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

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.

scholarly journals A global atlas of genetic associations of 220 deep phenotypes

2020 ◽  
Author(s):  
Saori Sakaue ◽  
Masahiro Kanai ◽  
Yosuke Tanigawa ◽  
Juha Karjalainen ◽  
Mitja Kurki ◽  
...  
Keyword(s):  
Association Studies ◽  
East Asian ◽  
Allergic Diseases ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Endemic Diseases ◽  
Genetic Components ◽  
Mhc Locus ◽  
The Uk ◽  
Meta Analyses

AbstractThe current genome-wide association studies (GWASs) do not yet capture sufficient diversity in terms of populations and scope of phenotypes. To address an essential need to expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype GWASs (disease endpoints, biomarkers, and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining results of electronic medical records. Meta-analyses with the harmonized phenotypes in the UK Biobank and FinnGen (ntotal = 628,000) identified over 4,000 novel loci, which substantially deepened the resolution of the genomic map of human traits, benefited from East Asian endemic diseases and East Asian specific variants. This atlas elucidated the globally shared landscape of pleiotropy as represented by the MHC locus, where we conducted fine-mapping by HLA imputation. Finally, to intensify the value of deep-phenotype GWASs, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified the latent genetic components, which pinpointed the responsible variants and shared biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (e.g., allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human disease classifications through genetics.

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 The Role of SNP Interactions when Determining Independence of Novel Signals in Genetic Association Studies—An Application to ARG1 and Bronchodilator Response

2021 ◽  
Vol 11 (2) ◽  
pp. 145
Author(s):  
Ryan Walsh ◽  
Kirsten Voorhies ◽  
Merry-Lynn McDonald ◽  
Michael McGeachie ◽  
Joanne E. Sordillo ◽  
...  
Keyword(s):  
Genetic Association ◽  
Association Studies ◽  
Critical Role ◽  
Genetic Association Studies ◽  
Genome Wide Association Studies ◽  
The Novel ◽  
Simulation Studies ◽  
Nucleotide Polymorphisms ◽  
Bronchodilator Response

Genome-wide association studies (GWAS) play a critical role in identifying many loci for common diseases and traits. There has been a rapid increase in the number of GWAS over the past decade. As additional GWAS are being conducted, it is unclear whether a novel signal associated with the trait of interest is independent of single nucleotide polymorphisms (SNPs) in the same region that has been previously associated with the trait of interest. The general approach to determining whether the novel association is independent of previous signals is to examine the association of the novel SNP with the trait of interest conditional on the previously identified SNP and/or calculate linkage disequilibrium (LD) between the two SNPs. However, the role of epistasis and SNP by SNP interactions are rarely considered. Through simulation studies, we examined the role of SNP by SNP interactions when determining the independence of two genetic association signals. We have created an R package on Github called gxgRC to generate these simulation studies based on user input. In genetic association studies of asthma, we considered the role of SNP by SNP interactions when determining independence of signals for SNPs in the ARG1 gene and bronchodilator response.

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 Heritability jointly Explained by Host Genotype and Microbiome:Will Improve Traits Prediction?

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

AbstractAs we observe the 70th 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 (GWAS) 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; ultimately also increasing 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 (MWAS), focusing on its estimation, from a statistical genetics perspective. We then discuss a possible method to incorporate the microbiome in the estimation of heritability in host GWAS.

scholarly journals The role of polymorphic ERAP1 in autoinflammatory disease

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Emma Reeves ◽  
Edward James
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Autoinflammatory Disease ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Cell Functions ◽  
The Impact

Autoimmune and autoinflammatory conditions represent a group of disorders characterized by self-directed tissue damage due to aberrant changes in innate and adaptive immune responses. These disorders possess widely varying clinical phenotypes and etiology; however, they share a number of similarities in genetic associations and environmental influences. Whilst the pathogenic mechanisms of disease remain poorly understood, genome wide association studies (GWAS) have implicated a number of genetic loci that are shared between several autoimmune and autoinflammatory conditions. Association of particular HLA alleles with disease susceptibility represents one of the strongest genetic associations. Furthermore, recent GWAS findings reveal strong associations with single nucleotide polymorphisms in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene and susceptibility to a number of these HLA-associated conditions. ERAP1 plays a major role in regulating the repertoire of peptides presented on HLA class I alleles at the cell surface, with the presence of single nucleotide polymorphisms in ERAP1 having a significant impact on peptide processing function and the repertoire of peptides presented. The impact of this dysfunctional peptide generation on CD8+ T-cell responses has been proposed as a mechanism of pathogenesis diseases where HLA and ERAP1 are associated. More recently, studies have highlighted a role for ERAP1 in innate immune-mediated pathways involved in inflammatory responses. Here, we discuss the role of polymorphic ERAP1 in various immune cell functions, and in the context of autoimmune and autoinflammatory disease pathogenesis.

Sign in / Sign up

Export Citation Format

Share Document