Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene

Duarte, Rodrigo R.R.; Pain, Oliver; Furler, Robert L.; Nixon, Douglas F.; Powell, Timothy R.

doi:10.1016/j.isci.2022.104854

Cited by 4 publications

(4 citation statements)

References 72 publications

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“…We considered whether our data supported gene-level findings from genomic studies of HIV acquisition since those studies also compare PLWH to people without HIV. Powell et al 78 and Duarte et al 79 conducted genetic association analyses that reported genes expressed in blood that were related to genetic risk of HIV acquisition ( EFCAB14 , HERC1, HIST1H4L, IER3 ). None were identified as DEGs in our study, suggesting that these potential HIV susceptibility genes are not persistently differentially expressed in PLWH on ART.…”

Section: Discussionmentioning

confidence: 99%

Gene dysregulation among virally suppressed people living with HIV links to non-AIDS defining cancer pathways

Quach,

Earley,

Zhou

et al. 2024

Preprint

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Combination antiretroviral therapy (ART) has changed the landscape of the HIV epidemic by providing an effective means for viral suppression to people living with HIV (PLWH). Understanding living with HIV as a chronic disease requires an improved understanding of how HIV and/or ART impacts susceptibility to and development of co-occurring conditions. Genome-wide gene expression (transcriptome) differences provide a key view into biological dysregulation associated with living with HIV. Here we present the first whole blood transcriptome-wide study comparing gene expression profiles between virally suppressed PLWH and HIV negative individuals (N=555). We identify 566 genes and 5 immune cell types with differential proportions by HIV status, which were significantly enriched for immune function and cancer pathways. Leveraging quantitative trait loci (QTL) for these HIV status-associated genes, partitioned heritability, and colocalization analyses, we observed limited genetic drivers of these relationships. Our findings suggest that gene dysregulation does not return to a pre-infection state for virally suppressed PLWH, and that persistent gene dysregulation is broadly associated with immune function and cancer pathways, highlighting potential biological drivers for these causes of excess mortality and targets for pharmacological preventative treatment among PLWH.

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Section: Discussionmentioning

confidence: 99%

Gene dysregulation among virally suppressed people living with HIV links to non-AIDS defining cancer pathways

Quach,

Earley,

Zhou

et al. 2024

Preprint

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“…We applied multiple testing correction to the rTWAS association signals per trait using the Bonferroni method, considering the total number of tested genetic features. Plots were generated and analyses performed using the FUSION pipeline and scripts adapted from https://opain.github.io/MDD-TWAS/ 5 and https://github.com/rodrigoduarte88/hiv-meta-twas-2021 87 .…”

Section: Methodsmentioning

confidence: 99%

Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions

Duarte,

Pain,

Bendall

et al. 2024

Nat Commun

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Human endogenous retroviruses (HERVs) are repetitive elements previously implicated in major psychiatric conditions, but their role in aetiology remains unclear. Here, we perform specialised transcriptome-wide association studies that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, we identify 1238 HERVs with expression regulated in cis, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent from neighbouring expression signals. Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures are identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power. Ultimately, our study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.

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“…The different diseases that have been related to HERC1 (depicted in blue) and to HERC2 (depicted in red) are listed. HERC1: several cancers [18]; Macrocephaly, Dysmorphic Facies and PsychoMotor Retardation (MDFPMR) syndrome [19][20][21][22][23]; autism spectrum disorder [24,25]; Parkinson's disease [26]; schizophrenia [27]; febrile seizures [28]; neuropathic periphery disease [29]; COVID-19 combined with major depression disorder (COVID-19-MDD) [30]; acquired immunodeficiency syndrome (AIDS) [31]; diabetes [32]; cardiovascular disease [33]; osteopenia [34]. HERC2: several cancers [18]; HERC2 Angelman-like syndrome [35][36][37][38][39][40][41][42][43][44]; autism spectrum disorder [17]; Parkinson's disease [45]; agenesis of the corpus callosum (ACC) [46]; brain arteriovenous malformation (BAVM) [47]; diabetic cerebral ischemia-reperfusion (I/R) injury [48]; central precocious puberty [49]; refractive astigmatism [50]; inflammatory diseases [51][52][53][54][55]; asthma [56]; hypertension [57,…”

Section: Figurementioning

confidence: 99%

“…Moreover, a missense mutation in mice that causes loss of cerebellar Purkinje cells, tremor and unstable gait also provokes myelin abnormalities in the peripheral nervous system, which are histological hallmarks of neuropathic periphery diseases [29]. Recently, HERC1 was identified as a differentially expressed gene in the major depressive disorder associated with COVID-19 [30]. Other non-neurological diseases related to HERC1 include human immunodeficiency virus (HIV) acquisition and acquired immunodeficiency syndrome (AIDS) [31], diabetes [32], cardiovascular disease [33] and osteopenia [34] (Figure 1, HERC1 section).…”

Section: Figurementioning

confidence: 99%

Regulation of MAPK Signaling Pathways by the Large HERC Ubiquitin Ligases

Sala-Gaston

Costa-Sastre

Pedrazza

et al. 2023

IJMS

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Protein ubiquitylation acts as a complex cell signaling mechanism since the formation of different mono- and polyubiquitin chains determines the substrate’s fate in the cell. E3 ligases define the specificity of this reaction by catalyzing the attachment of ubiquitin to the substrate protein. Thus, they represent an important regulatory component of this process. Large HERC ubiquitin ligases belong to the HECT E3 protein family and comprise HERC1 and HERC2 proteins. The physiological relevance of the Large HERCs is illustrated by their involvement in different pathologies, with a notable implication in cancer and neurological diseases. Understanding how cell signaling is altered in these different pathologies is important for uncovering novel therapeutic targets. To this end, this review summarizes the recent advances in how the Large HERCs regulate the MAPK signaling pathways. In addition, we emphasize the potential therapeutic strategies that could be followed to ameliorate the alterations in MAPK signaling caused by Large HERC deficiencies, focusing on the use of specific inhibitors and proteolysis-targeting chimeras.

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Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene

Cited by 4 publications

References 72 publications

Gene dysregulation among virally suppressed people living with HIV links to non-AIDS defining cancer pathways

Gene dysregulation among virally suppressed people living with HIV links to non-AIDS defining cancer pathways

Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions

Regulation of MAPK Signaling Pathways by the Large HERC Ubiquitin Ligases

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