to communicate genetic risk information and can enhance family function and emotional well-being. Furthermore, we demonstrate that it is feasible to train GCs in the delivery of the intervention and that it has the potential to be integrated into clinical practice. Its longer term implementation into routine clinical practice however relies on changes in both organisation of clinical genetics services and genetic counsellors' professional development.
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Conselheiros/educação , Educação Médica/normas , Família , Aconselhamento Genético/métodos , Doenças Genéticas Inatas , Feminino , HumanosAssuntos
Responsabilidade pela Informação/legislação & jurisprudência , Aconselhamento Genético/legislação & jurisprudência , Doenças Genéticas Inatas/genética , Papel do Médico , Confidencialidade/legislação & jurisprudência , Responsabilidade pela Informação/ética , Inglaterra , Ética Médica , Aconselhamento Genético/ética , Predisposição Genética para Doença/genética , Humanos , Responsabilidade Legal , Opinião Pública , Medicina Estatal/ética , Medicina Estatal/legislação & jurisprudênciaRESUMO
This is the protocol for a review and there is no abstract. The objectives are as follows. PRIMARY OBJECTIVE: The primary objective is to assess the effectiveness of interventions to improve patient identification, access to and utilisation of genetic and genomic counselling services when compared to: No intervention;Usual or current practice; andOther active intervention. SECONDARY OBJECTIVE: The secondary objective is to explore the resource use and costs associated with interventions aimed at improving patient identification, access to and utilisation of genetic and genomic counselling services from studies meeting the eligibility criteria. We will report on factors that may explain variation in the effectiveness of interventions aimed at improving patient identification, access to and utilisation of genetic and genomic counselling services from studies meeting the eligibility criteria. Another secondary objective is to explore how interventions which target improved patient identification, access to and utilisation of genetic and genomic counselling services affect the subsequent appropriate use of health services for the prevention or early detection of disease. It is also possible that the genetic counselling interaction itself will contribute to the possible use of preventative services.