GWAS in Mice Maps Susceptibility to HIV-Associated Nephropathy to the Ssbp2 Locus

2021 ◽  
pp. ASN.2021040543
Author(s):  
Nicholas J. Steers ◽  
Yask Gupta ◽  
Vivette D. D’Agati ◽  
Tze Y. Lim ◽  
Natalia DeMaria ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Interstitial Fibrosis ◽  
Susceptibility Gene ◽  
F1 Hybrids ◽  
Mouse Strains ◽  
Genome Wide ◽  
A Genome ◽  
Host Genetic ◽  
Hiv 1 ◽  
Host Genetic Factors

BackgroundTo gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide association study (GWAS) among inbred mouse strains using a murine model of HIV-1 associated nephropathy (HIVAN).MethodsWe first generated F1 hybrids between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Analysis of histology, BUN, and urinary NGAL demonstrated marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS in 365 transgenic F1 hybrids generated from these 20 inbred strains was performed.ResultsWe identified a genome-wide significant locus on chromosome 13-C3 and multiple additional suggestive loci. Crossannotation of the Chr. 13 locus, including single-cell transcriptomic analysis of wildtype and HIV-1 transgenic mouse kidneys, nominated Ssbp2 as the most likely candidate gene. Ssbp2 is highly expressed in podocytes, encodes a transcriptional cofactor that interacts with LDB1 and LMX1B, which are both previously implicated in FSGS. Consistent with these data, older Ssbp2 null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model.ConclusionsThese findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest Ssbp2 as susceptibility gene for HIVAN, potentially acting via the LDB1-LMX1B transcriptional network.

scholarly journals Influence of host genetics in shaping the rumen bacterial community in beef cattle

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Waseem Abbas ◽  
Jeremy T. Howard ◽  
Henry A. Paz ◽  
Kristin E. Hales ◽  
James E. Wells ◽  
...  
Keyword(s):  
Bacterial Community ◽  
Species Composition ◽  
Community Composition ◽  
Genetic Factors ◽  
Bacterial Community Composition ◽  
Gastrointestinal Microbiota ◽  
Host Genetics ◽  
A Genome ◽  
Host Genetic ◽  
Host Genetic Factors

Abstract In light of recent host-microbial association studies, a consensus is evolving that species composition of the gastrointestinal microbiota is a polygenic trait governed by interactions between host genetic factors and the environment. Here, we investigated the effect of host genetic factors in shaping the bacterial species composition in the rumen by performing a genome-wide association study. Using a common set of 61,974 single-nucleotide polymorphisms found in cattle genomes (n = 586) and corresponding rumen bacterial community composition, we identified operational taxonomic units (OTUs), Families and Phyla with high heritability. The top associations (1-Mb windows) were located on 7 chromosomes. These regions were associated with the rumen microbiota in multiple ways; some (chromosome 19; position 3.0–4.0 Mb) are associated with closely related taxa (Prevotellaceae, Paraprevotellaceae, and RF16), some (chromosome 27; position 3.0–4.0 Mb) are associated with distantly related taxa (Prevotellaceae, Fibrobacteraceae, RF16, RFP12, S24-7, Lentisphaerae, and Tenericutes) and others (chromosome 23; position 0.0–1.0) associated with both related and unrelated taxa. The annotated genes associated with identified genomic regions suggest the associations observed are directed toward selective absorption of volatile fatty acids from the rumen to increase energy availability to the host. This study demonstrates that host genetics affects rumen bacterial community composition.

scholarly journals Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population

2019 ◽  
Vol 30 (5) ◽  
pp. 855-864 ◽  
Author(s):  
Chizu Tanikawa ◽  
Yoichiro Kamatani ◽  
Chikashi Terao ◽  
Masayuki Usami ◽  
Atsushi Takahashi ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Japanese Population ◽  
Quantitative Traits ◽  
Genetic Factors ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Weighted Genetic Risk Score ◽  
Host Genetic ◽  
Host Genetic Factors

BackgroundA family history of urolithiasis is associated with a more than doubling of urolithiasis risk, and a twin study estimating 56% heritability of the condition suggests a pivotal role for host genetic factors. However, previous genome-wide association studies (GWAS) have identified only six risk-related loci.MethodsTo identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan.ResultsThe analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%).ConclusionsOur findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.

scholarly journals Genome‐wide association study for host genetic factors associated with equine herpesvirus type‐1 induced myeloencephalopathy

2020 ◽  
Vol 52 (6) ◽  
pp. 794-798
Author(s):  
Wangisa M. B. Dunuwille ◽  
Navid YousefiMashouf ◽  
Udeni B. R. Balasuriya ◽  
Nicola Pusterla ◽  
Ernest Bailey
Keyword(s):  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Equine Herpesvirus ◽  
Herpesvirus Type ◽  
Factors Associated ◽  
Genome Wide ◽  
Equine Herpesvirus Type 1 ◽  
Host Genetic ◽  
Host Genetic Factors

Influence of host genetic factors on efavirenz plasma and intracellular pharmacokinetics in HIV-1-infected patients

2010 ◽  
Vol 11 (9) ◽  
pp. 1223-1234 ◽  
Author(s):  
Laure Elens ◽  
Bernard Vandercam ◽  
Jean-Cyr Yombi ◽  
Dominique Lison ◽  
Pierre Wallemacq ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Host Genetic ◽  
Hiv 1 ◽  
Host Genetic Factors

Rising HIV-1 viral load set point at a population level coincides with a fading impact of host genetic factors on HIV-1 control

AIDS ◽  
2011 ◽  
Vol 25 (18) ◽  
pp. 2217-2226 ◽  
Author(s):  
Daniëlle van Manen ◽  
Luuk Gras ◽  
Brigitte D. Boeser-Nunnink ◽  
Ard I. van Sighem ◽  
Irma Maurer ◽  
...  
Keyword(s):  
Viral Load ◽  
Genetic Factors ◽  
Population Level ◽  
Set Point ◽  
Host Genetic ◽  
Viral Load Set Point ◽  
Hiv 1 ◽  
Host Genetic Factors

scholarly journals Pervasive epigenetic effects of Drosophila euchromatic transposable elements impact their evolution

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yuh Chwen G Lee ◽  
Gary H Karpen
Keyword(s):  
Transposable Elements ◽  
Genetic Factors ◽  
Critical Role ◽  
Epigenetic Silencing ◽  
Evolutionary Genomics ◽  
Critical Question ◽  
Epigenetic Effects ◽  
Genome Wide ◽  
Host Genetic ◽  
Host Genetic Factors

Transposable elements (TEs) are widespread genomic parasites, and their evolution has remained a critical question in evolutionary genomics. Here, we study the relatively unexplored epigenetic impacts of TEs and provide the first genome-wide quantification of such effects in D. melanogaster and D. simulans. Surprisingly, the spread of repressive epigenetic marks (histone H3K9me2) to nearby DNA occurs at >50% of euchromatic TEs, and can extend up to 20 kb. This results in differential epigenetic states of genic alleles and, in turn, selection against TEs. Interestingly, the lower TE content in D. simulans compared to D. melanogaster correlates with stronger epigenetic effects of TEs and higher levels of host genetic factors known to promote epigenetic silencing. Our study demonstrates that the epigenetic effects of euchromatic TEs, and host genetic factors modulating such effects, play a critical role in the evolution of TEs both within and between species.

scholarly journals Replication of LZTFL1 gene region as a susceptibility locus for COVID-19 in Latvian population.

2021 ◽  
Author(s):  
Raimonds Rescenko ◽  
Raitis Peculis ◽  
Monta Ustinova ◽  
Laura Ansone ◽  
Helena Daiga Litvina ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Genetic Factors ◽  
P Values ◽  
Genome Wide ◽  
Increased Risk ◽  
Host Genetic ◽  
Introgression Event ◽  
Functional Investigation ◽  
Host Genetic Factors ◽  
Independent Cohort

The severity of COVID-19 disease is partly determined by host genetic factors that have been reported by GWAS. We evaluated nine previously reported genome-wide significant associations regardless of the disease severity in a representative sample from the population of Latvia. Our cohort consisted of 475 SARS-CoV-2 positive cases, from which 146 were hospitalized individuals and 2217 controls. We found three variants from Neanderthal introgression event at the 3p21.31 region to be significantly associated with increased risk of SARS-CoV-2 infection and hospitalization status. The strongest association was displayed by rs71325088 with Bonferroni adjusted P=0.007, OR=1.46 [95% CI 1.17-1.81]. We performed fine-mapping by exploring 1 Mb region at 3p21.31 locus and identified 9 SNPs with even lower p-values with the strongest association estimated for rs2191031 P=5e-05, OR = 1.40[CI 95% 1.19-1.64] located in the LZTFL1. We show clear replication of 3p.21.31 locus in an independent cohort which favors further functional investigation of leading variants.

scholarly journals GWAS identifies nine nephrolithiasis susceptibility loci related with metabolic metabolic and crystallization pathways

2019 ◽  
Author(s):  
Chizu Tanikawa ◽  
Yoichiro Kamatani ◽  
Chikashi Terao ◽  
Masayuki Usami ◽  
Atsushi Takahashi ◽  
...  
Keyword(s):  
Genetic Background ◽  
Quantitative Traits ◽  
Large Scale ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Genetic Variations ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
Host Genetic ◽  
Host Genetic Factors

ABSTRACTNephrolithiasis is a common urological trait disorder with acute pain. Although previous studies have identified various genetic variations associated with nephrolithiasis, the host genetic factors remain largely unidentified. To identify novel nephrolithiasis loci in the Japanese population, we performed large-scale GWAS (Genome wide association study) using 11,130 cases and 187,639 controls, followed by a replication analysis using 2,289 cases and 3,817 controls. The analysis identified 14 significant loci, including 9 novel loci on 2p23.2-3, 6p21.2, 6p12.3, 6q23.2, 16p12.3, 16q12.2, 17q23.2, 19p13.12, and 20q13.2. Interestingly, 10 of the 14 regions showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic background among nephrolithiasis patients and these quantitative traits. Four novel loci are related to the metabolic pathway, while the remaining 10 loci are associated with the crystallization pathway. Our findings demonstrate the crucial roles of genetic variations in the development of nephrolithiasis.SIGNIFICANCE STATEMENTNephrolithiasis is a common urothelial disorders with frequent recurrence rate, but its genetic background is largely remained unidentified. Previous GWAS identified 6 genetic factors in total. Here we performed a GWAS using more than 200,000 samples in the Japanese populations, and identified 14 significant loci and nine of them are novel. We also found that 10 of the 14 loci showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (BMI, eGFR, UA, Ca etc). All 14 significant loci are associate with either metabolic or crystallization pathways. Thus, our findings elucidated the underlying molecular pathogenesis of nephrolithiasis.

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