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    9 research outputs found

    Understanding Pathophysiology of Nonsyndromic Autism by Examining and Extrapolating from Syndromic Variants

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    Autism spectrum disorder (ASD) is a broad, heterogeneous neurodevelopmental disorder encompassing a range of presentation and severity. The common characteristics include communication deficits, impaired social skills, dependency on routine, sensitivity to environmental change, and stereotyped behavior (DSM-5, 2013). When ASD is accompanied by a host of other symptoms it is often referred to as syndromic autism. Syndromic autism is usually severe and can usually be traced to deletions or duplications on a specific gene. These monogenic disorders are by definition easier to diagnose and are good candidates for study since specific biological markers can be assessed and tracked. There have been many discoveries about monogenic autism which help provide insight into the mechanisms of disease. Nonsyndromic autism (also called idiopathic autism) is defined by the absence of additional symptoms or underlying syndromes. Although nonsyndromic autism is far more common and often manifests in a milder form of the disorder, the genes and proteins involved are much more difficult to nail down, and therapeutics are harder to discover. Family and twin studies have provided evidence that the majority of cases are due to common genetic variation (Gaugler et al., 2014). Shifting the focus to syndromic autism has been a critical step in understanding the disease process that underlies the different manifestations of ASD. This is the key to solving the complex web of common genetic variants implicated in nonsyndromic autism. Keywords: Autism, ASD, monogenic, syndromic, common variants, loss of function
    The Touro College and University System

    Parkinson’s Disease: Causes, Symptoms, Research, and Interventions

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    This paper covers several pathogenic theories of Parkinson’s disease (PD); the physiology and biological pathways involved. This includes a mitochondrial DNA (mtDNA) route, a nuclear DNA route, and other hypotheses about idiopathic PD. The subsequent discussion of PD symptoms utilizes a neurological perspective, analyzing the neuroanatomical systems involved, and how they are treated. This includes medications and surgical techniques that are employed in an effort to manage symptomatology and increase health-related quality of life
    The Touro College and University System

    Lipoprotein(A): A Review of Risk Factors, Measurements, and Novel Treatment Modalities

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    The study of lipoprotein(a) [Lp(a)] has long been a source of interest as a possible independent risk factor for atherosclerotic cardiovascular disease (ASCVD). The results of large sample observational studies, genome-wide association studies, and Mendelian randomization studies have been strong indicators supporting the link between ASCVD and Lp(a) despite early studies, with less sensitive assays, failing to show a connection. The recommendations for the indications and frequency of testing Lp(a) levels vary between US, Canadian, and European organizations due to the uncertain role of Lp(a) in ASCVD. The innovation of recent therapies, such as antisense oligonucleotides and small interfering RNA, designed to specifically target and reduce Lp(a) levels by targeting mRNA translation have once more thrust LP(a) into the spotlight of inquiry. These emerging modalities serve the dual purpose of definitively elucidating the connection between elevated Lp(a) levels and atherosclerotic cardiovascular risk, as well as the possibility of providing clinicians with the tools necessary to manage elevated Lp(a) levels in vulnerable populations. This review seeks to examine the mechanisms of atherogenicity of Lp(a) and explore the most current pharmacologic therapies currently in development
    The Touro College and University System

    SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

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    Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types. © 2021 The Author(s
    Archivio della Ricerca - Università degli Studi di Siena
    Archivio istituzionale della ricerca - Università di Brescia

    A first update on mapping the human genetic architecture of COVID-19

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    peer reviewe
    Archivio della ricerca - Università degli studi di Napoli Federico II
    Crossref
    Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna
    Open Repository and Bibliography - Liège
    IRIS Università degli Studi dell'Aquila

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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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
    IRIS Università degli Studi dell'Aquila

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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
    Archivio della ricerca - Università degli studi di Napoli Federico II
    Diposit Digital de Documents de la UAB

    A first update on mapping the human genetic architecture of COVID-19

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    COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

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    The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p
    The Francis Crick Institute
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