An atlas of genetic variation for linking pathogen-induced cellular traits to human disease

SummaryGenome-wide association studies (GWAS) have identified thousands of genetic variants associated with disease. To facilitate moving from associations to disease mechanisms, we leveraged the role of pathogens in shaping human evolution with the Hi-HOST Phenome Project (H2P2): a catalog of cellular GWAS comprised of 79 phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance (p<5×10−8) for phenotypes ranging from pathogen replication to cytokine production. Combining H2P2 with clinical association data from the eMERGE Network and experimental validation revealed evidence for mechanisms of action and connections with diseases. We identified a SNP near CXCL10 as a cis-cytokine-QTL and a new risk factor for inflammatory bowel disease. A SNP in ZBTB20 demonstrated pleiotropy, partially mediated through NFκB signaling, and was associated with viral hepatitis. Data are available in an H2P2 web portal to facilitate further interpreting human genome variation through the lens of cell biology.

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The Genetics of Spondyloarthritis

Journal of Personalized Medicine ◽

10.3390/jpm10040151 ◽

2020 ◽

Vol 10 (4) ◽

pp. 151

Author(s):

Roberto Díaz-Peña ◽

Patricia Castro-Santos ◽

Josefina Durán ◽

Catalina Santiago ◽

Alejandro Lucia

Keyword(s):

Complex Disease ◽

Inflammatory Diseases ◽

Association Studies ◽

Human Leukocyte ◽

Genome Wide Association Studies ◽

Leukocyte Antigen ◽

Genome Wide ◽

Inflammatory Bowel ◽

New Treatment

The term spondyloarthritis (SpA) encompasses a group of chronic inflammatory diseases with common features in terms of clinical presentation and genetic predisposition. SpA is characterized by inflammation of the spine and peripheral joints, and is also be associated with extra-articular inflammatory manifestations such as psoriasis, uveitis, or inflammatory bowel disease (IBD). The etiology of SpA is not completely understood, but it is known to have a strong genetic component dominated by the human leukocyte antigen (HLA)-B27. In the last few years, our understanding of genetic susceptibility to SpA, particularly ankylosing spondylitis (AS), has greatly improved thanks to the findings derived from powered genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) arrays. These studies have identified many candidate genes, therefore providing new potential directions in the exploration of disease mechanisms, especially with regard to the key role of the immune system in the pathogenesis of SpA. SpA is a complex disease where genetic variability, environmental factors, and random events interact to trigger pathological pathways. The aim of this review is to summarize current findings on the genetics of SpA, some of which might help to study new treatment approaches.

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Genetic Determinants of Paget’s Disease of Bone

Current Osteoporosis Reports ◽

10.1007/s11914-021-00676-w ◽

2021 ◽

Author(s):

Navnit S. Makaram ◽

Stuart H. Ralston

Keyword(s):

Genetic Factors ◽

Association Studies ◽

Paget’S Disease ◽

Paget's Disease ◽

Paget’S Disease Of Bone ◽

Genome Wide Association Studies ◽

Paget's Disease Of Bone ◽

Genome Wide ◽

Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

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Enteric Viruses and Inflammatory Bowel Disease

Viruses ◽

10.3390/v13010104 ◽

2021 ◽

Vol 13 (1) ◽

pp. 104

Author(s):

Georges Tarris ◽

Alexis de Rougemont ◽

Maëva Charkaoui ◽

Christophe Michiels ◽

Laurent Martin ◽

...

Keyword(s):

Association Studies ◽

Enteric Viruses ◽

Enteric Virus ◽

Viral Gastroenteritis ◽

Blood Group Antigens ◽

Genome Wide Association Studies ◽

Virus Infections ◽

T Helper ◽

Inflammatory Bowel

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the FUT2 and FUT3 genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.

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Very early onset inflammatory bowel disease (VEO-IBD); spectrum of clinical presentation, diagnostic tools and outcome in children

Journal of the Pakistan Medical Association ◽

10.47391/jpma.05-725 ◽

2021 ◽

Vol 71 (10) ◽

pp. 2350-2354

Author(s):

Huma Arshad Cheema ◽

Nadia Waheed ◽

Anjum Saeed ◽

Zafar Fayyaz ◽

Muhammad Nadeem Anjum ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Early Onset ◽

Clinical Presentation ◽

Association Studies ◽

Diagnostic Tools ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Basic Work ◽

Inflammatory Bowel

Background: Very early-onset inflammatory bowel disease (VEO-IBD) is defined as diagnosis of Ulcerative Colitis (UC) or Crohn’s Disease (CD) in children under six years of age. Genome wide association studies have linked a strong genetic component responsible for VEO-IBD. Approximately, 30-40% children of VEO-IBD have underlying immunodeficiency states. We aimed to study the spectrum of presentation, underlying monogenetic defects and outcome in VEO-IBD. Methods: This is a prospective, observational study conducted at division of Gastroenterology, the Children's Hospital & the Institute of Child Health, Lahore, over 2 years. Children developing features of IBD under six-years of age were included. Data included demography, clinical presentation, diagnostic tools and outcome. Gastroscopy and colonoscopy were performed in all patients in addition to basic work up done for associatedimmunodeficiency states and molecular genetics. SPSS version 21 was used for analysis. Continuous...

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Stroke Genetics: Turning Discoveries into Clinical Applications

Stroke ◽

10.1161/strokeaha.121.032616 ◽

2021 ◽

Author(s):

Martin Dichgans ◽

Nathalie Beaufort ◽

Stephanie Debette ◽

Christopher D. Anderson

Keyword(s):

Mendelian Randomization ◽

Association Studies ◽

Clinical Applications ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Neuroprotective Agents ◽

Experimental Systems ◽

Genome Wide ◽

Rapid Pace

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

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Current knowledge in hypertension genetics: mosaic theory, candidate genes and genome-wide association studies

Arterial’naya Gipertenziya (Arterial Hypertension) ◽

10.18705/1607-419x-2020-26-5-490-500 ◽

2020 ◽

Vol 26 (5) ◽

pp. 490-500

Author(s):

A. O. Konradi

Keyword(s):

Candidate Genes ◽

High Performance ◽

New Technologies ◽

Current Knowledge ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Modern Approach ◽

Genome Wide

The article reviews monogenic forms of hypertension, data on the role of heredity of essential hypertension and candidate genes, as well as genome-wide association studies. Modern approach for the role of genetics is driven by implementation of new technologies and their productivity. High performance speed of new technologies like genome-wide association studies provide data for better knowledge of genetic markers of hypertension. The major goal nowadays for research is to reveal molecular pathways of blood pressure regulation, which can help to move from populational to individual level of understanding of pathogenesis and treatment targets.

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Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE

Clinical Science ◽

10.1042/cs20201033 ◽

2021 ◽

Vol 135 (15) ◽

pp. 1929-1944

Author(s):

Ezekiel Gonzalez-Fernandez ◽

Yedan Liu ◽

Alexander P. Auchus ◽

Fan Fan ◽

Richard J. Roman

Keyword(s):

Cognitive Impairment ◽

Association Studies ◽

Amyloid Β ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Cerebrovascular Risk ◽

Potent Vasoconstrictor ◽

Multiple Drugs ◽

Epidemiology Studies

Abstract The accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer’s disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aβ or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aβ or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood–brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.

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Heritability jointly explained by host genotype and microbiome: will improve traits prediction?

Briefings in Bioinformatics ◽

10.1093/bib/bbaa175 ◽

2020 ◽

Author(s):

Denis Awany ◽

Emile R Chimusa

Keyword(s):

Genetic Variants ◽

Association Studies ◽

Heritability Estimate ◽

Substantial Part ◽

Phenotypic Variance ◽

Genome Wide Association Studies ◽

Host Genotype ◽

Genome Wide ◽

Heritability Estimation

Abstract As we observe the $70$th anniversary of the publication by Robertson that formalized the notion of ‘heritability’, geneticists remain puzzled by the problem of missing/hidden heritability, where heritability estimates from genome-wide association studies (GWASs) fall short of that from twin-based studies. Many possible explanations have been offered for this discrepancy, including existence of genetic variants poorly captured by existing arrays, dominance, epistasis and unaccounted-for environmental factors; albeit these remain controversial. We believe a substantial part of this problem could be solved or better understood by incorporating the host’s microbiota information in the GWAS model for heritability estimation and may also increase human traits prediction for clinical utility. This is because, despite empirical observations such as (i) the intimate role of the microbiome in many complex human phenotypes, (ii) the overlap between genetic variants associated with both microbiome attributes and complex diseases and (iii) the existence of heritable bacterial taxa, current GWAS models for heritability estimate do not take into account the contributory role of the microbiome. Furthermore, heritability estimate from twin-based studies does not discern microbiome component of the observed total phenotypic variance. Here, we summarize the concept of heritability in GWAS and microbiome-wide association studies, focusing on its estimation, from a statistical genetics perspective. We then discuss a possible statistical method to incorporate the microbiome in the estimation of heritability in host GWAS.

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GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications

Pharmacogenomics ◽

10.2217/pgs-2019-0054 ◽

2019 ◽

Vol 20 (10) ◽

pp. 765-780 ◽

Cited By ~ 1

Author(s):

Diana Cruz ◽

Ricardo Pinto ◽

Margarida Freitas-Silva ◽

José Pedro Nunes ◽

Rui Medeiros

Keyword(s):

Atrial Fibrillation ◽

Genetic Variants ◽

Complex Traits ◽

Association Studies ◽

Cardioembolic Stroke ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Genetic Determinants ◽

Genome Wide ◽

Genome Wide Significance

Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

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Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

Journal of Clinical Medicine ◽

10.3390/jcm9041096 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1096

Author(s):

Jessica Gambardella ◽

Angela Lombardi ◽

Marco Bruno Morelli ◽

John Ferrara ◽

Gaetano Santulli

Keyword(s):

Human Disease ◽

Calcium Release ◽

Current Knowledge ◽

Association Studies ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genome Wide ◽

Inositol 1,4,5 Trisphosphate ◽

Human Disorders

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.

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