Publisher Correction:Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals (Nature Genetics, (2020), 52, 12, (1314-1332), 10.1038/s41588-020-00713-x)

In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

Age-Dependent Association of TNFSF15/TNFSF8 Variants and Leprosy Type 1 Reaction

Submitted by Sandra Infurna ([email protected]) on 2018-02-08T13:20:26Z No. of bitstreams: 1 carolinne_marques_etal_IOC_2017.pdf: 817655 bytes, checksum: 7cf81e0844947de7820c88276120a950 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-02-08T13:33:07Z (GMT) No. of bitstreams: 1 carolinne_marques_etal_IOC_2017.pdf: 817655 bytes, checksum: 7cf81e0844947de7820c88276120a950 (MD5)Made available in DSpace on 2018-02-08T13:33:07Z (GMT). No. of bitstreams: 1 carolinne_marques_etal_IOC_2017.pdf: 817655 bytes, checksum: 7cf81e0844947de7820c88276120a950 (MD5) Previous issue date: 2017Research Institute of the McGill University Health Centre. Program in Infectious Diseases and Immunity in Global Health. Montreal, Quebec, canada / McGill University. The McGill International TB Centre, Departments of Human Genetics and Medicine. Montreal, Quebec, Canada.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.Institut National de la Santé et de la Recherche Médicale. Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Paris, France / University Paris Descartes. Imagine Institute. Paris, France / Rockefeller University. Giles Laboratory of Human Genetics of Infectious Diseases. Rockefeller Branch. New York, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.Research Institute of the McGill University Health Centre. Program in Infectious Diseases and Immunity in Global Health. Montreal, Quebec, canada / McGill University. The McGill International TB Centre, Departments of Human Genetics and Medicine. Montreal, Quebec, Canada / McGill University. Deparment of Medicine. Montreal, QC, Canada.A current major challenge in leprosy control is the prevention of permanent disabilities. Host pathological inflammatory responses termed type 1 reaction (T1R) are a leading cause of nerve damage for leprosy patients. The environmental or inherited factors that predispose leprosy cases to undergo T1R are not known. However, studies have shown an important contribution of host genetics for susceptibility to T1R. We have previously identified variants encompassing the TNFSF15/TNFSF8 genes as T1R risk factors in a Vietnamese sample and replicated this association in a Brazilian sample. However, we failed to validate in Brazilian patients the strong association of TNFSF15/TNFSF8 markers rs6478108 and rs7863183 with T1R that we had observed in Vietnamese patients. Here, we investigated if the lack of validation of these variants was due to age-dependent effects on association using four independent population samples, two from Brazil and two from Vietnam. In the combined analysis across the four samples, we observed a strong association of the TNFSF15/TNFSF8 variants rs6478108, rs7863183, and rs3181348 with T1R (pcombined = 1.5E-05, pcombined = 1.8E-05, and pcombined = 6.5E-06, respectively). However, the association of rs6478108 with T1R was more pronounced in leprosy cases under 30 years of age compared to the global sample [odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.54-2.46, pcombined = 2.5E-08 versus OR = 1.46, 95% CI = 1.23-1.73, pcombined = 1.5E-05]. A multivariable analysis indicated that the association of rs6478108 with T1R was independent of either rs7863183 or rs3181348. These three variants are known regulators of the TNFSF8 gene transcription level in multiple tissues. The age dependency of association of rs6478108 and T1R suggests that the genetic control of gene expression varies across the human life span

Deciphering the genetic control of gene expression following Mycobacterium leprae antigen stimulation.

Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy susceptibility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for expression quantitative trait loci (eQTL) that are associated with transcript variation before and after stimulation with M. leprae sonicate in whole blood cells. We show that M. leprae antigen stimulation mainly triggered the upregulation of immune related genes and that a substantial proportion of the differential gene expression is genetically controlled. Indeed, using stringent criteria, we identified 318 genes displaying cis-eQTL at an FDR of 0.01, including 66 genes displaying response-eQTL (reQTL), i.e. cis-eQTL that showed significant evidence for interaction with the M. leprae stimulus. Such reQTL correspond to regulatory variations that affect the interaction between human whole blood cells and M. leprae sonicate and, thus, likely between the human host and M. leprae bacilli. We found that reQTL were significantly enriched among binding sites of transcription factors that are activated in response to infection, and that they were enriched among single nucleotide polymorphisms (SNPs) associated with susceptibility to leprosy per se and Type-I Reaction, and seven of them have been targeted by recent positive selection. Our study suggested that natural selection shaped our genomic diversity to face pathogen exposure including M. leprae infection

Reducing Aspergillus fumigatus Virulence through Targeted Dysregulation of the Conidiation Pathway

The mold Aspergillus fumigatus reproduces by the production of airborne spores (conidia), a process termed conidiation. In immunocompromised individuals, inhaled A. fumigatus conidia can germinate and form filaments that penetrate and damage lung tissues; however, conidiation does not occur during invasive infection. In this study, we demonstrate that forced activation of conidiation in filaments of A. fumigatus can arrest their growth and impair the ability of this fungus to cause disease in both an insect and a mouse model of invasive infection. Activation of conidiation was linked to profound changes in A. fumigatus metabolism, including a shift away from the synthesis of polysaccharides required for cell wall structure and virulence in favor of carbohydrates used for energy storage and stress resistance. Collectively, these findings suggest that activation of the conidiation pathway may be a promising approach for the development of new agents to prevent or treat A. fumigatus infection.Inhalation of conidia of the opportunistic mold Aspergillus fumigatus by immunocompromised hosts can lead to invasive pulmonary disease. Inhaled conidia that escape immune defenses germinate to form filamentous hyphae that invade lung tissues. Conidiation rarely occurs during invasive infection of the human host, allowing the bulk of fungal energy to be directed toward vegetative growth. We hypothesized that forced induction of conidiation during infection can suppress A. fumigatus vegetative growth, impairing the ability of this organism to cause disease. To study the effects of conidiation pathway dysregulation on A. fumigatus virulence, a key transcriptional regulator of conidiation (brlA) was expressed under the control of a doxycycline-inducible promoter. Time- and dose-dependent brlA overexpression was observed in response to doxycycline both in vitro and in vivo. Exposure of the inducible brlA overexpression strain to low doses of doxycycline under vegetative growth conditions in vitro induced conidiation, whereas high doses arrested growth. Overexpression of brlA attenuated A. fumigatus virulence in both an invertebrate and mouse model of invasive aspergillosis. RNA sequencing studies and phenotypic analysis revealed that brlA overexpression results in altered cell signaling, amino acid, and carbohydrate metabolism, including a marked upregulation of trehalose biosynthesis and a downregulation in the biosynthesis of the polysaccharide virulence factor galactosaminogalactan. This proof of concept study demonstrates that activation of the conidiation pathway in A. fumigatus can reduce virulence and suggests that brlA-inducing small molecules may hold promise as a new class of therapeutics for A. fumigatus infection

A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy

A major challenge of current leprosy control is the management of host pathological immune responses coined Type-1 Reactions (T1R). T1R are characterized by acute inflammatory episodes whereby cellular immune responses are directed against host peripheral nerve cells. T1R affects up half of all leprosy patients and are a major cause of leprosy-associated disabilities [...] Here, we show that variants overlapping the LRRK2 gene, reported as suggestive leprosy per se susceptibility factors in a previous genome-wide association study, are preferentially associated with T1R. The main SNP carrying most of the association signal is the amino-acid change M2397T (rs3761863) which is known to impact LRRK2 turnover. Interestingly, eQTL SNPs counterbalanced the effect of the M2397T variant but this compensatory mechanism was abrogated by Mycobacterium leprae antigen stimulation

Evidence for cis-eQTL in stimulated <i>versus</i> non-stimulated cells.

<p>For each gene, we plotted the SNP with the lowest <i>P</i> value obtained under an additive model in one condition (stimulated or non-stimulated) against the <i>P</i> value obtained under the alternative condition. Red and grey dashed lines correspond to the 0.01 and to the 0.5 FDR to classify response eQTL (reQTL). Green dots are general cis-eQTL (found in both conditions). Blue dots are reQTL specific to cells stimulated with <i>M</i>. <i>leprae</i> sonicate while pink dots are reQTL specific to untreated cells. For this figure, reQTL are variants that exhibit a significant <i>P</i> value for genotype-phenotype association in one condition at an FDR of 0.01 and not in the other condition at an FDR of 0.5 (without taking the entire 200-kb tested regions per gene into account). The orange cloud corresponds to all the variants detected as being cis-eQTL at an FDR of 0.01.</p

A genome wide association study identifies a lncRna as risk factor for pathological inflammatory responses in leprosy

Submitted by Sandra Infurna ([email protected]) on 2018-02-08T11:09:47Z No. of bitstreams: 1 milton_moraes_etal_IOC_2017.pdf: 3018090 bytes, checksum: 4f1884a5b459722255f6434f0d7dfe23 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-02-08T11:28:23Z (GMT) No. of bitstreams: 1 milton_moraes_etal_IOC_2017.pdf: 3018090 bytes, checksum: 4f1884a5b459722255f6434f0d7dfe23 (MD5)Made available in DSpace on 2018-02-08T11:28:23Z (GMT). No. of bitstreams: 1 milton_moraes_etal_IOC_2017.pdf: 3018090 bytes, checksum: 4f1884a5b459722255f6434f0d7dfe23 (MD5) Previous issue date: 2017Research Institute of the McGill University Health Centre. Program in Infectious Diseases and Immunity in Global Health. Montreal, Quebec, canada / McGill University. The McGill International TB Centre, Departments of Human Genetics and Medicine. Montreal, Quebec, Canada.Research Institute of the McGill University Health Centre. Program in Infectious Diseases and Immunity in Global Health. Montreal, Quebec, canada / McGill University. The McGill International TB Centre, Departments of Human Genetics and Medicine. Montreal, Quebec, Canada.Institut National de la Santé et de la Recherche Médicale. Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Paris, France / University Paris Descartes. Imagine Institute. Paris, France / Rockefeller University. Giles Laboratory of Human Genetics of Infectious Diseases. Rockefeller Branch. New York, USA.Research Institute of the McGill University Health Centre. Program in Infectious Diseases and Immunity in Global Health. Montreal, Quebec, canada / McGill University. The McGill International TB Centre, Departments of Human Genetics and Medicine. Montreal, Quebec, Canada.Hospital for Dermato-Venerology. Ho Chi Minh City, Vietnam.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.Universidade Federal de Goiás. Instituto de Saúde Pública e Patologia Tropical. Goiânia, GO, BrasilInstituto Lauro de Souza Lima. Bauru, SP. Brasil.Instituto Lauro de Souza Lima. Bauru, SP. Brasil.Hospital for Dermato-Venerology. Ho Chi Minh City, Vietnam.Institut National de la Santé et de la Recherche Médicale. Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Paris, France / University Paris Descartes. Imagine Institute. Paris, France / Rockefeller University. Giles Laboratory of Human Genetics of Infectious Diseases. Rockefeller Branch. New York, USA.Institut National de la Santé et de la Recherche Médicale. Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Paris, France / University Paris Descartes. Imagine Institute. Paris, France / Rockefeller University. Giles Laboratory of Human Genetics of Infectious Diseases. Rockefeller Branch. New York, USA.Research Institute of the McGill University Health Centre. Program in Infectious Diseases and Immunity in Global Health. Montreal, Quebec, canada / McGill University. The McGill International TB Centre, Departments of Human Genetics and Medicine. Montreal, Quebec, Canada.Leprosy Type-1 Reactions (T1Rs) are pathological inflammatory responses that afflict a sub-group of leprosy patients and result in peripheral nerve damage. Here, we employed a family-based GWAS in 221 families with 229 T1R-affect offspring with stepwise replication to identify risk factors for T1R. We discovered, replicated and validated T1R-specific associations with SNPs located in chromosome region 10p21.2. Combined analysis across the three independent samples resulted in strong evidence of association of rs1875147 with T1R (p = 4.5x10-8; OR = 1.54, 95% CI = 1.32-1.80). The T1R-risk locus was restricted to a lncRNA-encoding genomic interval with rs1875147 being an eQTL for the lncRNA. Since a genetic overlap between leprosy and inflammatory bowel disease (IBD) has been detected, we evaluated if the shared genetic control could be traced to the T1R endophenotype. Employing the results of a recent IBD GWAS meta-analysis we found that 10.6% of IBD SNPs available in our dataset shared a common risk-allele with T1R (p = 2.4x10-4). This finding points to a substantial overlap in the genetic control of clinically diverse inflammatory disorders