Integrative multiomics analysis highlights immune-cell regulatory mechanisms and shared genetic architecture for 14 immune-associated diseases and cancer outcomes

2021 ◽  
Author(s):  
Claire Prince ◽  
Ruth E. Mitchell ◽  
Tom G. Richardson
Keyword(s):  
Genetic Architecture ◽  
Immune Cell ◽  
Regulatory Mechanisms ◽  
Cancer Outcomes ◽  
Associated Diseases ◽  
Shared Genetic

scholarly journals An integrative multi-omics analysis of 16 autoimmune diseases and cancer outcomes highlights immune-cell regulatory mechanisms and shared genetic architecture

2020 ◽  
Author(s):  
C Prince ◽  
R. E Mitchell ◽  
T. G. Richardson
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Immune Cell ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Specific Cell ◽  
Cell Type ◽  
Cancer Outcomes ◽  
Shared Genetic

AbstractBackgroundDeveloping functional understanding into the causal molecular drivers of immunological disease is a critical challenge in genomic medicine. Here we systematically apply Mendelian randomization (MR), genetic colocalization, immune cell-type enrichment and phenome-wide association methods to investigate the effect of genetically predicted gene expression on 12 autoimmune and 4 cancer outcomes.ResultsUsing whole blood derived estimates for regulatory variants from the eQTLGen consortium (n=31,684) we constructed genetic risk scores (r2<0.1) for 10,104 genes. Applying the inverse-variance weighted Mendelian randomization method transcriptome-wide whilst accounting for linkage disequilibrium structure identified 773 unique genes with evidence of a genetically predicted effect on at least one disease outcome (P<4.81 × 10−5). We next undertook genetic colocalization to investigate whether these effects may be confined to specific cell-types using gene expression data derived from 18 types of immune cells. This highlighted many cell-type dependent effects, such as PRKCQ expression and asthma risk (posterior probability of association (PPA)=0.998), which was T-cell specific, as well as TPM3 expression and prostate cancer risk (PPA=0.821), which was restricted to monocytes. Phenome-wide analyses on 320 complex traits allowed us to explore the shared genetic architecture and prioritize key drivers of disease risk, such as CASP10 which provided evidence of an effect on 7 cancer-related outcomes. Similarly, these evaluations of pervasive pleiotropy may be valuable for evaluations of therapeutic targets to help identify potential adverse effects.ConclusionsOur atlas of results can be used to characterize known and novel loci in autoimmune disease and cancer susceptibility, both in terms of developing insight into cell-type dependent effects as well as dissecting shared genetic architecture and disease pathways. As exemplar, we have highlighted several key findings in this study, although similar evaluations can be conducted interactively at http://mrcieu.mrsoftware.org/immuno_MR/.

scholarly journals Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types

2017 ◽  
Vol 49 (4) ◽  
pp. 600-605 ◽  
Author(s):  
Sung Chun ◽  
Alexandra Casparino ◽  
Nikolaos A Patsopoulos ◽  
Damien C Croteau-Chonka ◽  
Benjamin A Raby ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Immune Cell ◽  
Cell Types ◽  
Genetic Effects ◽  
Statistical Evidence ◽  
Shared Genetic

scholarly journals Shared genetic background between children and adults with attention deficit/hyperactivity disorder

2019 ◽  
Author(s):  
Paula Rovira ◽  
Ditte Demontis ◽  
Cristina Sánchez-Mora ◽  
Tetyana Zayats ◽  
Marieke Klein ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Genetic Variants ◽  
Genetic Background ◽  
Genetic Architecture ◽  
Neurodevelopmental Disorder ◽  
Genome Wide Association Studies ◽  
Hyperactivity Disorder ◽  
Common Genetic Variants ◽  
Shared Genetic

AbstractAttention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

scholarly journals Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria

PLoS Genetics ◽  
2019 ◽  
Vol 15 (12) ◽  
pp. e1008517 ◽  
Author(s):  
Felix Day ◽  
Tugce Karaderi ◽  
Michelle R. Jones ◽  
Cindy Meun ◽  
Chunyan He ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genetic Architecture ◽  
Large Scale ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Ovary Syndrome ◽  
Genome Wide ◽  
Diagnosis Criteria ◽  
Shared Genetic

scholarly journals Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria

PLoS Genetics ◽  
2018 ◽  
Vol 14 (12) ◽  
pp. e1007813 ◽  
Author(s):  
Felix Day ◽  
Tugce Karaderi ◽  
Michelle R. Jones ◽  
Cindy Meun ◽  
Chunyan He ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genetic Architecture ◽  
Large Scale ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Ovary Syndrome ◽  
Genome Wide ◽  
Diagnosis Criteria ◽  
Shared Genetic

scholarly journals Macroevolutionary consequences of sexual conflict

2018 ◽  
Vol 14 (6) ◽  
pp. 20180186
Author(s):  
Jo S. Hermansen ◽  
Jostein Starrfelt ◽  
Kjetil L. Voje ◽  
Nils C. Stenseth
Keyword(s):  
Sexual Selection ◽  
Genetic Architecture ◽  
Time Frame ◽  
Sexual Conflicts ◽  
Males And Females ◽  
Selection For ◽  
Evolutionary Consequences ◽  
Future Work ◽  
Shared Genetic

Intralocus sexual conflicts arise whenever the fitness optima for a trait expressed in both males and females differ between the sexes and shared genetic architecture constrains the sexes from evolving independently towards their respective optima. Such sexual conflicts are commonplace in nature, yet their long-term evolutionary consequences remain unexplored. Using a Bayesian phylogenetic comparative framework, we studied the macroevolutionary dynamics of intersexual trait integration in stalk-eyed flies (Diopsidae) spanning a time frame of more than 25 Myr. We report that increased intensity of sexual selection on male eyestalks is associated with reduced intersexual eyestalk integration, as well as sex-specific rates of eyestalk evolution. Despite this, lineages where males have been under strong sexual selection for millions of years still exhibit high levels of intersexual trait integration. This low level of decoupling between the sexes may indicate that exaggerated female eyestalks are in fact adaptive—or alternatively, that there are strong constraints on reducing trait integration between the sexes. Future work should seek to clarify the relative roles of constraints and selection in contributing to the varying levels of intersexual trait integration in stalk-eyed flies, and in this way clarify whether sexual conflicts can act as constraints on adaptive evolution even on macroevolutionary time scales.

scholarly journals Comprehensive Analysis of a ceRNA Network Identifies lncR-C3orf35 Associated with Poor Prognosis in Osteosarcoma

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yi Shi ◽  
Jianhua Ren ◽  
Ze Zhuang ◽  
Wenhui Zhang ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Immune Cell ◽  
Bone Cancer ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Regulatory Mechanisms ◽  
Messenger Rnas ◽  
Cerna Network ◽  
Potential Biomarker ◽  
Hmgb1 Expression

Osteosarcoma is a highly malignant bone cancer which primarily occurs in children and young adults. Increasing evidence indicates that long noncoding RNAs (lncRNAs), which function as competing endogenous RNAs (ceRNAs) that sponge microRNAs (miRNAs) and messenger RNAs (mRNAs), play a pivotal role in the pathogenesis and progression of cancers. The regulatory mechanisms of lncRNA-mediated ceRNAs in osteosarcoma have not been fully elucidated. In this study, we identified differentially expressed lncRNAs, miRNAs, and mRNAs in osteosarcoma based on RNA microarray profiles in the Gene Expression Omnibus (GEO) database. A ceRNA network was constructed utilizing bioinformatic tools. Kaplan-Meier survival analysis showed that lncR-C3orf35 and HMGB1 were associated with poor prognosis of osteosarcoma patients. Furthermore, results of Gene Set Enrichment Analysis (GSEA) suggested that lncR-C3orf35 may be involved in cellular invasion, the Toll-like receptor signaling pathway, and immune cell infiltration in the tumor microenvironment. Further analysis showed that patients with osteosarcoma metastasis expressed higher levels of lncR-C3orf35 and HMGB1 compared to metastasis-free patients. Moreover, the metastasis-free survival rate of the high lncR-C3orf35/HMGB1 expression group was significantly lower than that of the low expression group. The ESTIMATE algorithm was used to calculate the immune score and stromal scores for each sample. High lncR-C3orf35 and HMGB1 levels were correlated with low immune scores. ImmuCellAI analysis revealed that a low proportion of macrophage infiltration was associated with high lncR-C3orf35 and HMGB1 expression. The differential expression of lncR-C3orf35, miR-142-3p, and HMGB1 was further verified by quantitative real-time PCR. This study indicates that lncR-C3orf35 could be considered as a novel potential biomarker and therapeutic target of osteosarcoma, which may contribute to a better understanding of ceRNA regulatory mechanisms.

scholarly journals Visualizing genetic similarity at the symptom level: The example of learning disabilities

2010 ◽  
Vol 33 (2-3) ◽  
pp. 155-157
Author(s):  
Oliver S. P. Davis ◽  
Robert Plomin
Keyword(s):  
Learning Disabilities ◽  
Cognitive Abilities ◽  
Genetic Similarity ◽  
Structural Equation ◽  
Genetic Architecture ◽  
Genetic Factors ◽  
Psychological Traits ◽  
Equation Modelling ◽  
Symptom Level ◽  
Shared Genetic

AbstractPsychological traits and disorders are often interrelated through shared genetic influences. A combination of maximum-likelihood structural equation modelling and multidimensional scaling enables us to open a window onto the genetic architecture at the symptom level, rather than at the level of latent genetic factors. We illustrate this approach using a study of cognitive abilities involving over 5,000 pairs of twins.

scholarly journals Transmembrane Domains Mediate Intra- and Extracellular Trafficking of Epstein-Barr Virus Latent Membrane Protein 1

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Dingani Nkosi ◽  
Lauren A. Howell ◽  
Mujeeb R. Cheerathodi ◽  
Stephanie N. Hurwitz ◽  
Deanna C. Tremblay ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Extracellular Vesicles ◽  
Viral Protein ◽  
Cell Function ◽  
Immune Cell ◽  
Latent Membrane Protein ◽  
Transmembrane Domains ◽  
Regulatory Mechanisms ◽  
Latent Membrane Protein 1 ◽  
N Terminus

ABSTRACTEBV latent membrane protein 1 (LMP1) is released from latently infected tumor cells in small membrane-enclosed extracellular vesicles (EVs). Accumulating evidence suggests that LMP1 is a major driver of EV content and functions. LMP1-modified EVs have been shown to influence recipient cell growth, migration, differentiation, and regulation of immune cell function. Despite the significance of LMP1-modified exosomes, very little is known about how this viral protein enters or manipulates the host EV pathway. In this study, LMP1 deletion mutants were generated to assess protein regions required for EV trafficking. Following transfection of LMP1 or mutant plasmids, EVs were collected by differential centrifugation, and the levels of specific cargo were evaluated by immunoblot analysis. The results demonstrate that, together, the N terminus and transmembrane region 1 of LMP1 are sufficient for efficient sorting into EVs. Consistent with these findings, a mutant lacking the N terminus and transmembrane domains 1 through 4 (TM5-6) failed to be packaged into EVs, and exhibited higher colocalization with endoplasmic reticulum and early endosome markers than the wild-type protein. Surprisingly, TM5-6 maintained the ability to colocalize and form a complex with CD63, an abundant exosome protein that is important for the incorporation of LMP1 into EVs. Other mutations within LMP1 resulted in enhanced levels of secretion, pointing to potential positive and negative regulatory mechanisms for extracellular vesicle sorting of LMP1. These data suggest new functions of the N terminus and transmembrane domains in LMP1 intra- and extracellular trafficking that are likely downstream of an interaction with CD63.IMPORTANCEEBV infection contributes to the development of cancers, such as nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin's disease, and posttransplant lymphomas, in immunocompromised or genetically susceptible individuals. LMP1 is an important viral protein expressed by EBV in these cancers. LMP1 is secreted in extracellular vesicles (EVs), and the transfer of LMP1-modified EVs to uninfected cells can alter their physiology. Understanding the cellular machinery responsible for sorting LMP1 into EVs is limited, despite the importance of LMP1-modified EVs. Here, we illustrate the roles of different regions of LMP1 in EV packaging. Our results show that the N terminus and TM1 are sufficient to drive LMP1 EV trafficking. We further show the existence of potential positive and negative regulatory mechanisms for LMP1 vesicle sorting. These findings provide a better basis for future investigations to identify the mechanisms of LMP1 targeting to EVs, which could have broad implications in understanding EV cargo sorting.

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