scholarly journals Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaomi Du ◽  
Natalie DeForest ◽  
Amit R. Majithia
Keyword(s):  
Human Genetics ◽  
Target Identification ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Diagnostic Methods ◽  
Genetic Associations ◽  
Alcoholic Fatty Liver ◽  
Diagnostic Measures ◽  
Challenges And Opportunities ◽  
Continuous Progression

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.

scholarly journals Genetics and genomics of human ageing

2011 ◽  
Vol 366 (1561) ◽  
pp. 43-50 ◽  
Author(s):  
Heather E. Wheeler ◽  
Stuart K. Kim
Keyword(s):  
Human Genetics ◽  
Association Studies ◽  
Transcriptional Profiling ◽  
Genetic Association Studies ◽  
Human Kidney ◽  
Age Related ◽  
Quantitative Trait Mapping ◽  
Human Ageing ◽  
Probability Of Death ◽  
Genomic Convergence

Ageing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death. Some individuals delay, escape or survive much of this age-related decline and live past age 100. Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3 , which have been replicated many times. However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations. Therefore, ageing is probably a highly polygenic trait. In humans, it is important to also consider differences in age-related decline that occur within and among tissues. Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time. Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing. Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association. The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing. New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.

scholarly journals Leveraging pleiotropy to discover and interpret GWAS results for sleep-associated traits

2019 ◽  
Author(s):  
Sebastian Akle ◽  
Sung Chun ◽  
Athanasios Teodosiadis ◽  
Brian E. Cade ◽  
Heming Wang ◽  
...  
Keyword(s):  
Statistical Power ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Genetic Associations ◽  
Genome Wide ◽  
Obstructive Sleep ◽  
A Chain ◽  
The Cost ◽  
Underlying Pathophysiology ◽  
Insight Into

AbstractGenetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and invasiveness of the required phenotyping. This reduces statistical power to discover multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology, using obstructive sleep apnea (OSA) as an exemplar. OSA is a common disorder diagnosed via overnight physiological testing (polysomnography). Here, we leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of diverse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For example we find links between OSA, a measure of lung function (FEV1/FVC), and an eQTL of desmoplakin (DSP) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase (HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble diverse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases.

scholarly journals Carotid Artery Atherosclerosis: A Review on Heritability and Genetics

2018 ◽  
Vol 21 (5) ◽  
pp. 333-346 ◽  
Author(s):  
Bianka Forgo ◽  
Emanuela Medda ◽  
Anita Hernyes ◽  
Laszlo Szalontai ◽  
David Laszlo Tarnoki ◽  
...  
Keyword(s):  
Association Studies ◽  
Genetic Association Studies ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Phenotypic Variance ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Carotid Artery Atherosclerosis ◽  
Meta Analyses

Carotid atherosclerosis (CAS) is associated with increased cardiovascular risk, and therefore, assessing the genetic versus environmental background of CAS traits is of key importance. Carotid intima-media-thickness and plaque characteristics seem to be moderately heritable, with remarkable differences in both heritability and presence or severity of these traits among ethnicities. Although the considerable role of additive genetic effects is obvious, based on the results so far, there is an important emphasis on non-shared environmental factors as well. We aimed to collect and summarize the papers that investigate twin and family studies assessing the phenotypic variance attributable to genetic associations with CAS. Genes in relation to CAS markers were overviewed with a focus on genetic association studies and genome-wide association studies. Although the role of certain genes is confirmed by studies conducted on large populations and meta-analyses, many of them show conflicting results. A great focus should be on future studies elucidating the exact pathomechanism of these genes in CAS in order to imply them as novel therapeutic targets.

scholarly journals Field synopsis and systematic meta-analyses of genetic association studies in isolated dystonia

2018 ◽  
Author(s):  
Olena Ohlei ◽  
Valerija Dobricic ◽  
Katja Lohmann ◽  
Christine Klein ◽  
Christina Lill ◽  
...  
Keyword(s):  
Genetic Association ◽  
Large Scale ◽  
Complex Disease ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Sufficient Information ◽  
Genetic Associations ◽  
Pubmed Database ◽  
The Status ◽  
Meta Analyses

AbstractBackground and objectivesDystonia is a genetically complex disease with both monogenic and polygenic causes. For the latter, numerous genetic associations studies have been performed with largely inconsistent results. The aim of this study was to perform a field synopsis including systematic meta-analyses of genetic association studies in isolated dystoniaMethodsFor the field synopsis we systematically screened and scrutinized the published literature using NCBI’s PubMed database. For genetic variants with sufficient information in at least two independent datasets, random-effects meta-analyses were performed, including meta-analyses stratified by ethnic descent and dystonia subtypes.ResultsA total of 3,575 articles were identified and scrutinized resulting in the inclusion of 42 independent publications allowing 134 meta-analyses on 45 variants across 17 genes. While our meta-analyses pinpointed several significant association signals with variants in TOR1A, DRD1, and ARSG, no single variant displayed compelling association with dystonia in the available data.ConclusionsOur study provides an up-to-date summary of the status of dystonia genetic association studies. Additional large-scale studies are needed to better understand the genetic causes of isolated dystonia.

scholarly journals XGMix: Local-Ancestry Inference with Stacked XGBoost

2020 ◽  
Author(s):  
Arvind Kumar ◽  
Daniel Mas Montserrat ◽  
Carlos Bustamante ◽  
Alexander Ioannidis
Keyword(s):  
Association Studies ◽  
Genomic Medicine ◽  
Genetic Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Local Ancestry ◽  
Genome Wide ◽  
Health Burdens ◽  
Local Ancestry Inference

AbstractGenomic medicine promises increased resolution for accurate diagnosis, for personalized treatment, and for identification of population-wide health burdens at rapidly decreasing cost (with a genotype now cheaper than an MRI and dropping). The benefits of this emerging form of affordable, data-driven medicine will accrue predominantly to those populations whose genetic associations have been mapped, so it is of increasing concern that over 80% of such genome-wide association studies (GWAS) have been conducted solely within individuals of European ancestry [1]. The severe under-representation of the majority of the world’s populations in genetic association studies stems in part from an addressable algorithmic weakness: lack of simple, accurate, and easily trained methods for identifying and annotating ancestry along the genome (local ancestry). Here we present such a method (XGMix) based on gradient boosted trees, which, while being accurate, is also simple to use, and fast to train, taking minutes on consumer-level laptops.

scholarly journals Quantifying posterior effect size distribution of susceptibility loci by common summary statistics

2019 ◽  
Author(s):  
Olga A. Vsevolozhskaya ◽  
Dmitri V. Zaykin
Keyword(s):  
Effect Size ◽  
Prior Distribution ◽  
Association Studies ◽  
Genetic Association Studies ◽  
P Value ◽  
Susceptibility Loci ◽  
Genetic Associations ◽  
Bayesian Approaches ◽  
P Values ◽  
Disease Gene Discovery

AbstractTesting millions of SNPs in genetic association studies has become standard routine for disease gene discovery, followed by prioritization of the strongest signals based on the set of the smallest P-values. In light of recent re-evaluation of statistical practice, it has been suggested that P-values are unfit as summaries of statistical evidence. Despite this criticism, P-values are commonly used and are unlikely to be abandoned by practitioners. Moreover, P-values contain information that can be utilized to address the concerns about their flaws and misuse. We present a new method for utilizing evidence summarized by P-values for estimating odds ratio (OR) based on its approximate posterior distribution. In our method, only P-value, sample size, and standard deviation for log(OR) are needed as summaries of data, accompanied by a suitable prior distribution for log(OR) that can assume any shape. The parameter of interest, log(OR), is the only parameter with a specified prior distribution, hence our model is a mix of classical and Bayesian approaches. We show that our “Mix Bayes” (MB) method retains the main advantages of the Bayesian approach: it yields direct probability statements about hypotheses for OR and is resistant to biases caused by selection of top-scoring SNPs. MB enjoys greater flexibility than similarly inspired methods in the assumed distribution for the summary statistic and in the form of the prior for the parameter of interest. We illustrate our method by presenting interval estimates of effect size for reported genetic associations with lung cancer. Although we focus on OR, our method is not limited to this particular measure of effect size and can be used broadly for assessing reliability of findings in studies testing multiple predictors.

scholarly journals Genetic Diversity of Toll-Like Receptors and Immunity toM. lepraeInfection

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Bryan E. Hart ◽  
Richard I. Tapping
Keyword(s):  
Association Studies ◽  
Genetic Association Studies ◽  
Adaptive Immune System ◽  
Mycobacterial Infection ◽  
Innate Immune ◽  
Genetic Associations ◽  
Toll Like Receptors ◽  
Adaptive Immune ◽  
Polymorphic Variants ◽  
And Function

Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection withMycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs) have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity.

scholarly journals Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer

Gut ◽  
2019 ◽  
Vol 69 (8) ◽  
pp. 1460-1471 ◽  
Author(s):  
Zahra Montazeri ◽  
Xue Li ◽  
Christine Nyiraneza ◽  
Xiangyu Ma ◽  
Maria Timofeeva ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Genome Wide ◽  
Discovery Probability ◽  
Assessment Of Evidence ◽  
Meta Analyses

ObjectiveTo provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2).DesignWe included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as ‘positive’ and ‘less-credible positive’ were further validated in three large GWAS consortia conducted in populations of European origin.ResultsWe initially identified 18 independent variants at 16 loci that were classified as ‘positive’ polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as ‘less-credible positive’ SNPs; 72.2% of the ‘positive’ SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to ‘less-credible’ positive (reducing the ‘positive’ variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with CRC risk.ConclusionThe CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.

scholarly journals Human genetics of tuberculosis: a long and winding road

2014 ◽  
Vol 369 (1645) ◽  
pp. 20130428 ◽  
Author(s):  
Laurent Abel ◽  
Jamila El-Baghdadi ◽  
Ahmed Aziz Bousfiha ◽  
Jean-Laurent Casanova ◽  
Erwin Schurr
Keyword(s):  
Human Genetics ◽  
Association Studies ◽  
Single Gene ◽  
Genetic Association Studies ◽  
Epidemiological Studies ◽  
Interferon Γ ◽  
Past Century ◽  
Inborn Errors ◽  
Novel Treatments ◽  
The Past

Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.

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