Compare and Contrast Meta Analysis (CCMA): A Method for Identification of Pleiotropic Loci in Genome-Wide Association Studies

Baurecht, Hansjörg; Hotze, Melanie; Rodríguez, Elke; Manz, Judith; Weidinger, Stephan; Cordell, Heather J.; Augustin, Thomas; Strauch, Konstantin

doi:10.1371/journal.pone.0154872

Cited by 3 publications

(3 citation statements)

References 11 publications

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“…On the other hand, RUNX3 plays a critical role in additional immune functions whose impairment is associated with disease. Inactivation of Runx3 in mice not only causes T cell defects in knockout mice, but also causes absence of Langerhans cells (41) and is associated with chronic inflammation of the lung (asthma) (42), skin (psoriasis) (43), and digestive tract (colonic and gastric mucosa) (44,45). In humans, genetic variants near or at the RUNX3 gene are associated with inflammatory bowel diseases and are responsible for the IBD7 locus mapped in genome-wide association studies (46).…”

Section: Discussionmentioning

confidence: 99%

ZBTB7B (ThPOK) Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

et al. 2020

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We used a genome-wide screen in N-ethyl-N-nitrosourea (ENU)-mutagenized mice to identify genes in which recessive loss-of-function mutations protect against pathological neuroinflammation. We identified an R367Q mutation in the ZBTB7B (ThPOK) protein in which homozygosity causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA. Zbtb7bR367Q homozygous mice show a defect in the lymphoid compartment expressed as severe reduction in the number of single-positive CD4 T cells in the thymus and in the periphery, reduced brain infiltration of proinflammatory leukocytes in P. berghei ANKA-infected mice, and reduced production of proinflammatory cytokines by primary T cells ex vivo and in vivo. Dampening of proinflammatory immune responses in Zbtb7bR367Q mice is concomitant to increased susceptibility to infection with avirulent (Mycobacterium bovis BCG) and virulent (Mycobacterium tuberculosis H37Rv) mycobacteria. The R367Q mutation maps to the first DNA-binding zinc finger domain of ThPOK and causes loss of base contact by R367 in the major groove of the DNA, which is predicted to impair DNA binding. Global immunoprecipitation of ThPOK-containing chromatin complexes coupled to DNA sequencing (ChIP-seq) identified transcriptional networks and candidate genes likely to play key roles in CD4+ CD8+ T cell development and in the expression of lineage-specific functions of these cells. This study highlights ThPOK as a global regulator of immune function in which alterations may affect normal responses to infectious and inflammatory stimuli.

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Section: Discussionmentioning

confidence: 99%

ZBTB7B (ThPOK) Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

et al. 2020

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“…To assess the reliability of our findings, ASSET results were compared with those obtained using an alternative approach, the compare and contrast meta-analysis (CCMA) [16]. For pleiotropic variants identified using ASSET, we calculated z-scores for each disease-specific association analysis as well as for all the possible combinations of diseases, assuming an agonistic or an antagonistic effect of the variants.…”

Section: Methodsmentioning

confidence: 99%

“…For each locus, the subset showing the largest z-score was considered as the best model. p values for the maximum z-scores were derived using an empirical null distribution by simulating 300,000,000 realizations of four normally distributed random variables ( p value < 1.00E−08 for z-score ≥ 6.45) (Additional file 2: Figure S2) [16].…”

Section: Methodsmentioning

confidence: 99%

Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations

et al. 2018

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BackgroundIn recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component.MethodsFor this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET.ResultsWe identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment.ConclusionsIn this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0604-8) contains supplementary material, which is available to authorized users.

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An Analytic Solution to the Computation of Power and Sample Size for Genetic Association Studies under a Pleiotropic Mode of Inheritance

Gordon

Londoño

Patel³

et al. 2016

Hum Hered

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Our motivation here is to calculate the power of 3 statistical tests used when there are genetic traits that operate under a pleiotropic mode of inheritance and when qualitative phenotypes are defined by use of thresholds for the multiple quantitative phenotypes. Specifically, we formulate a multivariate function that provides the probability that an individual has a vector of specific quantitative trait values conditional on having a risk locus genotype, and we apply thresholds to define qualitative phenotypes (affected, unaffected) and compute penetrances and conditional genotype frequencies based on the multivariate function. We extend the analytic power and minimum-sample-size-necessary (MSSN) formulas for 2 categorical data-based tests (genotype, linear trend test [LTT]) of genetic association to the pleiotropic model. We further compare the MSSN of the genotype test and the LTT with that of a multivariate ANOVA (Pillai). We approximate the MSSN for statistics by linear models using a factorial design and ANOVA. With ANOVA decomposition, we determine which factors most significantly change the power/MSSN for all statistics. Finally, we determine which test statistics have the smallest MSSN. In this work, MSSN calculations are for 2 traits (bivariate distributions) only (for illustrative purposes). We note that the calculations may be extended to address any number of traits. Our key findings are that the genotype test usually has lower MSSN requirements than the LTT. More inclusive thresholds (top/bottom 25% vs. top/bottom 10%) have higher sample size requirements. The Pillai test has a much larger MSSN than both the genotype test and the LTT, as a result of sample selection. With these formulas, researchers can specify how many subjects they must collect to localize genes for pleiotropic phenotypes.

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Compare and Contrast Meta Analysis (CCMA): A Method for Identification of Pleiotropic Loci in Genome-Wide Association Studies

Cited by 3 publications

References 11 publications

ZBTB7B (ThPOK) Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

ZBTB7B (ThPOK) Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations

An Analytic Solution to the Computation of Power and Sample Size for Genetic Association Studies under a Pleiotropic Mode of Inheritance

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