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 RIC3 variants are not associated with Parkinson's Disease in large European, Latin American, or East Asian cohorts

2021 ◽  
Author(s):  
Kajsa Brolin ◽  
Sara Bandres Ciga ◽  
Hampton Leonard ◽  
Mary B Makarious ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Latin American ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
East Asian ◽  
European Ancestry ◽  
Common Genetic Variants

Parkinson's disease (PD) is a complex neurodegenerative disorder in which both rare and common genetic variants contribute to disease risk. Multiple genes have been reported to be linked to monogenic PD, but these only explain a fraction of the observed familial aggregation. Rare variants in RIC3 have been suggested to be associated with PD in the Indian population. However, replication studies yielded inconsistent results. We further investigate the role of RIC3 variants in PD in European cohorts using individual-level genotyping data from 14,671 PD patients and 17,667 controls, as well as whole-genome sequencing data from 1,615 patients and 961 controls. We also investigated RIC3 using summary statistics from a Latin American cohort of 1,481 individuals, and from a cohort of 31,575 individuals of East Asian ancestry. We did not identify any association between RIC3 and PD in any of the cohorts. However, more studies of rare variants in non-European ancestry populations, in particular South Asian populations, are necessary to further evaluate the world-wide role of RIC3 in PD etiology.

scholarly journals An integrated personal and population-based Egyptian genome reference

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Inken Wohlers ◽  
Axel Künstner ◽  
Matthias Munz ◽  
Michael Olbrich ◽  
Anke Fähnrich ◽  
...  
Keyword(s):  
Genetic Variation ◽  
De Novo ◽  
Disease Risk ◽  
Population Based ◽  
European Ancestry ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Human Genomes ◽  
Genome Wide ◽  
Polygenic Scores

Abstract A small number of de novo assembled human genomes have been reported to date, and few have been complemented with population-based genetic variation, which is particularly important for North Africa, a region underrepresented in current genome-wide references. Here, we combine long- and short-read whole-genome sequencing data with recent assembly approaches into a de novo assembly of an Egyptian genome. The assembly demonstrates well-balanced quality metrics and is complemented with variant phasing via linked reads into haploblocks, which we associate with gene expression changes in blood. To construct an Egyptian genome reference, we identify genome-wide genetic variation within a cohort of 110 Egyptian individuals. We show that differences in allele frequencies and linkage disequilibrium between Egyptians and Europeans may compromise the transferability of European ancestry-based genetic disease risk and polygenic scores, substantiating the need for multi-ethnic genome references. Thus, the Egyptian genome reference will be a valuable resource for precision medicine.

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 Genetic Analysis Reveals Rare Variants in T-Cell Response Gene MR1 Associated with Poor Overall Survival after Urothelial Cancer Diagnosis

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1864
Author(s):  
Lisa Bang ◽  
Manu Shivakumar ◽  
Tullika Garg ◽  
Dokyoon Kim
Keyword(s):  
Overall Survival ◽  
Rare Variants ◽  
The United States ◽  
T Cell Response ◽  
European Ancestry ◽  
North American Population ◽  
P Value ◽  
Sequencing Data ◽  
Poor Overall Survival ◽  
Germline Variants

Urothelial carcinoma of the bladder (UC) is the fifth most common cancer in the United States. Germline variants, especially rare germline variants, may account for a portion of the disparity seen among patients in terms of UC incidence, presentation, and outcomes. The objectives of this study were to identify rare germline variant associations in UC incidence and to determine its association with clinical outcomes. Using exome sequencing data from the DiscovEHR UC cohort (n = 446), a European-ancestry, North American population, the complex influence of germline variants on known clinical phenotypes were analyzed using dispersion and burden metrics with regression tests. Outcomes measured were derived from the electronic health record (EHR) and included UC incidence, age at diagnosis, and overall survival (OS). Consequently, key rare variant association genes were implicated in MR1 and ADGRL2. The Kaplan–Meier survival analysis reveals that individuals with MR1 germline variants had significantly worse OS than those without any (log-rank p-value = 3.46 × 10−7). Those with ADGRL2 variants were found to be slightly more likely to have UC compared to a matched control cohort (FDR q-value = 0.116). These associations highlight several candidate genes that have the potential to explain clinical disparities in UC and predict UC outcomes.

scholarly journals The influence of human genetic variation on Epstein–Barr virus sequence diversity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sina Rüeger ◽  
◽  
Christian Hammer ◽  
Alexis Loetscher ◽  
Paul J. McLaren ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Epstein Barr Virus ◽  
Rare Variants ◽  
Amino Acid Level ◽  
Genomic Variation ◽  
Human Genetic Variation ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
The Impact

AbstractEpstein–Barr virus (EBV) is one of the most common viruses latently infecting humans. Little is known about the impact of human genetic variation on the large inter-individual differences observed in response to EBV infection. To search for a potential imprint of host genomic variation on the EBV sequence, we jointly analyzed paired viral and human genomic data from 268 HIV-coinfected individuals with CD4 + T cell count < 200/mm3 and elevated EBV viremia. We hypothesized that the reactivated virus circulating in these patients could carry sequence variants acquired during primary EBV infection, thereby providing a snapshot of early adaptation to the pressure exerted on EBV by the individual immune response. We searched for associations between host and pathogen genetic variants, taking into account human and EBV population structure. Our analyses revealed significant associations between human and EBV sequence variation. Three polymorphic regions in the human genome were found to be associated with EBV variation: one at the amino acid level (BRLF1:p.Lys316Glu); and two at the gene level (burden testing of rare variants in BALF5 and BBRF1). Our findings confirm that jointly analyzing host and pathogen genomes can identify sites of genomic interactions, which could help dissect pathogenic mechanisms and suggest new therapeutic avenues.

scholarly journals Author response: A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

2013 ◽  
Author(s):  
István Bartha ◽  
Jonathan M Carlson ◽  
Chanson J Brumme ◽  
Paul J McLaren ◽  
Zabrina L Brumme ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Genome Analysis ◽  
Sequence Diversity ◽  
Author Response ◽  
Human Genetic Variation ◽  
Viral Control ◽  
A Genome ◽  
Hiv 1

scholarly journals The influence of human genetic variation on Epstein-Barr virus sequence diversity

2020 ◽  
Author(s):  
Sina Rüeger ◽  
Christian Hammer ◽  
Alexis Loetscher ◽  
Paul J McLaren ◽  
Dylan Lawless ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Epstein Barr Virus ◽  
Rare Variants ◽  
Amino Acid Level ◽  
Genomic Variation ◽  
Human Genetic Variation ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
The Impact

AbstractEpstein-Barr virus (EBV) is one of the most common viruses latently infecting humans. Little is known about the impact of human genetic variation on the large inter-individual differences observed in response to EBV infection. To search for a potential imprint of host genomic variation on the EBV sequence, we jointly analyzed paired viral and human genomic data from 268 HIV-coinfected individuals with CD4+ T cell count <200/mm3 and elevated EBV viremia. We hypothesized that the reactivated virus circulating in these patients could carry sequence variants acquired during primary EBV infection, thereby providing a snapshot of early adaptation to the pressure exerted on EBV by the individual immune response. We searched for associations between host and pathogen genetic variants, taking into account human and EBV population structure. Our analyses revealed significant associations between human and EBV sequence variation. Three polymorphic regions in the human genome were found to be associated with EBV variation: one at the amino acid level (BRLF1:p.Lys316Glu); and two at the gene level (burden testing of rare variants in BALF5 and BBRF1). Our findings confirm that jointly analyzing host and pathogen genomes can identify sites of genomic interactions, which could help dissect pathogenic mechanisms and suggest new therapeutic avenues.

scholarly journals The impact of rare variation on gene expression across tissues

Nature ◽  
2017 ◽  
Vol 550 (7675) ◽  
pp. 239-243 ◽  
Author(s):  
Xin Li ◽  
◽  
Yungil Kim ◽  
Emily K. Tsang ◽  
Joe R. Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Rare Variants ◽  
Disease Risk ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Sequencing Data ◽  
Common Genetic Variants ◽  
Coding Variants ◽  
The Impact

Abstract Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk1,2,3,4. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants1,5. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles1,6,7, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues8,9,10,11, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release12. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.

Sign in / Sign up

Export Citation Format

Share Document