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Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.

ABSTRACT: Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.

SUBMITTER: Kotliar D

PROVIDER: S-EPMC10914620 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.

Kotliar Dylan D Raju Siddharth S Tabrizi Shervin S Odia Ikponmwosa I Goba Augustine A Momoh Mambu M Sandi John Demby JD Nair Parvathy P Phelan Eric E Tariyal Ridhi R Eromon Philomena E PE Mehta Samar S Robles-Sikisaka Refugio R Siddle Katherine J KJ Stremlau Matt M Jalloh Simbirie S Gire Stephen K SK Winnicki Sarah S Chak Bridget B Schaffner Stephen F SF Pauthner Matthias M Karlsson Elinor K EK Chapin Sarah R SR Kennedy Sharon G SG Branco Luis M LM Kanneh Lansana L Vitti Joseph J JJ Broodie Nisha N Gladden-Young Adrianne A Omoniwa Omowunmi O Jiang Pan-Pan PP Yozwiak Nathan N Heuklom Shannon S Moses Lina M LM Akpede George O GO Asogun Danny A DA Rubins Kathleen K Kales Susan S Happi Anise N AN Iruolagbe Christopher O CO Dic-Ijiewere Mercy M Iraoyah Kelly K Osazuwa Omoregie O OO Okonkwo Alexander K AK Kunz Stefan S McCormick Joseph B JB Khan S Humarr SH Honko Anna N AN Lander Eric S ES Oldstone Michael B A MBA Hensley Lisa L Folarin Onikepe A OA Okogbenin Sylvanus A SA Günther Stephan S Ollila Hanna M HM Tewhey Ryan R Okokhere Peter O PO Schieffelin John S JS Andersen Kristian G KG Reilly Steven K SK Grant Donald S DS Garry Robert F RF Barnes Kayla G KG Happi Christian T CT Sabeti Pardis C PC

Nature microbiology 20240207 3

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and ...[more]

PMID: 38326571

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Project description:BackgroundOvine footrot caused by Dichelobacter nodosus (D. nodosus) is a contagious disease with serious economic and welfare impacts in sheep production systems worldwide. A better understanding of the host genetic architecture regarding footrot resistance/susceptibility is crucial to develop disease control strategies that efficiently reduce infection and its severity. A genome-wide association study was performed using a customized SNP array (47,779 SNPs in total) to identify genetic variants associated to footrot resistance/susceptibility in two Portuguese native breeds, i.e. Merino Branco and Merino Preto, and a population of crossbred animals. A cohort of 1375 sheep sampled across 17 flocks, located in the Alentejo region (southern Portugal), was included in the analyses.ResultsPhenotypes were scored from 0 (healthy) to 5 (severe footrot) based on visual inspection of feet lesions, following the Modified Egerton System. Using a linear mixed model approach, three SNPs located on chromosome 24 reached genome-wide significance after a Bonferroni correction (p < 0.05). Additionally, six genome-wide suggestive SNPs were identified each on chromosomes 2, 4, 7, 8, 9 and 15. The annotation and KEGG pathway analyses showed that these SNPs are located within regions of candidate genes such as the nonsense mediated mRNA decay associated PI3K related kinase (SMG1) (chromosome 24) and the RALY RNA binding protein like (RALYL) (chromosome 9), both involved in immunity, and the heparan sulfate proteoglycan 2 (HSPG2) (chromosome 2) and the Thrombospodin 1 (THBS1) (chromosome 7) implicated in tissue repair and wound healing processes.ConclusionThis is the first attempt to identify molecular markers associated with footrot in Portuguese Merino sheep. These findings provide relevant information on a likely genetic association underlying footrot resistance/susceptibility and the potential candidate genes affecting this trait. Genetic selection strategies assisted on the information obtained from this study could enhance Merino sheep-breeding programs, in combination with farm management strategies, for a more effective and sustainable long-term solution for footrot control.

Project description:A rotator cuff is a muscle and tendon surrounding the shoulder joint, and a rotator cuff tear can be caused by overuse or injury, which leads to great pain in affected individuals. However, rotator cuff tear is a multifactorial process whose underlying mechanism is still unclear. Many previous studies have suggested an important role of genetic predisposition, such as single-nucleotide polymorphisms (SNPs), in explaining the genesis of tendinopathy. This study aimed to identify specific genes or genetic variants associated with rotator cuff tears by performing a genome-wide association study (GWAS) using an independent case of rotator cuff tears. GWAS was performed using data from CHA Bundang Medical Center with 20 cases of rotator cuff tears, and 20 cases of healthy controls genotyped on the Illumina HiSeq 2500. Tests of association were performed using the Burrows−Wheeler Aligner (BWA) software at 284,246 SNPs. Data were filtered based on sequence ontology, minor allele frequency, and Hardy−Weinberg equilibrium values, and SNPs were considered significant if the p-value was <0.05. The tests of association revealed more than 20 significantly associated SNPs. SNPs showing the highest significance occurred in candidate genes, including LAIR2 (rs2287828, OR 9.116, p-value 5.49 × 10−4) on chromosome 19 and CRIPAK (rs9328733, OR 6, p-value 1.11 × 10−3) and REST (rs2228991, OR 8.222, p-value 1.20 × 10−3) on chromosome 4. This study attempted to identify genetic variants influencing rotator cuff tears through a genome-wide association study using a dense set of SNPs. More than 20 SNPs were significantly associated with rotator cuff tears. The major limitation of this study is that it was conducted on a small study group and requires further validation. Nevertheless, the identification of potential genetic variants related to rotator cuff injury would aid in the early detection of individuals at risk for the development of tendinopathy and will provide insight into future gene therapies.

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Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.

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Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.

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