Identifying functional genes and pathways towards a unifying model for atrial fibrillation

ABSTRACTRationaleGenome wide association studies (GWAS) have associated >100 genetic loci with atrial fibrillation (AF), yet the biological pathways of AF remain elusive.ObjectiveTo determine candidate causal genes associated with AF risk loci and their coexpression partners, modules, biologic and mechanistic pathways.Methods and ResultsCis-expression quantitative trait loci (eQTLs) were identified for candidate genes near AF risk single nucleotide polymorphisms (SNPs) in human left atrial tissues. Genes were categorized into 3 sets according to likelihood of being a causative AF gene: 1) All Candidate Genes (with significant eQTLs or previously prioritized); 2) Any eQTL Genes (with ≥1 significant eQTL); and 3) Top GWAS SNP eQTL Genes (top SNP within the top 10 eQTL SNPs). Coexpression partners were identified for each candidate gene. Weighted gene coexpression network analysis (WGCNA) identified modules and modules with overrepresentation of candidate AF genes. Ingenuity Pathway Analysis (IPA) was applied to the coexpression partners of each candidate gene, and IPA and gene set enrichment analysis (GSEA) to each WGCNA module. 166 AF-risk SNPs were located in 135 distinct loci. The All Candidate Genes group contained 233, the Any eQTL Genes group 131 (83 novel), and the Top GWAS SNP eQTL Genes group 37 genes. IPA identified mitochondrial dysfunction, oxidative stress, epithelial adherens junction signaling, and sirtuin signaling as the most frequent pathways. WGCNA characterized 64 modules; candidate AF genes were overrepresented in 8. Modules were represented by cell injury, death, stress, developmental, metabolic/mitochondrial, transcription/translation, and immune activation/inflammation regulatory pathways.ConclusionsAF candidate gene coexpression analyses suggest significant roles for cellular stress and remodeling in AF. We propose a dual risk model for AF: Genetic susceptibility to AF may not manifest until later in life, when cellular stressors overwhelm adaptive responses. These analyses provide a resource for further functional studies on potential causal AF genes.

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Genome-wide association studies reveal the coordinated regulatory networks underlying photosynthesis and wood formation in Populus

Journal of Experimental Botany ◽

10.1093/jxb/erab122 ◽

2021 ◽

Author(s):

Mingyang Quan ◽

Xin Liu ◽

Qingzhang Du ◽

Liang Xiao ◽

Wenjie Lu ◽

...

Keyword(s):

Candidate Genes ◽

Regulatory Networks ◽

Genome Wide Association Study ◽

Association Studies ◽

Wood Properties ◽

Wood Formation ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Regulatory Pathways ◽

Genome Wide

Abstract Photosynthesis and wood formation underlie the ability of trees to provide renewable resources and perform ecosystem services; however, the genetic basis and regulatory pathways coordinating these two linked processes remain unclear. Here, we used a systems genetics strategy, integrating genome-wide association study, transcriptomic analyses, and transgenic experiments, to investigate the genetic architecture of photosynthesis and wood properties among 435 unrelated individuals of Populus tomentosa and unravel the coordinated regulatory networks causative of two trait categories. We totally detected 222 significant single-nucleotide polymorphisms, annotated to 177 candidate genes, for 10 traits of photosynthesis and wood properties. Epistasis uncovered 74 epistatic interactions for phenotypes. Strikingly, we deciphered the coordinated regulation patterns of pleiotropic genes underlying phenotypic variations for two trait categories. Furthermore, expression quantitative trait nucleotide mapping and coexpression analysis were integrated to unravel the potential transcriptional regulatory networks of candidate genes coordinating photosynthesis and wood properties. Finally, we heterologously expressed two pleiotropic genes, PtoMYB62 and PtoMYB80, in Arabidopsis thaliana, and demonstrated that they coordinate regulatory networks balancing photosynthesis and stem secondary cell wall components, respectively. Our study provides insight into the regulatory mechanisms coordinating photosynthesis and wood formation in poplar, which will accelerate the genetic breeding in trees via molecular design.

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cageminer: an R/Bioconductor package to prioritize candidate genes by integrating GWAS and gene coexpression networks

10.1101/2021.08.04.455037 ◽

2021 ◽

Author(s):

Fabricio Almeida-Silva ◽

Thiago M. Venancio

Keyword(s):

Candidate Genes ◽

Expression Profiles ◽

Association Studies ◽

Real Data ◽

R Package ◽

Genome Wide Association Studies ◽

High Confidence ◽

Data Set ◽

Gene Coexpression ◽

Coexpression Networks

Summary: Although genome-wide association studies (GWAS) identify variants associated with traits of interest, they often fail in identifying causative genes underlying a given phenotype. Integrating GWAS and gene coexpression networks can help prioritize high-confidence candidate genes, as the expression profiles of trait-associated genes can be used to mine novel candidates. Here, we present cageminer, the first R package to prioritize candidate genes through the integration of GWAS and coexpression networks. Genes are considered high-confidence candidates if they pass all three filtering criteria implemented in cageminer, namely physical proximity to SNPs, coexpression with known trait-associated genes, and significant changes in expression levels in conditions of interest. Prioritized candidates can also be scored and ranked to select targets for experimental validation. By applying cageminer to a real data set, we demonstrate that it can effectively prioritize candidates, leading to >99% reductions in candidate gene lists. Availability and implementation: The package is available at Bioconductor (http://bioconductor.org/packages/cageminer).

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Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

Psychological Medicine ◽

10.1017/s0033291711001607 ◽

2011 ◽

Vol 42 (3) ◽

pp. 607-616 ◽

Cited By ~ 59

Author(s):

A. L. Collins ◽

Y. Kim ◽

P. Sklar ◽

M. C. O'Donovan ◽

P. F. Sullivan ◽

...

Keyword(s):

Genetic Variation ◽

Candidate Gene ◽

Candidate Genes ◽

Association Studies ◽

Human Diseases ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Common Genetic Variation ◽

Genome Wide ◽

Candidate Gene Studies

BackgroundCandidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS).MethodWe describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC).ResultsSZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISCpvalues in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT,DRD3,DRD2,HTR2A,NRG1,BDNF,DTNBP1andSLC6A4) had no notable ISC results.ConclusionsWe did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively.

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A meta-analysis of genome-wide association studies for average daily gain and lean meat percentage in two Duroc pig populations

BMC Genomics ◽

10.1186/s12864-020-07288-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Shenping Zhou ◽

Rongrong Ding ◽

Fanming Meng ◽

Xingwang Wang ◽

Zhanwei Zhuang ◽

...

Keyword(s):

Candidate Genes ◽

Growth And Development ◽

Genetic Architecture ◽

Association Studies ◽

Meta Analysis ◽

Average Daily Gain ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Daily Gain

Abstract Background Average daily gain (ADG) and lean meat percentage (LMP) are the main production performance indicators of pigs. Nevertheless, the genetic architecture of ADG and LMP is still elusive. Here, we conducted genome-wide association studies (GWAS) and meta-analysis for ADG and LMP in 3770 American and 2090 Canadian Duroc pigs. Results In the American Duroc pigs, one novel pleiotropic quantitative trait locus (QTL) on Sus scrofa chromosome 1 (SSC1) was identified to be associated with ADG and LMP, which spans 2.53 Mb (from 159.66 to 162.19 Mb). In the Canadian Duroc pigs, two novel QTLs on SSC1 were detected for LMP, which were situated in 3.86 Mb (from 157.99 to 161.85 Mb) and 555 kb (from 37.63 to 38.19 Mb) regions. The meta-analysis identified ten and 20 additional SNPs for ADG and LMP, respectively. Finally, four genes (PHLPP1, STC1, DYRK1B, and PIK3C2A) were detected to be associated with ADG and/or LMP. Further bioinformatics analysis showed that the candidate genes for ADG are mainly involved in bone growth and development, whereas the candidate genes for LMP mainly participated in adipose tissue and muscle tissue growth and development. Conclusions We performed GWAS and meta-analysis for ADG and LMP based on a large sample size consisting of two Duroc pig populations. One pleiotropic QTL that shared a 2.19 Mb haplotype block from 159.66 to 161.85 Mb on SSC1 was found to affect ADG and LMP in the two Duroc pig populations. Furthermore, the combination of single-population and meta-analysis of GWAS improved the efficiency of detecting additional SNPs for the analyzed traits. Our results provide new insights into the genetic architecture of ADG and LMP traits in pigs. Moreover, some significant SNPs associated with ADG and/or LMP in this study may be useful for marker-assisted selection in pig breeding.

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A gene co-association network regulating gut microbial communities in a Duroc pig population

Microbiome ◽

10.1186/s40168-020-00994-8 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Antonio Reverter ◽

Maria Ballester ◽

Pamela A. Alexandre ◽

Emilio Mármol-Sánchez ◽

Antoni Dalmau ◽

...

Keyword(s):

Microbial Communities ◽

Candidate Genes ◽

Relative Abundance ◽

Association Studies ◽

Single Gene ◽

Host Genome ◽

Genome Wide Association Studies ◽

Vaccine Response ◽

Microbiome Composition ◽

Host Genetic

Abstract Background Analyses of gut microbiome composition in livestock species have shown its potential to contribute to the regulation of complex phenotypes. However, little is known about the host genetic control over the gut microbial communities. In pigs, previous studies are based on classical “single-gene-single-trait” approaches and have evaluated the role of host genome controlling gut prokaryote and eukaryote communities separately. Results In order to determine the ability of the host genome to control the diversity and composition of microbial communities in healthy pigs, we undertook genome-wide association studies (GWAS) for 39 microbial phenotypes that included 2 diversity indexes, and the relative abundance of 31 bacterial and six commensal protist genera in 390 pigs genotyped for 70 K SNPs. The GWAS results were processed through a 3-step analytical pipeline comprised of (1) association weight matrix; (2) regulatory impact factor; and (3) partial correlation and information theory. The inferred gene regulatory network comprised 3561 genes (within a 5 kb distance from a relevant SNP–P < 0.05) and 738,913 connections (SNP-to-SNP co-associations). Our findings highlight the complexity and polygenic nature of the pig gut microbial ecosystem. Prominent within the network were 5 regulators, PRDM15, STAT1, ssc-mir-371, SOX9 and RUNX2 which gathered 942, 607, 588, 284 and 273 connections, respectively. PRDM15 modulates the transcription of upstream regulators of WNT and MAPK-ERK signaling to safeguard naive pluripotency and regulates the production of Th1- and Th2-type immune response. The signal transducer STAT1 has long been associated with immune processes and was recently identified as a potential regulator of vaccine response to porcine reproductive and respiratory syndrome. The list of regulators was enriched for immune-related pathways, and the list of predicted targets includes candidate genes previously reported as associated with microbiota profile in pigs, mice and human, such as SLIT3, SLC39A8, NOS1, IL1R2, DAB1, TOX3, SPP1, THSD7B, ELF2, PIANP, A2ML1, and IFNAR1. Moreover, we show the existence of host-genetic variants jointly associated with the relative abundance of butyrate producer bacteria and host performance. Conclusions Taken together, our results identified regulators, candidate genes, and mechanisms linked with microbiome modulation by the host. They further highlight the value of the proposed analytical pipeline to exploit pleiotropy and the crosstalk between bacteria and protists as significant contributors to host-microbiome interactions and identify genetic markers and candidate genes that can be incorporated in breeding program to improve host-performance and microbial traits.

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Genetics and Epigenetics of Atrial Fibrillation

International Journal of Molecular Sciences ◽

10.3390/ijms21165717 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5717 ◽

Cited By ~ 1

Author(s):

Estefanía Lozano-Velasco ◽

Diego Franco ◽

Amelia Aranega ◽

Houria Daimi

Keyword(s):

Atrial Fibrillation ◽

Regulatory Networks ◽

Association Studies ◽

Functional Characterization ◽

The Elderly ◽

Supraventricular Arrhythmia ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Transcriptional Regulatory ◽

Transcriptional Regulatory Mechanisms

Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks

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Children’s Greenness Exposure and IQ-Associated DNA Methylation: A Prospective Cohort Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18147429 ◽

2021 ◽

Vol 18 (14) ◽

pp. 7429

Author(s):

Kyung-Shin Lee ◽

Yoon-Jung Choi ◽

Jin-Woo Cho ◽

Sung-Ji Moon ◽

Youn-Hee Lim ◽

...

Keyword(s):

Dna Methylation ◽

Cohort Study ◽

Literature Review ◽

Cognitive Ability ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Association Studies ◽

The Body ◽

Genome Wide Association Studies ◽

Regulatory Pathways

Epigenetics is known to be involved in regulatory pathways through which greenness exposure influences child development and health. We aimed to investigate the associations between residential surrounding greenness and DNA methylation changes in children, and further assessed the association between DNA methylation and children’s intelligence quotient (IQ) in a prospective cohort study. We identified cytosine-guanine dinucleotide sites (CpGs) associated with cognitive abilities from epigenome- and genome-wide association studies through a systematic literature review for candidate gene analysis. We estimated the residential surrounding greenness at age 2 using a geographic information system. DNA methylation was analyzed from whole blood using the HumanMethylationEPIC array in 59 children at age 2. We analyzed the association between greenness exposure and DNA methylation at age 2 at the selected CpGs using multivariable linear regression. We further investigated the relationship between DNA methylation and children’s IQ. We identified 8743 CpGs associated with cognitive ability based on the literature review. Among these CpGs, we found that 25 CpGs were significantly associated with greenness exposure at age 2, including cg26269038 (Bonferroni-corrected p ≤ 0.05) located in the body of SLC6A3, which encodes a dopamine transporter. DNA methylation at cg26269038 at age 2 was significantly associated with children’s performance IQ at age 6. Exposure to surrounding greenness was associated with cognitive ability-related DNA methylation changes, which was also associated with children’s IQ. Further studies are warranted to clarify the epigenetic pathways linking greenness exposure and neurocognitive function.

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Identification of Novel Genome-Wide Associations for Oral Inflammatory Traits

10.21203/rs.3.rs-104530/v1 ◽

2020 ◽

Author(s):

Yanjiao Jin ◽

Jie Yang ◽

Shuyue Zhang ◽

Jin Li ◽

Songlin Wang

Keyword(s):

Candidate Genes ◽

Immune Regulation ◽

Functional Annotation ◽

Inflammatory Diseases ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Protein Protein Interaction ◽

Genome Wide ◽

Causal Variants

Abstract Background: Oral diseases impact the majority of the world’s population. The following traits are common in oral inflammatory diseases: mouth ulcers, painful gums, bleeding gums, loose teeth, and toothache. Despite the prevalence of genome-wide association studies, the associations between these traits and common genomic variants, and whether pleiotropic loci are shared by some of these traits remain poorly understood. Methods: In this work, we conducted multi-trait joint analyses based on the summary statistics of genome-wide association studies of these five oral inflammatory traits from the UK Biobank, each of which is comprised of over 10,000 cases and over 300,000 controls. We estimated the genetic correlations between the five traits. We conducted fine-mapping and functional annotation based on multi-omics data to better understand the biological functions of the potential causal variants at each locus. To identify the pathways in which the candidate genes were mainly involved, we applied gene-set enrichment analysis, and further performed protein-protein interaction (PPI) analyses.Results: We identified 39 association signals that surpassed genome-wide significance, including three that were shared between two or more oral inflammatory traits, consistent with a strong correlation. Among these genome-wide significant loci, two were novel for both painful gums and toothache. We performed fine-mapping and identified causal variants at each novel locus. Further functional annotation based on multi-omics data suggested IL10 and IL12A/TRIM59 as potential candidate genes at the novel pleiotropic loci, respectively. Subsequent analyses of pathway enrichment and protein-protein interaction networks suggested the involvement of candidate genes at genome-wide significant loci in immune regulation.Conclusions: Our results highlighted the importance of immune regulation in the pathogenesis of oral inflammatory diseases. Some common immune-related pleiotropic loci or genetic variants are shared by multiple oral inflammatory traits. These findings will be beneficial for risk prediction, prevention, and therapy of oral inflammatory diseases.

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Genome-wide association study reveals candidate genes for flowering time in cowpea (Vigna unguiculata [L.] Walp)

10.1101/2021.04.01.438123 ◽

2021 ◽

Author(s):

Dev Paudel ◽

Rocheteau Dareus ◽

Julia Rosenwald ◽

Maria Munoz-Amatriain ◽

Esteban Rios

Keyword(s):

Flowering Time ◽

Candidate Genes ◽

Vigna Unguiculata ◽

Association Studies ◽

Snp Markers ◽

Genome Wide Association ◽

Human Consumption ◽

Phenotypic Variance ◽

Genome Wide Association Studies ◽

Genome Wide

Cowpea (Vigna unguiculata [L.] Walp., diploid, 2n = 22) is a major crop used as a protein source for human consumption as well as a quality feed for livestock. It is drought and heat tolerant and has been bred to develop varieties that are resilient to changing climates. Plant adaptation to new climates and their yield are strongly affected by flowering time. Therefore, understanding the genetic basis of flowering time is critical to advance cowpea breeding. The aim of this study was to perform genome-wide association studies (GWAS) to identify marker trait associations for flowering time in cowpea using single nucleotide polymorphism (SNP) markers. A total of 367 accessions from a cowpea mini-core collection were evaluated in Ft. Collins, CO in 2019 and 2020, and 292 accessions were evaluated in Citra, FL in 2018. These accessions were genotyped using the Cowpea iSelect Consortium Array that contained 51,128 SNPs. GWAS revealed seven reliable SNPs for flowering time that explained 8-12% of the phenotypic variance. Candidate genes including FT, GI, CRY2, LSH3, UGT87A2, LIF2, and HTA9 that are associated with flowering time were identified for the significant SNP markers. Further efforts to validate these loci will help to understand their role in flowering time in cowpea, and it could facilitate the transfer of some of this knowledge to other closely related legume species.

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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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