scholarly journals CCmed: cross-condition mediation analysis for identifying robust trans-eQTLs and assessing their effects on human traits

2019 ◽  
Author(s):  
Fan Yang ◽  
Kevin J. Gleason ◽  
Jiebiao Wang ◽  
Jubao Duan ◽  
Xin He ◽  
...  
Keyword(s):  
Tissue Expression ◽  
Summary Statistics ◽  
Nucleotide Polymorphisms ◽  
Susceptibility Loci ◽  
Single Nucleotide ◽  
Expression Variation ◽  
Gene Level ◽  
Show Evidence ◽  
Schizophrenia Susceptibility ◽  
Trans Gene

AbstractTrans-eQTLs collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are individually weak. Many trans-effects are mediated by cis-gene expression and some of those effects are shared across tissue types/conditions. To detect robust cis-mediated trans-associations at the gene-level and for specific single nucleotide polymorphisms (SNPs), we proposed two Cross-Condition Mediation methods – CCmedgene and CCmedGWAS, respectively. We analyzed data from 13 brain tissue types from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-eQTLs of a cis-gene having associations with a trans-gene, many of which show evidence of replication in other datasets. By applying CCmedGWAS, we identified trans-genes associated with known schizophrenia susceptibility loci. We further conducted validation analyses assessing the schizophrenia-risk-associations of the identified trans-genes, by harnessing GWAS summary statistics from the Psychiatric Genomics Consortium and multitissue eQTL statistics from GTEx.

Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE

Rheumatology ◽  
2019 ◽  
Vol 59 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Declan Webber ◽  
Jingjing Cao ◽  
Daniela Dominguez ◽  
Dafna D Gladman ◽  
Deborah M Levy ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Tertiary Care ◽  
Logistic Models ◽  
Risk Scores ◽  
Nucleotide Polymorphisms ◽  
Adult Onset ◽  
Susceptibility Loci ◽  
Childhood Onset ◽  
Single Nucleotide ◽  
Independent Cohort

Abstract Objective LN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). Methods Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed <18 years) and aSLE patients (diagnosed ⩾18 years). Patients met ACR and/or SLICC SLE criteria and were genotyped on the Illumina Multi-Ethnic Global Array or Omni1-Quad arrays. We identified those with and without biopsy-confirmed LN. HLA and non-HLA additive SLE risk-weighted genetic risk scores (GRSs) were tested for association with LN risk in logistic models, stratified by cSLE/aSLE and ancestry. Stratified effect estimates were meta-analysed. Results Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002). Conclusion We observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort.

scholarly journals Transposable elements are important contributors to standing variation in gene expression in Capsella grandiflora

2018 ◽  
Author(s):  
Jasmina Uzunović ◽  
Emily B. Josephs ◽  
John R. Stinchcombe ◽  
Stephen I. Wright
Keyword(s):  
Gene Expression ◽  
Single Nucleotide Polymorphisms ◽  
Transposable Elements ◽  
Genomic Diversity ◽  
Nucleotide Polymorphisms ◽  
Mobile Dna ◽  
Gene Expression Variation ◽  
Single Nucleotide ◽  
Expression Variation ◽  
A Genome

AbstractTransposable elements (TEs) make up a significant portion of eukaryotic genomes, and thus are important drivers of genome evolution. However, the evolutionary forces controlling TE copy number and the extent to which TEs affect phenotypic variation on a genome-wide scale are still unclear. We characterised TE insertion polymorphism and its effects on gene expression in 124 whole genome sequences from a single population of Capsella grandiflora. The frequency of insertions was negatively correlated with distance to genes, as well as density of conserved non-coding elements, suggesting that the negative effects of TEs on gene regulation are important in limiting their abundance. Rare TE variants strongly influence gene expression variation, predominantly through downregulation. In contrast, rare single nucleotide polymorphisms (SNPs) contribute equally to up- and down-regulation, but have a weaker effect. Taken together, these results imply that TEs are a significant contributor to gene expression variation and can be more likely than rare SNPs to cause extreme changes in gene expression.Author SummaryTransposable elements (TEs), mobile DNA elements with the ability to excise from the genome and reinsert in new locations, are important components of genomic diversity. Due to their abundance and mobility, TEs play an influential role in genomic evolution, often deleterious. Here we show that TEs in a population of the plant Capsella grandiflora are most deleterious when they insert in genic and regulatory regions. We find that TEs indeed are associated with unusual levels of gene expression, predominantly decreased expression.Furthermore, this effect is stronger than the association of single nucleotide polymorphisms with gene expression variation, highlighting the importance of TE contribution to the maintenance of expression variation.

scholarly journals Unravelling the Roles Of susceptibility Loci for Autoimmune Diseases in the Post-GWAS Era

2018 ◽  
Author(s):  
Jody Ye ◽  
Kathleen Gillespie ◽  
Santiago Rodriguez
Keyword(s):  
Autoimmune Diseases ◽  
Disease Risk ◽  
Association Studies ◽  
Copy Number Variations ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Susceptibility Loci ◽  
Single Nucleotide ◽  
Environmental Interactions ◽  
Genome Wide

Although genome-wide association studies (GWAS) have identified several hundred loci associated with autoimmune diseases, their mechanistic insights are still poorly understood. The human genome is more complex than common single nucleotide polymorphisms (SNPs) that are interrogated by GWAS arrays. Some structural variants such as insertions-deletions, copy number variations, and minisatellites that are not very well tagged by SNPs cannot be fully explored by GWAS. Therefore, it is possible that some of these loci may have large effects on autoimmune disease risk. In addition, other layers of regulations such as gene-gene interactions, epigenetic-determinants, gene and environmental interactions also contribute to the heritability of autoimmune diseases. This review focuses on discussing why studying these elements may allow us to gain a more comprehensive understanding of the aetiology of complex autoimmune traits.

scholarly journals A comprehensive gene-centric pleiotropic association analysis for 14 psychiatric disorders with GWAS summary statistics

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Haojie Lu ◽  
Jiahao Qiao ◽  
Zhonghe Shao ◽  
Ting Wang ◽  
Shuiping Huang ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Correlation ◽  
Large Scale ◽  
Association Studies ◽  
Single Gene ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Nucleotide Polymorphisms ◽  
Entire Genome ◽  
Gene Level

Abstract Background Recent genome-wide association studies (GWASs) have revealed the polygenic nature of psychiatric disorders and discovered a few of single-nucleotide polymorphisms (SNPs) associated with multiple psychiatric disorders. However, the extent and pattern of pleiotropy among distinct psychiatric disorders remain not completely clear. Methods We analyzed 14 psychiatric disorders using summary statistics available from the largest GWASs by far. We first applied the cross-trait linkage disequilibrium score regression (LDSC) to estimate genetic correlation between disorders. Then, we performed a gene-based pleiotropy analysis by first aggregating a set of SNP-level associations into a single gene-level association signal using MAGMA. From a methodological perspective, we viewed the identification of pleiotropic associations across the entire genome as a high-dimensional problem of composite null hypothesis testing and utilized a novel method called PLACO for pleiotropy mapping. We ultimately implemented functional analysis for identified pleiotropic genes and used Mendelian randomization for detecting causal association between these disorders. Results We confirmed extensive genetic correlation among psychiatric disorders, based on which these disorders can be grouped into three diverse categories. We detected a large number of pleiotropic genes including 5884 associations and 2424 unique genes and found that differentially expressed pleiotropic genes were significantly enriched in pancreas, liver, heart, and brain, and that the biological process of these genes was remarkably enriched in regulating neurodevelopment, neurogenesis, and neuron differentiation, offering substantial evidence supporting the validity of identified pleiotropic loci. We further demonstrated that among all the identified pleiotropic genes there were 342 unique ones linked with 6353 drugs with drug-gene interaction which can be classified into distinct types including inhibitor, agonist, blocker, antagonist, and modulator. We also revealed causal associations among psychiatric disorders, indicating that genetic overlap and causality commonly drove the observed co-existence of these disorders. Conclusions Our study is among the first large-scale effort to characterize gene-level pleiotropy among a greatly expanded set of psychiatric disorders and provides important insight into shared genetic etiology underlying these disorders. The findings would inform psychiatric nosology, identify potential neurobiological mechanisms predisposing to specific clinical presentations, and pave the way to effective drug targets for clinical treatment.

scholarly journals A robust two-sample Mendelian Randomization method integrating GWAS with multi-tissue eQTL summary statistics

2020 ◽  
Author(s):  
Kevin J. Gleason ◽  
Fan Yang ◽  
Lin S. Chen
Keyword(s):  
Mixed Model ◽  
Mendelian Randomization ◽  
Summary Statistics ◽  
Nucleotide Polymorphisms ◽  
Model Framework ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Causal Genes ◽  
Detect Gene Expression ◽  
Gene Expression Levels

AbstractIn the post-genome-wide association era, two-sample Mendelian Randomization (MR) methods have been applied to detect genetically-regulated risk factors for complex diseases. Two-sample MR considers single nucleotide polymorphisms (SNPs) associated with a putative exposure as instrumental variables (IVs) to assess the effect of the exposure on an outcome by leveraging two sets of summary statistics: IV-to-exposure and IV-to-outcome statistics from existing GWASs. Traditional MR methods impose strong assumptions on the validity of IVs, and recent literature has relaxed the assumptions allowing some IVs to be invalid but generally requiring a large number of nearly independent IVs. When treating expression-quantitative-trait-loci (eQTLs) as IVs to detect gene expression levels affecting diseases, existing methods are limited in applicability since the numbers of independent eQTLs for most genes in the genome are limited. To address those challenges, we propose a robust two-sample MR framework that requires fewer IVs and allows moderate IV correlations and some IVs to be invalid. This is achieved by leveraging existing multi-tissue eQTL summary statistics (multiple sets of IV-to-exposure statistics) and GWAS statistics in a mixed model framework. We conducted simulation studies to evaluate the performance of the proposed method and apply it to detect putative causal genes for schizophrenia.

scholarly journals Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

2015 ◽  
Author(s):  
Padhraig Gormley ◽  
Verneri Anttila ◽  
Bendik S Winsvold ◽  
Priit Palta ◽  
Tonu Esko ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Meta Analysis ◽  
Nucleotide Polymorphisms ◽  
Susceptibility Loci ◽  
Single Nucleotide ◽  
Full Sample ◽  
Muscle Tissues ◽  
Genome Wide ◽  
Gwa Studies

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

scholarly journals Investigation of type 1 diabetes and coeliac disease susceptibility loci for association with juvenile idiopathic arthritis

2010 ◽  
Vol 69 (12) ◽  
pp. 2169-2172 ◽  
Author(s):  
Anne Hinks ◽  
Paul Martin ◽  
Edward Flynn ◽  
Steve Eyre ◽  
Jon Packham ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Juvenile Idiopathic Arthritis ◽  
Coeliac Disease ◽  
Trend Test ◽  
Nucleotide Polymorphisms ◽  
Susceptibility Loci ◽  
Single Nucleotide ◽  
Specific Association ◽  
Armitage Trend Test

BackgroundThere is strong evidence suggesting that juvenile idiopathic arthritis (JIA) shares many susceptibility loci with other autoimmune diseases.ObjectiveTo investigate variants robustly associated with type 1 diabetes (T1D) or coeliac disease (CD) for association with JIA.MethodsSixteen single-nucleotide polymorphisms (SNPs) already identified as susceptibility loci for T1D/CD were selected for genotyping in patients with JIA (n=1054) and healthy controls (n=3129). Genotype and allele frequencies were compared using the Cochrane–Armitage trend test implemented in PLINK.ResultsOne SNP in the LPP gene, rs1464510, showed significant association with JIA (ptrend=0.002, OR=1.18, 95% CI 1.06 to 1.30). A second SNP, rs653178 in ATXN2, also showed nominal evidence for association with JIA (ptrend=0.02, OR=1.13, 95% CI 1.02 to 1.25). The SNP, rs17810546, in IL12A showed subtype-specific association with enthesitis-related arthritis (ERA) subtype (ptrend=0.005, OR=1.88, 95% CI 1.2 to 2.94).ConclusionsEvidence for a novel JIA susceptibility locus, LPP, is presented. Association at the SH2B3/ATXN2 locus, previously reported to be associated with JIA in a US series, also supports this region as contributing to JIA susceptibility. In addition, a subtype-specific association of IL12A with ERA is identified. All findings will require validation in independent JIA cohorts.

Replication of European Rheumatoid Arthritis Loci in a Pakistani Population

2013 ◽  
Vol 40 (4) ◽  
pp. 401-407 ◽  
Author(s):  
Syed Fazal Jalil ◽  
Attya Bhatti ◽  
F. Yesim Demirci ◽  
Xingbin Wang ◽  
Iltaf Ahmed ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Nucleotide Polymorphisms ◽  
Susceptibility Loci ◽  
Control Software ◽  
Single Nucleotide ◽  
Genetic Studies ◽  
P Values ◽  
Pakistani Population ◽  
Family Case ◽  
Different Populations

Objective.Genetic studies have identified several rheumatoid arthritis (RA) susceptibility loci in European-derived populations. The same biological pathways may be involved in determining the RA risk in different population groups. We sought to replicate the association of 33 single-nucleotide polymorphisms (SNP) from 31 RA susceptibility loci confirmed among Europeans in a unique Pakistani population.Methods.We genotyped 33 SNP in a sample of 366 Pakistanis that comprised related and unrelated cases and controls. Genotyping was performed using TaqMan assays and the results were analyzed with family case-control software.Results.Twelve of the 33 SNP were replicated in this sample with significant p values ranging from 7.05E-06 to 3.72E-02, the most significant being the KIF5A-PIP4K2C/rs1678542 SNP.Conclusion.Our observations suggest that a number of RA susceptibility loci and related pathways are shared across different populations.

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