scholarly journals Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Rosanne C. van Deuren ◽  
Peer Arts ◽  
Giulio Cavalli ◽  
Martin Jaeger ◽  
Marloes Steehouwer ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Genetic Variants ◽  
Complex Traits ◽  
Rare Variants ◽  
Interleukin 1 ◽  
Healthy Individuals ◽  
Cytokine Responses ◽  
Common Genetic Variants ◽  
Bidirectional Association

Abstract Background The interleukin (IL)-1 pathway is primarily associated with innate immunological defense and plays a major role in the induction and regulation of inflammation. Both common and rare genetic variation in this pathway underlies various inflammation-mediated diseases, but the role of rare variants relative to common variants in immune response variability in healthy individuals remains unclear. Methods We performed molecular inversion probe sequencing on 48 IL-1 pathway-related genes in 463 healthy individuals from the Human Functional Genomics Project. We functionally grouped common and rare variants, over gene, subpathway, and inflammatory levels and performed the Sequence Kernel Association Test to test for association with in vitro stimulation-induced cytokine responses; specifically, IL-1β and IL-6 cytokine measurements upon stimulations that represent an array of microbial infections: lipopolysaccharide (LPS), phytohaemagglutinin (PHA), Candida albicans (C. albicans), and Staphylococcus aureus (S. aureus). Results We identified a burden of NCF4 rare variants with PHA-induced IL-6 cytokine and showed that the respective carriers are in the 1% lowest IL-6 producers. Collapsing rare variants in IL-1 subpathway genes produces a bidirectional association with LPS-induced IL-1β cytokine levels, which is reflected by a significant Spearman correlation. On the inflammatory level, we identified a burden of rare variants in genes encoding for proteins with an anti-inflammatory function with S. aureus-induced IL-6 cytokine. In contrast to these rare variant findings which were based on different types of stimuli, common variant associations were exclusively identified with C. albicans-induced cytokine over various levels of grouping, from the gene, to subpathway, to inflammatory level. Conclusions In conclusion, this study shows that functionally grouping common and rare genetic variants enables the elucidation IL-1-mediated biological mechanisms, specifically, for IL-1β and IL-6 cytokine responses induced by various stimuli. The framework used in this study may allow for the analysis of rare and common genetic variants in a wider variety of (non-immune) complex phenotypes and therefore has the potential to contribute to better understanding of unresolved, complex traits and diseases.

scholarly journals Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses

2020 ◽  
Author(s):  
Rosanne C. van Deuren ◽  
Peer Arts ◽  
Giulio Cavalli ◽  
Martin Jaeger ◽  
Marloes Steehouwer ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Genetic Variants ◽  
Rare Variants ◽  
Common Genetic Variation ◽  
Common Variants ◽  
Healthy Individuals ◽  
Cytokine Responses ◽  
Human Cytokine

ABSTRACTBackgroundInterleukin(IL)-1 signaling is of major importance in human innate cytokine responses. Common variants in related genes have been linked to various inflammation-mediated diseases and stimulation-induced cytokine responses, but the role of rare variants remains to be elucidated.MethodsIn this study, we characterize the role of rare and common genetic variation, as identified by molecular inversion probe-based sequencing, in 48 genes related to the IL-1 pathway. Using a systems biology approach, we examined the inter-individual variability of in vitro stimulation-specific human cytokine responses from 463 healthy individuals of the Human Functional Genomics Project and assessed the role of rare and common genetic variants, separately and combined, by means of the Sequence Kernel Association Test.ResultsWe identified strong associations for rare genetic variants in NCF4 (adjP=7.2E−05) and CASP1 (adjP=3.0E−05) with IL-6 production in response to PHA and LPS stimulation, respectively. In addition, common variants in IL36A and IL38 were associated to both C. albicans-induced IL-1β (IL36AadjP=0.0442; IL38adjP=0.0092) and IL-6 production (IL36AadjP=0.0037; IL38adjP=0.0082), an effect that was stronger at the subpathway level both for IL-1β (adjP=0.0017) and IL-6 (adjP=1.8E−04). The common variant signature for the IL-1β and IL-6 response to C. albicans was confirmed by an association with all anti-inflammatory genes (adjP=1.87E−03 and adjP=5.75E−04), and we validated this finding for non-coding common variants. Lastly, we identified a burden of rare variants in pro-inflammatory genes and LPS-induced IL-6 production (adjP=2.42E−04), and a new role for anti-inflammatory rare variants on S. aureus-stimulated IL-6 production (adjP=6.71E−03).ConclusionsIn conclusion, we show that both common and rare genetic variation in genes of the IL-1 pathway, separately and combined, differentially influence in vitro cytokine responses to various stimuli in healthy individuals. This study therefore accentuates potential mechanisms that are translatable into new hypothesis-driven characterization of common and rare variant involvement in a wide variety of inflammatory and immunological mechanisms and diseases.

scholarly journals Core gene identification using gene expression

2020 ◽  
Author(s):  
◽  
Annique Claringbould
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Genetic Code ◽  
Genetic Variants ◽  
Complex Traits ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Altered Level ◽  
Common Genetic Variants

While humans share most of their genetic code with one another, small differences in the DNA can have an impact on an individual’s risk of disease. Common genetic variants exert individually small effects on the development of a disease, but their combined impact is substantial. Although recent research has identified thousands of variants that are associated to complex traits, our understanding of the molecular mechanisms that eventually lead to disease is limited. One way to dive into the molecular changes that result from genetic variation, is to look at changes in gene activity (‘gene expression’). Each cell contains the same genetic code, but genes are only expressed when and where they are required. Research has shown that many disease-associated genetic variants also affect gene expression. Such a change in the expression of a gene can lead to an altered level of the protein it encodes, which in turn can be the start of a dysregulation in the system that can eventually develop into a disease. This thesis describes how gene expression patterns can be used to prioritise and describe the function of trait-relevant genes. The first chapters evaluate methodological considerations for doing gene expression research. Another study covers the systematic linking of genetic variation to gene expression in blood and the last research chapter describes a method for gene prioritisation that leverages the idea that multiple genetic variants converge onto disease-causing genes. These insights can be used to better understand disease and to identify potential drug targets.

scholarly journals The contribution of rare whole genome sequencing variants to plasma protein levels and to the missing heritability

2021 ◽  
Author(s):  
Marcin Kierczak ◽  
Nima Rafati ◽  
Julia Höglund ◽  
Hadrien Gourle ◽  
Daniel Schmitz ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Variants ◽  
Complex Traits ◽  
Rare Variants ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Missing Heritability ◽  
Common Genetic Variants

Abstract Despite the success in identifying effects of common genetic variants, using genome-wide association studies (GWAS), much of the genetic contribution to complex traits remains unexplained. Here, we analysed high coverage whole-genome sequencing (WGS) data, to evaluate the contribution of rare genetic variants to 414 plasma proteins. The frequency distribution of genetic variants was skewed towards the rare spectrum, and damaging variants were more often rare. However, only 2.24% of the heritability was estimated to be explained by rare variants. A gene-based approach, developed to also capture the effect of rare variants, identified associations for 249 of the proteins, which was 25% more as compared to a GWAS. Out of those, 24 associations were driven by rare variants, clearly highlighting the capacity of aggregated tests and WGS data. We conclude that, while many rare variants have considerable phenotypic effects, their contribution to the missing heritability is limited by their low frequencies.

scholarly journals Genome-wide association study identifies 48 common genetic variants associated with handedness

2019 ◽  
Author(s):  
Gabriel Cuellar Partida ◽  
Joyce Y Tung ◽  
Nicholas Eriksson ◽  
Eva Albrecht ◽  
Fazil Aliev ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Variants ◽  
Complex Traits ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Genome Wide Association ◽  
Left Handedness ◽  
Left Handed ◽  
Genome Wide ◽  
Common Genetic Variants

AbstractHandedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

scholarly journals Exome Sequencing to Detect Rare Variants Associated With General Cognitive Ability: A Pilot Study

2015 ◽  
Vol 18 (2) ◽  
pp. 117-125 ◽  
Author(s):  
Michelle Luciano ◽  
Victoria Svinti ◽  
Archie Campbell ◽  
Riccardo E. Marioni ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
Cognitive Ability ◽  
Exome Sequencing ◽  
Genetic Variants ◽  
Complex Traits ◽  
Rare Variants ◽  
Copy Number Variant ◽  
Apical Part ◽  
General Cognitive Ability ◽  
Sequencing Studies ◽  
Rare Genetic Variants

Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile.

scholarly journals Vaccination with Adenovirus Serotypes 35, 26, and 48 Elicits Higher Levels of Innate Cytokine Responses than Adenovirus Serotype 5 in Rhesus Monkeys

2012 ◽  
Vol 86 (18) ◽  
pp. 9590-9598 ◽  
Author(s):  
Jeffrey E. Teigler ◽  
M. Justin Iampietro ◽  
Dan H. Barouch
Keyword(s):  
Immune Responses ◽  
Rhesus Monkeys ◽  
Interleukin 1 ◽  
Experimental Models ◽  
Gamma Interferon ◽  
Vaccine Vectors ◽  
Adenovirus Serotype ◽  
Cytokine Responses ◽  
Serotype 5

Adenovirus (Ad) vaccine vectors have proven highly immunogenic in multiple experimental models, but the innate immune responses induced by these vectors remain poorly characterized. Here we report innate cytokine responses to 5 different Ad vectors in 26 rhesus monkeys. Vaccination with adenovirus serotype 35 (Ad35), Ad26, and Ad48 induced substantially higher levels of antiviral (gamma interferon [IFN-γ], 10-kDa gamma interferon-induced protein [IP-10]) and proinflammatory (interleukin 1 receptor antagonist [IL-1RA], IL-6) cytokines than vaccination with Ad5 on day 1 following immunization.In vitrostudies with capsid chimeric vectors and receptor-blocking monoclonal antibodies suggested that fiber-receptor interactions, as well as other capsid components, were critical for triggering these innate responses. Moreover, multiple cell populations, including dendritic cells, monocytes/macrophages, and T lymphocytes, contributed to these innate cytokine profiles. These data demonstrate that Ad35, Ad26, and Ad48, which utilize CD46 as their primary cellular receptor, induce significantly greater innate cytokine responses than Ad5, which uses the coxsackievirus and adenovirus receptor (CAR). These differences in innate triggering result in markedly different immunologic milieus for the subsequent generation of adaptive immune responses by these vaccine vectors.

scholarly journals The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar

Obesity Facts ◽  
2022 ◽  
Author(s):  
Nadien AbouHashem ◽  
Roan E. Zaied ◽  
Kholoud Al-Shafai ◽  
Mariam Nofal ◽  
Najeeb Syed ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Rare Variants ◽  
Normal Weight ◽  
Routine Testing ◽  
Monogenic Obesity ◽  
Syndromic Obesity ◽  
The Impact

Introduction: Monogenic obesity (MO) is a rare genetic disease characterized by severe early-onset obesity in affected individuals. Previous genetic studies revealed 8 definitive genes for monogenic non-syndromic obesity; many were discovered in consanguineous populations. Here, we examined MO in the Qatari population, whose population is largely consanguineous (54%) and characterized by extensive obesity (45%). Methods: Whole genome sequences of Qatar Biobank samples from 250 subjects with obesity and 250 subjects with normal weight, obtained in association with the Qatar Genome Programme, were searched for genetic variants in the genes known to be associated with MO (i.e., LEP, LEPR, POMC, PCSK1, MC3R, MC4R, MRAP2 and ADCY3). The impact of the variants identified was investigated utilizing in silico tools for prediction in combination with protein visualization by PyMOL. Results: We identified potential MO variants in more than 5% of the cases in our cohort. We revealed 11 rare variants in 6 of the genes targeted, including two disease-causing variants in MC4R and MRAP2, all of which were heterozygous. Moreover, enrichment of a heterozygous ADCY3 variant (c.1658C>T; p.A553V) appeared to cause severe obesity in an autosomal dominant manner. Conclusion: These findings highlight the importance of implementing routine testing for genetic variants that predispose for MO in Qatar. Clearly, additional studies of this nature on populations not yet examined are required. At the same time, functional investigations, both in vitro and in vivo, are necessary in order to better understand the role of the variants identified in the pathogenesis of obesity.

scholarly journals Host genomics of the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment

2019 ◽  
Author(s):  
Christian W. Thorball ◽  
Alessandro Borghesi ◽  
Nadine Bachmann ◽  
Chantal von Siebenthal ◽  
Valentina Vongrad ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Decay Rate ◽  
Antiretroviral Treatment ◽  
Rare Variants ◽  
European Ancestry ◽  
Viral Reservoir ◽  
Human Genetic Variation ◽  
Sequencing Data ◽  
Common Genetic Variants ◽  
Hiv 1

ABSTRACTIntroductionA major hurdle to HIV-1 eradication is the establishment of a latent viral reservoir early after primary infection. Several factors are known to influence the HIV-1 reservoir size and decay rate on suppressive antiretroviral treatment (ART), but little is known about the role of human genetic variation.MethodsWe measured the reservoir size at three time points over a median of 5.4 years, and searched for associations between human genetic variation and two phenotypic readouts: the reservoir size at the first time point and its decay rate over the study period. We assessed the contribution of common genetic variants using genome-wide genotyping data from 797 patients with European ancestry enrolled in the Swiss HIV Cohort Study and searched for a potential impact of rare variants and exonic copy number variants using exome sequencing data generated in a subset of 194 study participants.ResultsGenome- and exome-wide analyses did not reveal any significant association with the size of the HIV-1 reservoir or its decay rate on suppressive ART.ConclusionsOur results point to a limited influence of human genetics on the size of the HIV-1 reservoir and its long-term dynamics in successfully treated individuals.

scholarly journals Integration of rare large-effect expression variants improves polygenic risk prediction

2020 ◽  
Author(s):  
Craig Smail ◽  
Nicole M. Ferraro ◽  
Matthew G. Durrant ◽  
Abhiram S. Rao ◽  
Matthew Aguirre ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Rare Variants ◽  
Complex Trait ◽  
Risk Scores ◽  
Multiple Traits ◽  
Polygenic Risk ◽  
Common Genetic Variants ◽  
Using Data ◽  
The Uk ◽  
The Impact

SummaryPolygenic risk scores (PRS) aim to quantify the contribution of multiple genetic loci to an individual’s likelihood of a complex trait or disease. However, existing PRS estimate genetic liability using common genetic variants, excluding the impact of rare variants. We identified rare, large-effect variants in individuals with outlier gene expression from the GTEx project and then assessed their impact on PRS predictions in the UK Biobank (UKB). We observed large deviations from the PRS-predicted phenotypes for carriers of multiple outlier rare variants; for example, individuals classified as “low-risk” but in the top 1% of outlier rare variant burden had a 6-fold higher rate of severe obesity. We replicated these findings using data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) biobank and the Million Veteran Program, and demonstrated that PRS across multiple traits will significantly benefit from the inclusion of rare genetic variants.

scholarly journals A Novel Approach for the Simultaneous Analysis of Common and Rare Variants in Complex Traits

2012 ◽  
Vol 6 ◽  
pp. BBI.S8852 ◽  
Author(s):  
Ao Yuan ◽  
Guanjie Chen ◽  
Yanxun Zhou ◽  
Amy Bentley ◽  
Charles Rotimi
Keyword(s):  
Complex Traits ◽  
Rare Variants ◽  
Sequence Data ◽  
Association Studies ◽  
Simultaneous Analysis ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Disease Etiology ◽  
Novel Approach ◽  
Common Genetic Variants

Genome-wide association studies (GWAS) have been successful in detecting common genetic variants underlying common traits and diseases. Despite the GWAS success stories, the percent trait variance explained by GWAS signals, the so called “missing heritability” has been, at best, modest. Also, the predictive power of common variants identified by GWAS has not been encouraging. Given these observations along with the fact that the effects of rare variants are often, by design, unaccounted for by GWAS and the availability of sequence data, there is a growing need for robust analytic approaches to evaluate the contribution of rare variants to common complex diseases. Here we propose a new method that enables the simultaneous analysis of the association between rare and common variants in disease etiology. We refer to this method as SCARVA (simultaneous common and rare variants analysis). SCARVA is simple to use and is efficient. We used SCARVA to analyze two independent real datasets to identify rare and common variants underlying variation in obesity among participants in the Africa America Diabetes Mellitus (AADM) study and plasma triglyceride levels in the Dallas Heart Study (DHS). We found common and rare variants associated with both traits, consistent with published results.

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