scholarly journals Short-term heritable variation overwhelms two hundred generations of mutational variance for metabolic traits in Caenorhabditis elegans

2020 ◽  
Author(s):  
Charles F. Baer ◽  
Dan Hahn ◽  
Lindsay M Johnson ◽  
Olivia J Smith
Keyword(s):  
Enzyme Activity ◽  
Caenorhabditis Elegans ◽  
Association Studies ◽  
Spontaneous Mutation ◽  
Metabolic Enzyme ◽  
Genome Wide Association Studies ◽  
Short Term ◽  
Heritable Variation ◽  
Metabolic Traits ◽  
Heritable Effects

ABSTRACTMetabolic disorders have a large heritable component, and have increased over the past few generations. Genome-wide association studies of metabolic traits typically find a substantial unexplained fraction of total heritability, suggesting an important role of spontaneous mutation. An alternative explanation is that epigenetic effects contribute significantly to the heritable variation. Here we report a study designed to quantify the cumulative effects of spontaneous mutation on adenosine metabolism in the nematode Caenorhabditis elegans, including both the activity and concentration of two metabolic enzymes and the standing pools of their associated metabolites. The only prior studies on the effects of mutation on metabolic enzyme activity, in Drosophila melanogaster, found that total enzyme activity presents a mutational target similar to that of morphological and life-history traits. However, those studies were not designed to account for short-term heritable effects. We find that the short-term heritable variance for most traits is of similar magnitude as the variance among MA lines. This result suggests that the potential heritable effects of epigenetic variation in metabolic disease warrant additional scrutiny.

scholarly journals Short‐term heritable variation overwhelms 200 generations of mutational variance for metabolic traits in Caenorhabditis elegans

Evolution ◽  
2020 ◽  
Vol 74 (11) ◽  
pp. 2451-2464
Author(s):  
Lindsay M. Johnson ◽  
Olivia J. Smith ◽  
Daniel A. Hahn ◽  
Charles F. Baer
Keyword(s):  
Caenorhabditis Elegans ◽  
Short Term ◽  
Heritable Variation ◽  
Metabolic Traits ◽  
Mutational Variance

scholarly journals Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gregory R. Keele ◽  
Jeremy W. Prokop ◽  
Hong He ◽  
Katie Holl ◽  
John Littrell ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genetic Model ◽  
Association Studies ◽  
Model Systems ◽  
Linear Mixed Effect Model ◽  
Genome Wide Association Studies ◽  
Tubulointerstitial Injury ◽  
Heritable Variation ◽  
Mixed Effect

AbstractChronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.

Characterizing a common CERS2 polymorphism in a mouse model of metabolic disease and in subjects from the Utah CAD Study

2021 ◽  
Author(s):  
Rebekah J Nicholson ◽  
Annelise M Poss ◽  
J Alan Maschek ◽  
James E Cox ◽  
Paul N Hopkins ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Coronary Artery Disease ◽  
Enzyme Activity ◽  
Coronary Artery ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Serum Samples ◽  
Artery Disease ◽  
Disease Study

Abstract Context Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP, rs267738) in CERS2 – a gene that encodes a (dihydro)ceramide synthase involved in the biosynthesis of very-long chain sphingolipids (e.g. C20-C26) – and indices of metabolic dysfunction (e.g. impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved. Objective The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes. Design We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring one (n = 163) or both (n = 22) rs267738 alleles. Results In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based CERT1 risk score of cardiovascular disease were not significantly affected by rs267738 allele count. Conclusions The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.

scholarly journals Polygenic risk scores for psychiatric, inflammatory, and cardio-metabolic traits and diseases highlight possible genetic overlaps with suicide attempt and treatment-emergent suicidal ideation

2021 ◽  
Author(s):  
Giuseppe Fanelli ◽  
Marcus Sokolowski ◽  
Danuta Wasserman ◽  
Siegfried Kasper ◽  
Joseph Zohar ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Suicide Attempt ◽  
Association Studies ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genetic Covariance ◽  
Polygenic Risk ◽  
Metabolic Traits ◽  
Gene Sets ◽  
Artery Disease

AbstractSuicide is the second leading cause of death among young people. Genetics may contribute to suicidal phenotypes and their co-occurrence in other psychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 22 psychiatric, inflammatory, and cardio-metabolic traits and diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI).PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts, including up to 3,834 individuals, and results were meta-analyzed across samples. Stratified genetic covariance analyses were performed to investigate the biology underlying cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was positively associated with SA (p=1.7e-4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p=4.6e-3) or loneliness (p=0.009) and SA, PRSs for MDD or CAD and TWESI (p=0.033 and p=0.032, respectively). Genetic covariance between MDD and SA was shown in 35 gene sets related to drugs having anti-suicidal effects.A higher genetic liability for MDD may underlie a higher risk of SA. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.

scholarly journals Genome-wide association studies for fatty acid metabolic traits in five divergent pig populations

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Wanchang Zhang ◽  
Bin Yang ◽  
Junjie Zhang ◽  
Leilei Cui ◽  
Junwu Ma ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Metabolic Traits ◽  
Genome Wide

scholarly journals Modelling the Functional Genomics of Parkinson’s in Caenorhabditis elegans: LRRK2 and Beyond

2021 ◽  
Author(s):  
Rachael J Chandler ◽  
Susanna Cogo ◽  
Patrick A Lewis ◽  
Eva Kevei
Keyword(s):  
Caenorhabditis Elegans ◽  
Current Knowledge ◽  
Association Studies ◽  
Mendelian Disease ◽  
Genome Wide Association Studies ◽  
Cellular Mechanisms ◽  
C Elegans ◽  
Functional Models

For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits

2011 ◽  
Vol 43 (10) ◽  
pp. 990-995 ◽  
Author(s):  
Young Jin Kim ◽  
◽  
Min Jin Go ◽  
Cheng Hu ◽  
Chang Bum Hong ◽  
...  
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
East Asians ◽  
Metabolic Traits ◽  
Genome Wide

scholarly journals Genetic correlation and causal relationships between cardio-metabolic traits and Lung function Impairment

2020 ◽  
Author(s):  
Matthias Wielscher ◽  
Andre FS Amaral ◽  
Diana van der Plaat ◽  
Louise V Wain ◽  
Sylvain Sebert ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Lung Function ◽  
Genetic Correlation ◽  
Large Scale ◽  
Causal Effect ◽  
Association Studies ◽  
Metabolic Health ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Metabolic Traits

Background: Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods We performed three analyses: 1) cardio-metabolic health to lung function association tests in NFBC1966, 2) cross trait LD score regression to compare genetic backgrounds and 3) Mendelian Randomization (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from UK Biobank data or published large-scale genome-wide association studies (N > 82,000). Results We observed negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR) we found associations between Type 2 Diabetes instruments and FVC as well as FEV1/FVC. BMI instruments were associated to all lung function traits and CRP instruments to FVC. These genetic association provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Conclusions: The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being mediated by CRP. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

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