The genetics of gene expression.
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Gene Expression Profiling↗
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Results for “expression quantitative trait loci”
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SNPannotator: automated functional annotation of genetic variants and linked proxies.
SUMMARY: Genome-wide association studies (GWASs) have identified thousands of genetic variants associated with complex traits and diseases. However, explaining the mechanisms underlying phenotypic variation remains challenging. Here, we introduce SNPannotator, an automated post-GWAS analysis software package designed to streamline the interpretation of GWAS findings. Our pipeline implements a multi-step process that identifies proxy variants in high linkage disequilibrium (LD) with associated lead variants, then queries comprehensive resources (including Ensembl, the GTEx Portal, the eQTL Catalog, and STRING DB) for genomic position, deleteriousness, regulatory annotations, clinical significance, trait associations, expression (eQTLs) and splicing quantitative trait loci (sQTLs), and functional enrichment analyses and compiles the results into user-friendly reports. This package is implemented in the R programming language and includes auxiliary functions for variant lookup and LD exploration. SNPannotator provides a practical framework for efficiently deriving biologically meaningful insights from GWAS data and for assisting researchers in prioritizing candidate variants for functional validation. AVAILABILITY AND IMPLEMENTATION: The SNPannotator package is available from the Comprehensive R Archive Network (CRAN) at https://cran.r-project.org/web/packages/SNPannotator. The development version and tutorial is available on GitHub (https://github.com/omicslaboratory/SNPannotator). The online version of the package is available at https://omicslab.org/snpannotator.
Software↗
Species-wide quantitative transcriptomes and proteomes reveal distinct genetic control of gene expression variation in yeast.
Gene expression varies between individuals and corresponds to a key step linking genotypes to phenotypes. However, our knowledge regarding the species-wide genetic control of protein abundance, including its dependency on transcript levels, is very limited. Here, we have determined quantitative proteomes of a large population of 942 diverse natural Saccharomyces cerevisiae yeast isolates. We found that mRNA and protein abundances are weakly correlated at the population gene level. While the protein coexpression network recapitulates major biological functions, differential expression patterns reveal proteomic signatures related to specific populations. Comprehensive genetic association analyses highlight that genetic variants associated with variation in protein (pQTL) and transcript (eQTL) levels poorly overlap (3%). Our results demonstrate that transcriptome and proteome are governed by distinct genetic bases, likely explained by protein turnover. It also highlights the importance of integrating these different levels of gene expression to better understand the genotype-phenotype relationship.
Saccharomyces cerevisiae↗
Identification of multiple genetic loci that regulate adenovirus gene therapy.
A key aspect of the immune response to adenovirus (Ad) gene therapy is the generation of a cytotoxic T-cell (CTL) response. To better understand the genetic network underlying these events, 20 strains of C57BL/6 x DBA/2 (BXD) recombinant inbred (RI) mice were administered with AdLacZ and analyzed at days 7, 21, 30, and 50 for liver beta-galactosidase (LacZ) expression and CTL response. Sera levels of interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were analyzed at different times after AdLacZ. There was a distinct strain-dependent expression of LacZ, which was strongly correlated with the CTL response. Among the five BXD RI strains that exhibited significantly prolonged LacZ expression, four also exhibited a marked defect in the production of Ad-specific CTL. There was a strong correlation between the sera levels of IFN-gamma, TNF-alpha, and IL-6, but cytokine responses were not significantly correlated with LacZ expression or the CTL response. Quantitative trait loci regulating LacZ on day 30 were found on chromosome (Chr) 19 (33 cM) and Chr 15 (42.8 cM). Cytotoxicity mapped to Chr 7 (41.0 and 57.4-65.2 cM), Chr 15 (61.7 cM), and Chr X (27.8 cM). IFN-gamma production mapped to Chr 18 (22, 27, and 32 cM) and Chr 11 (64.0 cM). TNF-alpha and IL-6 production mapped to Chr 6 (91.5 cM) Chr 9 (42.0 cM) and Chr 8 (52 and 73.0 cM). These results indicate that different strains of mice exhibit different pathways for effective clearance of AdLacZ depending on genetic polymorphisms and interactions at multiple genetic loci.
Adenoviridae↗
Susceptibility to autoimmune disease and drug addiction in inbred rats. Are there mechanistic factors in common related to abnormalities in hypothalamic-pituitary-adrenal axis and stress response function?
DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental autoimmune diseases. These diseases include rheumatoid arthritis models such as collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA), multiple sclerosis models such as myelin-basic-protein (MBP)-induced experimental autoimmune encephalomyelitis (MBP-EAE), and autoimmune uveitis models such as retinal S antigen (SAG) and interphotoreceptor-retinoid-binding-protein (IRBP)-induced experimental autoimmune uveitis (SAG-EAU and IRBP-EAU, respectively). DA and LEW rats are also addiction-prone to various drugs of abuse, such as cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction. By contrast, F344 and BN rats show quite different phenotypes. They are relatively resistant to CIA, AIA, MBP-EAE, SAG-EAU, and IRBP-EAU, and they are relatively resistant to addiction. Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function. For example, circadian production of corticosteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in corticosterone levels. Since corticosteroids potentially have significant influences on immune function and autoimmune disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect genetic control of these various phenotypic differences, focusing initially on the regulation of autoimmune disease expression. Using genomewide scanning techniques involving F2 crosses of DA x F344 (CIA and AIA), DA x BN (CIA), and LEW x F344 [IRBP-EAU and streptococcal-cell-wall arthritis (SCWA)], we have identified, to date, 14 genomic regions [quantitative trait loci (QTL)] that regulate disease expression in these crosses. Development and analysis of QTL-congenic rats involving these loci are in progress and should permit us to address the relationships among autoimmune disease susceptibility, drug addiction, and HPA axis and stress response function. These initial data, however, indicate that the genetic control of the autoimmune disease traits is highly complex.
Animals↗
Pathophysiology of beta thalassemia--a guide to molecular therapies.
The central mechanism underlying the pathophysiology of the beta thalassemias can be related to the deleterious effects of imbalanced globin chain synthesis on erythroid maturation and survival. An imbalance of the alpha/non-alpha globin chains leads to an excess of unmatched alpha globin which precipitates out, damaging membrane structures leading to accelerated apoptosis and premature destruction of the erythroid precursors in the bone marrow (ineffective erythropoiesis). Close observation of the genotype/phenotype relationships confirms the pathophysiological mechanism and provides clues to molecular therapies, all of which aim to reduce the alpha/non-alpha chain imbalance. They include inheritance of the milder forms of beta thalassemia, co-inheritance of alpha thalassemia, or genetic factors (quantitative trait loci, QTLs) for increasing gamma globin expression. Currently, the most promising molecular therapeutic approaches include increasing beta globin gene expression by stem cell gene therapy and increasing gamma globin expression using pharmacological agents or by transduction of the gamma globin genes.
Erythropoiesis↗
Molecular-marker-facilitated investigations of quantitative-trait loci in maize. I. Numbers, genomic distribution and types of gene action.
Individual genetic factors which underlie variation in quantitative traits of maize were investigated in each of two F2 populations by examining the mean trait expressions of genotypic classes at each of 17-20 segregating marker loci. It was demonstrated that the trait expression of marker locus classes could be interpreted in terms of genetic behavior at linked quantitative trait loci (QTLs). For each of 82 traits evaluated, QTLs were detected and located to genomic sites. The numbers of detected factors varied according to trait, with the average trait significantly influenced by almost two-thirds of the marked genomic sites. Most of the detected associations between marker loci and quantitative traits were highly significant, and could have been detected with fewer than the 1800-1900 plants evaluated in each population. The cumulative, simple effects of marker-linked regions of the genome explained between 8 and 40% of the phenotypic variation for a subset of 25 traits evaluated. Single marker loci accounted for between 0.3% and 16% of the phenotypic variation of traits. Individual plant heterozygosity, as measured by marker loci, was significantly associated with variation in many traits. The apparent types of gene action at the QTLs varied both among traits and between loci for given traits, although overdominance appeared frequently, especially for yield-related traits. The prevalence of apparent overdominance may reflect the effects of multiple QTLs within individual marker-linked regions, a situation which would tend to result in overestimation of dominance. Digenic epistasis did not appear to be important in determining the expression of the quantitative traits evaluated. Examination of the effects of marked regions on the expression of pairs of traits suggests that genomic regions vary in the direction and magnitudes of their effects on trait correlations, perhaps providing a means of selecting to dissociate some correlated traits. Marker-facilitated investigations appear to provide a powerful means of examining aspects of the genetic control of quantitative traits. Modifications of the methods employed herein will allow examination of the stability of individual gene effects in varying genetic backgrounds and environments.
Chromosome Mapping↗
Lipid level and type alter stearoyl CoA desaturase mRNA abundance differently in mice with distinct susceptibilities to diet-influenced diseases.
Chronic diseases develop in susceptible individuals following exposure to environmental conditions including high fat diets. Inbred strains of mice differing in susceptibility to atherosclerosis, diabetes, obesity and certain cancers are models for understanding the genetic basis and molecular mechanisms whereby diet influences these polygenic and multifactorial disorders. Expression sequence tags (EST) and disease quantitative trait loci (QTL) are also being identified with these strains. Reported here are comparisons of food intake, growth, nonfasting serum lipids and expression of mRNA for hepatic apolipoprotein E (ApoE), hepatic stearoyl CoA desaturase (Scd1) and heart lipoprotein lipase (Lpl) in a 2 x 2 x 2 design with C57BL/6J and BALB/cByJ mice fed semipurified diets with 4 or 20% saturated (coconut) or unsaturated (corn) oils for 4 mo. Histological studies of aortas and coronary arteries are also reported for these animals. After 4 mo, BALB/cByJ mice were significantly heavier and had significantly higher total serum cholesterol, HDL cholesterol and triglyceride concentrations in the fed state than C57BL/6J mice. Efficiency of utilizing dietary energy did not differ consistently between strains. Oil level affected serum total cholesterol, triglycerides and HDL cholesterol, which were significantly greater in mice fed high fat diets. Lpl and ApoE mRNA expression levels were not significantly affected by mouse strain, oil source or oil level. Scd1 mRNA expression, however, was significantly higher in C57BL/6J than in BALB/cByJ mice and was lower in all mice fed 20% compared with those fed 4% fat diets. Genes regulated differently by diet among strains with distinct susceptibility to diet-influenced disease may be associated with molecular pathways contributing to incidence or severity.
Animals↗
gamma-Aminobutyric acid A receptor subunit mutant mice: new perspectives on alcohol actions.
gamma-Aminobutyric acid A (GABA(A)) receptors are believed to mediate a number of alcohol's behavioral actions. Because the subunit composition of GABA(A) receptors determines receptor pharmacology, behavioral sensitivity to alcohol (ethanol) may depend on which subunits are present (or absent). A number of knock-out and/or transgenic mouse models have been developed (alpha1, alpha2, alpha5, alpha6, beta2, beta3, gamma2S, gamma2L, delta) and tested for behavioral sensitivity to ethanol. Here we review the current GABA(A) receptor subunit knock-out and transgenic literature for ethanol sensitivity, and integrate these results into those obtained using quantitative trait loci (QTL) analysis and gene expression assays. Converging evidence from these three approaches support the notion that different behavioral actions of ethanol are mediated by specific subunits, and suggest that new drugs that target specific GABA(A) subunits may selectively alter some behavioral actions of ethanol, without altering others. Current data sets provide strongest evidence for a role of alpha1-subunits in ethanol-induced loss of righting reflex, and alpha5-subunits in ethanol-stimulated locomotion. However, three-way validation is hampered by the incomplete behavioral characterization of many of the mutant mice, and additional subunits are likely to be linked to alcohol actions as behavioral testing progresses.
Animals↗
Multiple polymorphic loci determine basal hepatic and splenic iron status in mice.
Polymorphisms of genes linked to iron metabolism may account for individual variability in hemochromatosis and iron status connected with liver and cardiovascular diseases, cancers, toxicity, and infection. Mouse strains exhibit marked differences in levels of non-heme iron, with C57BL/6J and SWR showing low and high levels, respectively. The genetic basis for this variability was examined using quantitative trait loci (QTL) analysis together with expression profiling and chromosomal positions of known iron-related genes. Non-heme iron levels in liver and spleen of C57BL/6J x SWR F2 mice were poorly correlated, indicating independent regulation. Highly significant (P < .01) polymorphic loci were found on chromosomes 2 and 16 for liver and on chromosomes 8 and 9 for spleen. With sex as a covariate, additional significant or suggestive (P < 0.1) QTL were detected on chromosomes 7, 8, 11, and 19 for liver and on chromosome 2 for spleen. A gene array showed no clear association between most loci and differential iron-related gene expression. The gene for transferrin and a transferrin-like gene map close to the QTL on chromosome 9. Transferrin saturation was significantly lower in C57BL/6J mice than in SWR mice, but there was no significant difference in the serum level of transferrin, hepatic expression, or functional change in cDNA sequence. beta2-Microglobulin, which, unlike other loci, was associated with C57BL/6J alleles, is a candidate for the chromosome 2 QTL for higher iron. In conclusion, the findings show the location of polymorphic genes that determine basal iron status in wild-type mice. Human equivalents may be pertinent in predisposition to hepatic and other disorders.
Animals↗
Genetic control of dormancy in a Triumph/Morex cross in barley.
Seed dormancy in barley ( Hordeum vulgare L.) is one of the most important parameters affecting malting. Seed dormancy is quantitatively inherited and variously influenced by the environment. The objectives of the present study were to determine the genome location and effects of quantitative trait loci (QTLs) involved in the expression of seed dormancy in a barley cross between two varieties derived from different germplasm pools. Using a doubled-haploid population of 107 lines of the cross between the malting types Triumph (two-row, dormant) and Morex (six-row, non-dormant), seed dormancy phenotypic data sets from five environments and a 147-marker linkage map were developed in order to perform QTL analyses with simple interval mapping and simplified composite interval mapping procedures. Two different types of variables were considered for seed dormancy characterization: (1) level of dormancy induced during seed development, which was indirectly measured as germination percentage at 3 days and 7 days, GP3 and GP7 respectively; (2) rate of dormancy release in the course of a period after seed harvest (after-ripening). Different mechanisms of genetic control were detected for these two types of dormancy-related traits. A major and consistent dormancy QTL near the centromere on chromosome 7(5H) was associated with the establishment of dormancy during seed development and accounted for 52% and 33% of the variability for GP3 and GP7, respectively. Two other QTLs located in the vicinity of the vrs1 locus on chromosome 2(2H) and near the long arm telomere on chromosome 7(5H) explained 9% and 19% of variation, respectively, for the rate of dormancy release during after-ripening. Likewise, seed dormancy was assessed in an F(2) population derived from the cross between two dormant types of distinct germplasm groups, Triumph (European, two-row, malt) and Steptoe (North American, six-row, feed), which showed similar but not identical genetic control for dormancy. Interestingly, there is remarkable dormancy QTL conservation in both regions on chromosome 7(5H) identified in this study and among other barley mapping populations. These widely conserved QTLs show potential as targets for selection of a moderate level of seed dormancy in breeding programs.
Chromosome Mapping↗
Integration of Genome-Wide Association Studies With Single-Cell and Bulk Expression Quantitative Trait Locus to Identify Stroke Susceptibility Genes.
BACKGROUND: Previous studies have integrated genome-wide association studies with expression quantitative trait locus (eQTL) data from bulk tissues to identify stroke susceptibility genes. However, eQTL data exhibit high cell-type specificity, and genetic variants may have distinct effects across stroke subtypes. METHODS: We applied the summary-data-based Mendelian randomization (MR) method to integrate eQTL data from 7 brain cell types with genome-wide association studies data for 5 stroke phenotypes (stroke, ischemic stroke, cardioembolic stroke, large artery stroke, and small vessel stroke). Results were compared with summary-data-based MR using eQTL data from 49 tissues in the Genotype-Tissue Expression project. Robustness of significant single-cell summary-data-based MR associations was assessed via MR and colocalization analyses. Further evaluations included single-cell RNA-seq differential expression, protein-protein interaction, druggability, and phenome-wide association studies. RESULTS: Single-cell summary-data-based MR identified many novel significant genes not detected using bulk tissue eQTL data. Validated associations revealed 2 stroke risk genes (LRCH1, ICA1L), 3 stroke protective genes (AHI1, LYRM9, CENPQ), 2 large artery stroke risk genes (LIPA, ELL), and 1 ischemic stroke protective gene (CENPQ). Single-cell RNA-seq showed significantly increased LIPA expression in mouse stroke samples compared with controls. Protein-protein interaction and druggability analyses, along with phenome-wide association studies, prioritized LIPA and LRCH1 as potential therapeutic targets for stroke while indicating possible adverse effects. CONCLUSIONS: Integrating single-cell eQTL with stroke-subtype genome-wide association studies uncovers novel cell-type-specific causal genes and highlights promising therapeutic targets, advancing understanding of stroke pathogenesis.
Genome-Wide Association Study↗
Quantitative trait loci for floral morphology in Arabidopsis thaliana.
A central question in biology is how genes control the expression of quantitative variation. We used statistical methods to estimate genetic variation in eight Arabidopsis thaliana floral characters (fresh flower mass, petal length, petal width, sepal length, sepal width, long stamen length, short stamen length, and pistil length) in a cosmopolitan sample of 15 ecotypes. In addition, we used genome-wide quantitative trait locus (QTL) mapping to evaluate the genetic basis of variation in these same traits in the Landsberg erecta x Columbia recombinant inbred line population. There was significant genetic variation for all traits in both the sample of naturally occurring ecotypes and in the Ler x Col recombinant inbred line population. In addition, broad-sense genetic correlations among the traits were positive and high. A composite interval mapping (CIM) analysis detected 18 significant QTL affecting at least one floral character. Eleven QTL were associated with several floral traits, supporting either pleiotropy or tight linkage as major determinants of flower morphological integration. We propose several candidate genes that may underlie these QTL on the basis of positional information and functional arguments. Genome-wide QTL mapping is a promising tool for the discovery of candidate genes controlling morphological development, the detection of novel phenotypic effects for known genes, and in generating a more complete understanding of the genetic basis of floral development.
Arabidopsis↗
From gene to behavior and back again: new perspectives on GABAA receptor subunit selectivity of alcohol actions.
gamma-Aminobutyric acid A (GABA(A)) receptors are believed to mediate a number of alcohol's behavioral actions. Because the subunit composition of GABA(A) receptors determines receptor pharmacology, behavioral sensitivity to alcohol (ethanol) may depend on which subunits are present (or absent). A number of knockout and/or transgenic mouse models have been developed (alpha1, alpha2, alpha5, alpha6, beta2, beta3, gamma2S, gamma2L, delta) and tested for behavioral sensitivity to ethanol. Here we review the current GABA(A) receptor subunit knockout and transgenic literature for ethanol sensitivity, and integrate these results into those obtained using quantitative trait loci (QTL) analysis and gene expression assays. Converging evidence from these three approaches support the notion that different behavioral actions of ethanol are mediated by specific subunits, and suggest that new drugs that target specific GABA(A subunits may selectively alter some behavioral actions of ethanol without altering others. Current data sets provide stronge)st evidence for a role of alpha1 subunits in ethanol-induced loss of righting reflex and alpha5 subunits in ethanol-stimulated locomotion. Nevertheless, three-way validation is hampered by the incomplete behavioral characterization of many of the mutant mice, and additional subunits are likely to be linked to alcohol actions as behavioral testing progresses.
Journal Article↗
Behavioural and physiological characterization of inbred mouse strains: prospects for elucidating the molecular mechanisms of mammalian learning and memory.
With the advent of recombinant DNA methodology, it has become possible to dissect the molecular mechanisms of complex traits, including brain function and behaviour. The increasing amount of available information on the genomes of mammalian organisms, including our own, has facilitated this research. The present review focuses on a somewhat neglected area of genetics, one that involves the study of inbred mouse strains. It is argued that the use of inbred mice is complementary to transgenic approaches in the analysis of molecular mechanisms of complex traits. Whereas transgenic technology allows one to manipulate a single gene and investigate the in vivo effects of highly specific, artificially induced mutations, the study of inbred mouse strains should shed light on the roles of naturally occurring allelic variants in brain function and behaviour. Systematic characterization of the behavioural, electrophysiological, neurochemical, and neuroanatomical properties of a large number of inbred strains is required to elucidate mechanisms of mammalian brain function and behaviour. In essence, a 'mouse phenome' project is needed, entailing the construction of databases to investigate possible causal relationships amongst the phenotypical characteristics. This review focuses on electrophysiological and behavioural characterization of mouse strains. Nevertheless, it is emphasized that the full potential of the analysis of inbred mouse strains may be attained if techniques of numerous disciplines, including gene expression profiling, biochemical analysis, and quantitative trait loci (QTL) mapping, to name but a few, are also included.
Animals↗
The role of reactive oxygen species on Plasmodium melanotic encapsulation in Anopheles gambiae.
Malaria transmission depends on the competence of some Anopheles mosquitoes to sustain Plasmodium development (susceptibility). A genetically selected refractory strain of Anopheles gambiae blocks Plasmodium development, melanizing, and encapsulating the parasite in a reaction that begins with tyrosine oxidation, and involves three quantitative trait loci. Morphological and microarray mRNA expression analysis suggest that the refractory and susceptible strains have broad physiological differences, which are related to the production and detoxification of reactive oxygen species. Physiological studies corroborate that the refractory strain is in a chronic state of oxidative stress, which is exacerbated by blood feeding, resulting in increased steady-state levels of reactive oxygen species, which favor melanization of parasites as well as Sephadex beads.
Animals↗
Addiction and its brain science.
AIMS: To illustrate how modern neurobiological approaches will help to identify the neurocircuits and genes involved in addictive behavior. BACKGROUND: The current disorder concept of addiction includes neurobiological foundations and neurobiological research assuming irreversible molecular and structural changes within the brain dopamine reinforcement system, constituting the 'molecular and structural switch' from controlled drug intake to compulsive drug abuse. However, those irreversible changes have not so far been identified and it is suggested that in addition to the mesolimbic dopamine system, other brain systems including the mesocortical and nigrostriatal pathways as well as their non-dopaminergic feedback-loops might be involved in addictive behavior. NEUROBIOLOGICAL APPROACH: A three-step neurobiological approach is described that allows in a first step via novel animal models and imaging techniques to identify the neuroanatomical sites mediating voluntary drug intake, reinstatement of drug-seeking behavior, relapse, loss of control and drug intake despite negative consequences. In a subsequent step, forward genetic approaches including quantitative trait loci (QTL)-analysis and gene expression profiling are helpful in identifying so-called candidate genes. In a final step, conditional animal mutants and selective pharmacological tools are used to functionally validate candidate genes. Following this validation process, the transfer to the human situation has to be made and candidate genes have to be verified further in well-phenotyped cohorts of addicted patients. CONCLUSION: This three-step neurobiological approach, that must involve an interdisciplinary team including experimental psychologists, geneticists, molecular biologists and finally clinical addiction researchers, will allow us to understand where and how the addicted brain goes awry.
Animals↗
Potential mitochondria-associated pathogenic genes in sepsis: a multi-omics Mendelian randomization study.
BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of sepsis. However, human genetic evidence linking mitochondria-related genes to sepsis susceptibility remains limited. This study aimed to identify mitochondria-related genes associated with sepsis risk using a multi-omics Mendelian randomization framework. METHODS: Summary-data-based Mendelian randomization (SMR) was applied using sepsis genome-wide association study (GWAS) summary statistics from the UK Biobank and FinnGen databases. Expression, methylation, single-cell, and protein quantitative trait loci (QTLs) were used as genetic instruments. Colocalization analyses were conducted to evaluate whether SMR associations were driven by shared genetic variants. Expression of prioritized candidate genes was further examined in clinical septic samples, and correlations with disease severity (SOFA scores) were assessed. RESULTS: SMR analysis prioritized 13 mitochondria-related genes associated with sepsis risk. Immune cell-specific eQTL analysis suggested that genetically predicted SURF1 expression in memory B cells and naïve T cells was associated with sepsis risk. Differential expression of 12 candidate genes was confirmed in septic patients by qPCR, and PPOX expression showed a negative correlation with SOFA scores. Integration of mQTL and eQTL data supported a regulatory relationship between methylation at cg06661924 and AK4 expression. Increased genetically predicted AK4 expression was associated with higher sepsis risk (OR = 1.21, 95% CI 1.02-1.42). Protein-level analysis identified DUT as a potential sepsis-associated candidate, with consistent evidence across streptococcal and pneumococcal septicemia subtypes. Subtype analyses also suggested heterogeneous genetic signals across different sepsis subtypes. CONCLUSION: This study prioritized several mitochondria-related genes associated with sepsis susceptibility based on human genetic evidence. These findings provide candidate targets for further mechanistic and translational investigation.
Humans↗