Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.Radiolog

The genetic overlap between Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease

Neurodegenerative diseases are a group of disorders characterized by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterized by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. The majority of previous genetic evidence for overlap between neurodegenerative diseases has been pairwise. In this study, we aimed to identify overlap between the 4 investigated neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between 3 or more diseases. Using local genetic correlation, we found 2 loci (TMEM175 and HLA) that were shared across 3 disorders. We also highlighted genes, genomic loci, gene sets, cell types, and tissue types which may be important to 2 or more disorders by analyzing the association of variants with a common factor estimated from the 4 disorders. Our study successfully highlighted genetic loci and tissues associated with 2 or more neurodegenerative diseases

Associated Genetics and Connectomic Circuitry in Schizophrenia and Bipolar Disorder

Background: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions that can involve symptoms of psychosis and cognitive dysfunction. The 2 conditions share symptomatology and genetic etiology and are regularly hypothesized to share underlying neuropathology. Here, we examined how genetic liability to SCZ and BD shapes normative variations in brain connectivity. Methods: We examined the effect of the combined genetic liability for SCZ and BD on brain connectivity from two perspectives. First, we examined the association between polygenic scores for SCZ and BD for 19,778 healthy subjects from the UK Biobank and individual variation in brain structural connectivity reconstructed by means of diffusion weighted imaging data. Second, we conducted genome-wide association studies using genotypic and imaging data from the UK Biobank, taking SCZ-/BD-involved brain circuits as phenotypes of interest. Results: Our findings showed brain circuits of superior parietal and posterior cingulate regions to be associated with polygenic liability for SCZ and BD, circuitry that overlaps with brain networks involved in disease conditions (r = 0.239, p <.001). Genome-wide association study analysis showed 9 significant genomic loci associated with SCZ-involved circuits and 14 loci associated with BD-involved circuits. Genes related to SCZ-/BD-involved circuits were significantly enriched in gene sets previously reported in genome-wide association studies for SCZ and BD. Conclusions: Our findings suggest that polygenic liability of SCZ and BD is associated with normative individual variation in brain circuitry

The genetic architectures of functional and structural connectivity properties within cerebral resting-state networks

Functional connectivity within resting-state networks (RSN-FC) is vital for cognitive functioning. RSN-FC is heritable and partially translates to the anatomical architecture of white matter, but the genetic component of structural connections of RSNs (RSN-SC) and their potential genetic overlap with RSN-FC remain unknown. Here we perform genome-wide association studies (Ndiscovery=24,336; Nreplication=3,412) and annotation on RSN-SC and RSN-FC. We identify genes for visual network-SC that are involved in axon guidance and synaptic functioning. Genetic variation in RSN-FC impacts biological processes relevant to brain disorders that previously were only phenotypically associated with RSN-FC alterations. Correlations of the genetic components of RSNs are mostly observed within the functional domain, whereas less overlap is observed within the structural domain and between the functional and structural domains. This study advances the understanding of the complex functional organization of the brain and its structural underpinnings from a genetics viewpoint.Significance StatementBrain regions with synchronized activity can be clustered into distinct networks. We investigate which genetic effects contribute to structural and functional connectivity within seven networks and assess their degree of shared genetic signal. Multiple genetic effects are identified and highlight relevant biological processes for brain connectivity and brain disorders related to the networks. Overlap between the genetics of network connectivity is mostly observed within the functional domain. These results advance our biological understanding of the complex functional organisation of the brain and its structural underpinnings, and their relevance for the genetics of neuropsychiatry

Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

A genome-wide association study on MRI cerebellar volume in the UK Biobank cohort identifies 30 loci with genome-wide significance that might be relevant to brain structure and cognitive function

Associated Genetics and Connectomic Circuitry in Schizophrenia and Bipolar Disorder

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions that can involve symptoms of psychosis and cognitive dysfunction. The 2 conditions share symptomatology and genetic etiology and are regularly hypothesized to share underlying neuropathology. Here, we examined how genetic liability to SCZ and BD shapes normative variations in brain connectivity. METHODS: We examined the effect of the combined genetic liability for SCZ and BD on brain connectivity from two perspectives. First, we examined the association between polygenic scores for SCZ and BD for 19,778 healthy subjects from the UK Biobank and individual variation in brain structural connectivity reconstructed by means of diffusion weighted imaging data. Second, we conducted genome-wide association studies using genotypic and imaging data from the UK Biobank, taking SCZ-/BD-involved brain circuits as phenotypes of interest. RESULTS: Our findings showed brain circuits of superior parietal and posterior cingulate regions to be associated with polygenic liability for SCZ and BD, circuitry that overlaps with brain networks involved in disease conditions (r = 0.239, p < .001). Genome-wide association study analysis showed 9 significant genomic loci associated with SCZ-involved circuits and 14 loci associated with BD-involved circuits. Genes related to SCZ-/BD-involved circuits were significantly enriched in gene sets previously reported in genome-wide association studies for SCZ and BD. CONCLUSIONS: Our findings suggest that polygenic liability of SCZ and BD is associated with normative individual variation in brain circuitry

Profiling of Patients with COPD for Adequate Referral to Exercise-Based Care: The Dutch Model

A loss of physical functioning (i.e., a low physical capacity and/or a low physical activity) is a common feature in patients with chronic obstructive pulmonary disease (COPD). To date, the primary care physiotherapy and specialized pulmonary rehabilitation are clearly underused, and limited to patients with a moderate to very severe degree of airflow limitation (GOLD stage 2 or higher). However, improved referral rates are a necessity to lower the burden for patients with COPD and for society. Therefore, a multidisciplinary group of healthcare professionals and scientists proposes a new model for referral of patients with COPD to the right type of exercise-based care, irrespective of the degree of airflow limitation. Indeed, disease instability (recent hospitalization, yes/no), the burden of disease (no/low, mild/moderate or high), physical capacity (low or preserved) and physical activity (low or preserved) need to be used to allocate patients to one of the six distinct patient profiles. Patients with profile 1 or 2 will not be referred for physiotherapy; patients with profiles 3-5 will be referred for primary care physiotherapy; and patients with profile 6 will be referred for screening for specialized pulmonary rehabilitation. The proposed Dutch model has the intention to get the right patient with COPD allocated to the right type of exercise-based care and at the right moment

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien–Dindo classification system. Results: A total of 3288 patients were included in the analysis, of whom 301 (9·2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4–7) and 7 (6–8) days respectively (P &lt; 0·001). There were no significant differences in rates of readmission between these groups (6·6 versus 8·0 per cent; P = 0·499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0·90, 95 per cent c.i. 0·55 to 1·46; P = 0·659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34·7 versus 39·5 per cent; major 3·3 versus 3·4 per cent; P = 0·110). Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system. Results A total of 3288 patients were included in the analysis, of whom 301 (9 center dot 2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P &lt; 0 center dot 001). There were no significant differences in rates of readmission between these groups (6 center dot 6 versus 8 center dot 0 per cent; P = 0 center dot 499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0 center dot 90, 95 per cent c.i. 0 center dot 55 to 1 center dot 46; P = 0 center dot 659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34 center dot 7 versus 39 center dot 5 per cent; major 3 center dot 3 versus 3 center dot 4 per cent; P = 0 center dot 110). Conclusion Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients