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PubMed1995

Diagnosing senescence: inferring evolutionary causes from phenotypic patterns can be misleading.

Based on the predictions of two theories for the evolution of senescence, the 'antagonistic pleiotropy' and the 'mutation accumulation' theory, an age-specific increase in mortality and a decrease in fecundity are widely used criteria to diagnose senescence in natural, and laboratory populations. In this study we question the reliability of these criteria. Using a simple model we show that similar phenotypic patterns result from optimal life histories without senescence. With a tradeoff between reproduction and period survival, optimal life histories produce patterns of increasing mortality and decreasing fecundity as organisms age, even if the tradeoff does not deteriorate with age, so that we are not forced to invoke genetic effects such as antagonistic pleiotropy or accumulation of deleterious mutations to explain such patterns. Furthermore, if optimal life history theory is applied to senescent organisms, phenotypic patterns can result that are usually not associated with senescence. We conclude that the reliability of a diagnosis of senescence based on phenotypic patterns and the comprehension of the phenomenon senescence depends critically on understanding to what extent tradeoffs are determined by the effects of segregating genes.

Aging↗

PubMed1991

Evolution of senescence: late survival sacrificed for reproduction.

In so far as it is associated with declining fertility and increasing mortality, senescence is directly detrimental to reproductive success. Natural selection should therefore act in the direction of postponing or eliminating senescence from the life history. The widespread occurrence of senescence is explained by observing that (i) the force of natural selection is generally weaker at late ages than at early ages, and (ii) the acquisition of greater longevity usually involves some cost. Two convergent theories are the 'antagonistic pleiotropy' theory, based in population genetics, and the 'disposable soma' theory, based in physiological ecology. The antagonistic pleiotropy theory proposes that certain alleles that are favoured because of beneficial early effects also have deleterious later effects. The disposable soma theory suggests that because of the competing demands of reproduction less effort is invested in the maintenance of somatic tissues than is necessary for indefinite survival.

Aging↗

PubMed2025

Associations of Genetic Liability to Six Psychiatric Disorders With Cardiometabolic Diseases.

IMPORTANCE: Individuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVE: Identify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN SETTING AND PARTICIPANTS: Three Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURES: Exposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTS: The MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCE: Associations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking.

Journal Article↗

PubMed2004

Extensive phenotypic variation in early flowering mutants of Arabidopsis.

Flowering time, the major regulatory transition of plant sequential development, is modulated by multiple endogenous and environmental factors. By phenotypic profiling of 80 early flowering mutants of Arabidopsis, we examine how mutational reduction of floral repression is associated with changes in phenotypic plasticity and stability. Flowering time measurements in mutants reveal deviations from the linear relationship between the number of leaves and number of days to bolting described for natural accessions and late flowering mutants. The deviations correspond to relative early bolting and relative late bolting phenotypes. Only a minority of mutants presents no detectable phenotypic variation. Mutants are characterized by a broad release of morphological pleiotropy under short days, with leaf characters being most variable. They also exhibit changes in phenotypic plasticity across environments for florigenic-related responses, including the reaction to light and dark, photoperiodic behavior, and Suc sensitivity. Morphological pleiotropy and plasticity modifications are differentially distributed among mutants, resulting in a large diversity of multiple phenotypic changes. The pleiotropic effects observed may indicate that floral repression defects are linked to global developmental perturbations. This first, to our knowledge, extensive characterization of phenotypic variation in early flowering mutants correlates with the reports that most factors recruited in floral repression at the molecular genetic level correspond to ubiquitous regulators. We discuss the importance of functional ubiquity for floral repression with respect to robustness and flexibility of network biological systems.

Arabidopsis↗

PubMed2001

Host-induced assortative mating in host races of the larch budmoth.

The likelihood of sympatric speciation is enhanced when assortative mating is a by-product of adaptation to different habitats. Pleiotropy of this kind is recognized as important in parasites that use their hosts as a long-range cue for finding mates, but is generally assumed to have limited applicability for most other organisms. In the larch budmoth, Zeiraphera diniana (Lepidoptera: Tortricidae), sympatric host races feed on larch or pine. Zeiraphera diniana females attract males (call) by releasing host-independent long-range pheromones. Pheromone composition differs strongly between host races, but we show in an experimental field study that cross-attraction can occur at a rate of 0.03-0.38. Cross-attraction to larch females increases when they call from neighborhoods (8-m radius) rich in pine or from pine trees. Cross-attraction to pine females similarly increases when calling from neighborhoods rich in larch, but there is no significant effect of calling substrate. Males, as well as females, of this species preferentially alight on their own host, and in neighborhoods where their own host is common. This effect of tree species and host neighborhood on assortative mating is therefore due, at least in part, to the numbers of males of each host race present within approximately 200 m2 surrounding the female. This proximity effect is enhanced by the clumped distributions of the hosts themselves. Host chemistry might also affect pheromone production and/or response directly, but we have evidence neither for nor against this. This work provides empirical evidence that host adaptation has a pleiotropic effect on assortative mating in a species with host-independent long-range mating signals. Sympatric speciation via pleiotropy between ecological traits and assortative mating may thus be more common than generally supposed: Clumped resource distributions and habitat choice by adults are widespread.

Alleles↗

PubMed2006

Evolution of late-life fecundity in Drosophila melanogaster.

Late-life fecundity has been shown to plateau at late ages in Drosophila analogously to late-life mortality rates. In this study, we test an evolutionary theory of late life based on the declining force of natural selection that can explain the occurrence of these late-life plateaus in Drosophila. We also examine the viability of eggs laid by late-age females and test a population genetic mechanism that may be involved in the evolution of late-life fecundity: antagonistic pleiotropy. Together these experiments demonstrate that (i) fecundity plateaus at late ages, (ii) plateaus evolve according to the age at which the force of natural selection acting on fecundity reaches zero, (iii) eggs laid by females in late life are viable and (iv) antagonistic pleiotropy is involved in the evolution of late-life fecundity. This study further supports the evolutionary theory of late life based on the age-specific force of natural selection.

Aging↗

PubMed2006

Genotype x environment interaction for male attractiveness in an acoustic moth: evidence for plasticity and canalization.

The lek paradox arises when choosy females deplete the genetic variance for male display traits from a population, yet substantial additive genetic variation (V(A)) in male traits persists. Thus, the lek paradox can be more generally stated as one of the most fundamental evolutionary questions: What maintains genetic variation in natural populations? One solution to this problem may be found in the condition-dependent nature of many sexually selected traits. Genotype x environment (G x E) interactions can maintain V(A) under conditions of environmental heterogeneity provided certain restrictions are met, although antagonistic pleiotropy has also been proposed as a mechanism. Here, we provide evidence for G x E interactions and against the role of antagonistic pleiotropy in the maintenance of V(A) for sexually selected traits. Using inbred lines of the lesser waxmoth Achroia grisella, we measured V(A) for song attractiveness, condition and development rate under different competitive environments and found that genotypes differed in their plasticity. We argue that variation persists in natural populations because G x E interactions prevent any one variant from producing the optimal phenotype across all environments.

Animals↗

PubMed2005

Bivariate linkage scan for reading disability and attention-deficit/hyperactivity disorder localizes pleiotropic loci.

BACKGROUND: There is a growing interest in the study of the genetic origins of comorbidity, a direct consequence of the recent findings of genetic loci that are seemingly linked to more than one disorder. There are several potential causes for these shared regions of linkage, but one possibility is that these loci may harbor genes with manifold effects. The established genetic correlation between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD) suggests that their comorbidity is due at least in part to genes that have an impact on several phenotypes, a phenomenon known as pleiotropy. METHODS: We employ a bivariate linkage test for selected samples that could help identify these pleiotropic loci. This linkage method was employed to carry out the first bivariate genome-wide analysis for RD and ADHD, in a selected sample of 182 sibling pairs. RESULTS: We found evidence for a novel locus at chromosome 14q32 (multipoint LOD=2.5; singlepoint LOD=3.9) with a pleiotropic effect on RD and ADHD. Another locus at 13q32, which had been implicated in previous univariate scans of RD and ADHD, seems to have a pleiotropic effect on both disorders. 20q11 is also suggested as a pleiotropic locus. Other loci previously implicated in RD or ADHD did not exhibit bivariate linkage. CONCLUSIONS: Some loci are suggested as having pleiotropic effects on RD and ADHD, while others might have unique effects. These results highlight the utility of this bivariate linkage method to study pleiotropy.

Adolescent↗

PubMed2006

Darwinian evolution can follow only very few mutational paths to fitter proteins.

Five point mutations in a particular beta-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of approximately 100,000. In principle, evolution to this high-resistance beta-lactamase might follow any of the 120 mutational trajectories linking these alleles. However, we demonstrate that 102 trajectories are inaccessible to Darwinian selection and that many of the remaining trajectories have negligible probabilities of realization, because four of these five mutations fail to increase drug resistance in some combinations. Pervasive biophysical pleiotropy within the beta-lactamase seems to be responsible, and because such pleiotropy appears to be a general property of missense mutations, we conclude that much protein evolution will be similarly constrained. This implies that the protein tape of life may be largely reproducible and even predictable.

Alleles↗

PubMed1971

Phenotypic reversion in some early blocked sporulation mutants of Bacillus subtilis: isolation and phenotype identification of partial revertants.

Single-step mutants of Bacillus subtilis blocked at stage zero of sporulation (spoO mutants) are pleiotropic. They are impaired in several traits, including increased sensitivity to polymyxin B, when compared to the wild type. Revertants for one or another of the traits associated in this pleiotropy have been isolated and classified according to their phenotypes. Attention was centered on partial revertants (spoO still), of which at least three classes could be recognized. Class I partial revertants recovered a high level of resistance to polymyxin and, in a constant order, a variable number of the other traits; some kind of hierarchy is thus revealed to exist among the traits affected in the original pleiotropy. Partial revertants in the other two classes are still hypersensitive to polymyxin. In class II revertants, ability to excrete exoenzymes and antibiotic(s) is recovered to various extents. Only inducibility of nitrate reductase by nitrate is recovered in class III mutants. The possible significance of these observations is discussed.

Anti-Bacterial Agents↗

PubMed2002

The rpoZ gene, encoding the RNA polymerase omega subunit, is required for antibiotic production and morphological differentiation in Streptomyces kasugaensis.

The occurrence of pleiotropic mutants that are defective in both antibiotic production and aerial mycelium formation is peculiar to streptomycetes. Pleiotropic mutant KSB was isolated from wild-type Streptomyces kasugaensis A1R6, which produces kasugamycin, an antifungal aminoglycoside antibiotic. A 9.3-kb DNA fragment was cloned from the chromosomal DNA of strain A1R6 by complementary restoration of kasugamycin production and aerial hypha formation to mutant KSB. Complementation experiments with deletion plasmids and subsequent DNA analysis indicated that orf5, encoding 90 amino acids, was responsible for the restoration. A protein homology search revealed that orf5 was a homolog of rpoZ, the gene that is known to encode RNA polymerase subunit omega (omega), thus leading to the conclusion that orf5 was rpoZ in S. kasugaensis. The pleiotropy of mutant KSB was attributed to a 2-bp frameshift deletion in the rpoZ region of mutant KSB, which probably resulted in a truncated, incomplete omega of 47 amino acids. Furthermore, rpoZ-disrupted mutant R6D4 obtained from strain A1R6 by insertion of Tn5 aphII into the middle of the rpoZ-coding region produced neither kasugamycin nor aerial mycelia, similar to mutant KSB. When rpoZ of S. kasugaensis and Streptomyces coelicolor, whose deduced products differed in the sixth amino acid residue, were introduced into mutant R6D4 via a plasmid, both transformants produced kasugamycin and aerial hyphae without significant differences. This study established that rpoZ is required for kasugamycin production and aerial mycelium formation in S. kasugaensis and responsible for pleiotropy.

Amino Acid Sequence↗

PubMed1976

The genetic relationship between the Hbb locus and body size in a population of mice divergently selected for six-week body weight.

Both pleiotropy and linkage were examined as possible explanations for the fixation of the Hbb3 allele in the six Large lines of a population of mice divergently selected for six-week body weight (six replicates in each direction and six controls). A survey of over 1200 individuals in the lines still segregating at the Hbb locus excluded pleiotropy as a possible explanation. The results showed a nonsignificant effect of haemoglobin genotype on body weight. The linkage relationship of the Hbb locus was examined using a backcross mating system. The Hbb3 c+ region (chromosome 7) of a Large line was backcrossed into its corresponding Small line (Hbb4 c). The resultant difference in body weight between the two segregants (Hbb8 c+ [Hbb4 c; Hbb4 c/Hbb4 c) was measured. The results suggested linkage as the most plausible explanation for the fixation of the Hbb4 allele in the six Large lines.

Alleles↗

PubMed1997

Cross-trait familial resemblance for body fat and blood lipids: familial correlations in the Quebec Family Study.

In an attempt to better understand the genetic basis of the metabolic syndrome, we have undertaken a series of studies on the familial aggregation in the clustering of the coronary heart disease risk factors which characterize this syndrome. In the present study, the hypothesis of shared genetic (pleiotropy) and/or environmental factors between body fat and blood lipids is investigated by examining cross-trait (eg, father's body fat with his son's blood lipid) familial resemblance between 4 indicators of body fat (body mass index [BMI], sum of 6 skin folds [SF6]) and fat distribution (the ratio of the trunk to extremity skin folds adjusted [TER-sf] and unadjusted [TER] for SF6), and 5 blood lipid variables (total cholesterol [CH], triglycerides [TG], cholesterol associated with high-density lipoproteins [HDL], the CH/ HDL ratio and the difference between CH and HDL [CH-HDL]) measured in 1239 individuals from 309 families participating in the Quebec Family Study. A bivariate correlation model was used to obtain maximum likelihood estimates of cross-trait spouse, parent-offspring, and sibling correlations after adjustment of body fat and lipid data for the effects of age, separately in the four sex-by-generation groups. Likelihood ratio tests revealed the presence of significant (P < .05) cross-trait resemblance between body fat (BMI and SF6) and all lipid traits except CH and also between fat distribution (TER and TER-sf) and CH/HDL and CH-HDL. Only sibling cross-trait correlations were significant for all body fat-lipid pairs of measures, with bivariate familiality estimates (i.e., shared genetic and/or environmental factors) ranging from 8% to 40%. Although the hypothesis of genetic pleiotropy cannot be ruled out from the pattern of cross-trait correlations found in the present study, we conclude that environmental factors shared within sibships are probably more important than common genes in determining the covariation between body fat and blood lipids.

Adolescent↗

PubMed1995

Plasma HDL cholesterol, triglycerides, and adiposity. A quantitative genetic test of the conjoint trait hypothesis in the San Antonio Family Heart Study.

BACKGROUND: The conjoint trait hypothesis proposes that combined low HDL cholesterol (HDL-C) and high triglyceride (TG) levels represent a single, inherited phenotype that adiposity may influence in an unspecified manner. We conducted formal statistical genetic tests of the conjoint trait hypothesis and the relation of the conjoint trait to adiposity using data for 569 subjects in 25 pedigrees from the San Antonio Family Heart Study. METHODS AND RESULTS: We conducted multivariate genetic analyses to detect the effects of genes and environmental factors on variation in plasma concentrations of HDL-C and TG, fat mass (as percent body weight [FM%], determined by bioelectric impedance), and body mass index (BMI). We used maximum-likelihood methods to simultaneously estimate the phenotypic means and SDs, heritabilities (h2), effects of sex, age-by-sex, eight dietary and medical covariates, and genetic and environmental correlations. Likelihood ratio tests disclosed significant heritabilities (P < .001) for all traits (h2HDL-C = 0.55, h2TG = 0.53, h2FM% = 0.37, h2BMI = 0.44) but significant genetic correlations (P < .001), indicating pleiotropy, between two trait pairs only: HDL-C and TG (PG = -0.52) and fat mass and BMI (PG = 0.86). We obtained significant environmental correlations between all trait pairs except HDL-C and BMI (P > .05). CONCLUSIONS: Both shared genes (pleiotropy) and shared environmental factors contribute to the commonly observed inverse phenotypic association between plasma levels of HDL-C and TG. Rather than low HDL-C and high TG being a single, genetically transmissible entity, it is the inverse relation between these two phenotypes throughout their normal ranges of variation as well as at the extremes that is influenced by shared genes and shared environments. However, common environmental factors, not shared genes, account for reported associations of plasma HDL-C and TG levels with measures of adiposity.

Adipose Tissue↗

PubMed2025

From genetic causality to druggable targets: A multiomics framework identifies ZSCAN16 in gout pathogenesis.

ObjectiveGout is a prevalent form of inflammatory arthritis in which many patients respond suboptimally to current therapies. Drug development is hampered by a lack of genetically validated targets, leading to high clinical trial attrition. This study aimed to systematically identify and prioritize novel, druggable targets for gout via a multilayered genetic and functional genomics approach.MethodsWe performed two-sample Mendelian randomization (MR) using cis-expression quantitative trait locus (cis-eQTL) data and dual independent gout genome-wide association study (GWAS) cohorts (openGWAS and FinnGen). The candidate genes were subjected to a rigorous validation pipeline including Bayesian colocalization, phenome-wide association studies (PheWASs) to assess pleiotropy and on-target safety, and single-cell RNA sequencing (scRNA-seq) to delineate the cellular context. Molecular docking was used to evaluate the structural druggability of prioritized targets.ResultsMR analysis revealed 15 genes causally associated with gout. Colocalization analysis (PPH4 > 0.8) prioritized two targets: ZSCAN16 (risk-increasing, OR = 1.04, 95% CI [1.02-1.06]) and TRIM10 (protective, OR = 0.96, 95% CI [0.94-0.98]). Crucially, PheWAS revealed that ZSCAN16 is highly specific to gout, whereas TRIM10 exhibited extensive pleiotropy with hematological and cardiometabolic traits, indicating significant safety risks. Single-cell analysis provided orthogonal validation, demonstrating flare-specific upregulation of ZSCAN16 in cytotoxic T/NK cells. Molecular docking confirmed ZSCAN16 as a structurally druggable target, showing high-affinity binding with known compounds (e.g. digoxin, binding energy = -9.6 kcal/mol).ConclusionsOur study identifies ZSCAN16 as a high-potential, druggable therapeutic target for gout, highlighting its genetic influence on specific immune cell activities during acute flares. Conversely, TRIM10 was deprioritized owing to substantial pleiotropic liabilities and poor chemical tractability. These findings suggest that ZSCAN16 could play a crucial role in the pathogenesis of gout and may provide a valuable lead for future drug discovery efforts.

Humans↗

PubMed2024

Causal effect of the age at first birth with depression: a mendelian randomization study.

BACKGROUND: This study aimed to explore the causal relationship between age at first birth (AFB) and depression. METHODS: Using the univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) methods to examine the potential correlation between age at first birth (AFB) and major depressive disorder and postpartum depression. A public database was used to obtain the genome-wide association studies (GWAS) summary data. We put inverse-variance-weighted (IVW) as the primary method in Mendelian randomization (MR) analysis and used sensitivity analysis to confirm the robustness of our result. RESULTS: We found a significant causal association between AFB and major depressive disorder by using the IVW algorithm (odd ratio [OR] 0.826; 95% confidence interval [CI] 0.793 - 0.861; P = 4.51 × 10- 20). MR-Egger, weighted median, simple mode and weighted mode method concluded the same result (P < 0.05). During the sensitivity analysis, the heterogeneity test (Q-value = 55.061, df = 48, P = 2.81 × 10- 01, I2 = 12.82%) and the leave-one-out plot analysis confirmed the stability of the results. The outcomes of the pleiotropy test (MR-Egger intercept = 8.932 × 10- 3. SE = 6.909 × 10- 3. P = 2.02 × 10- 01) and MR_PRESSO global test (P = 2.03 × 10- 01) indicated there is no pleiotropy. CONCLUSION: There is solid evidence that a higher age at first birth is associated with a lower risk of major depressive disorder.

Humans↗

PubMed2025

Causal relationship between educational attainment and the occurrence of venous thromboembolism.

BACKGROUND: The association between educational attainment (EA) and arterial thrombotic disease has been reported, but the causal relationship between EA and venous thromboembolism (VTE) is not clear. We aimed to assess the causal effect of EA on VTE using the two-sample mendelian randomization (MR) method. METHODS: Data mining was conducted on the genome wide association studies (GWAS), with exposure factor EA and outcome factor VTE. Two-sample Mendelian Randomization (TSMR) analysis was conducted, with the results obtained from the random effects inverse variance weighted method (IVW). Use the MR-Egger method for pleiotropy analysis and leave one method for sensitivity analysis to verify the reliability of the data. RESULTS: Genetically predicted decreased EA was associated with a decreased risk of VTE in both the FinnGen consortium and UK Biobank (FinnGen-VTE: OR = 0.848; 95% CI 0.776-0.927; P = 2.84 × 10-4; UKB-VTE OR = 0.996; 95% CI 0.994-0.999; P = 0.008) under a multiplicative random-effects IVW model. Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. CONCLUSIONS: The MR technique instructed a potential inverse causative relationship between EA and occurrence of VTE. Therefore, patients with low EA should be more vigilant about the occurrence of VTE.

Venous Thromboembolism↗

PubMed2025

Severe traumatic brain injury and risk for osteoporosis: a Mendelian randomization study.

BACKGROUND: The influence of nervous system activity on bone remodeling has been widely reported. Patients with traumatic brain injury (TBI) exhibit a high incidence of osteoporosis (OP). Nevertheless, the relationship between severe TBI (sTBI) and OP remains unclear. We performed Mendelian randomization (MR) analysis to assess the potential causal relationship between sTBI and OP. METHODS: Data on exposure and outcomes were acquired from genome-wide association studies (GWAS). Data on OP was obtained from UK Biobank (5,266 cases of OP and 331,893 controls). Data on sTBI was obtained from FinnGen Consortium (6,687 cases and 370,590 controls). Single nucleotide polymorphisms (SNPs) that underwent strict screening were regarded as instrumental variables. We used the inverse variance weighted (IVW), constrained maximum likelihood and model averaging (CML-MA), MR-Egger, and weighted median methods for causal effect estimation. To test the reliability of the results, sensitivity analysis was performed using Cochran's Q, leave-one-out, MR-Egger intercept, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) tests. RESULTS: The IVW analysis indicates that sTBI and OP have a suggestive association (odds ratio [OR] = 1.004, 95% confidence interval [CI] = 1.001,1.007; p = 0.002), and no heterogeneity (Q = 11.536, p = 0.241) or directional pleiotropy was observed (egger_intercept = 7.368 × 10- 5, p = 0.870). The robustness of the results was validated using a leave-one-out sensitivity test. CONCLUSION: According to the MR analysis, sTBI and OP are likely suggestively related. This finding contributes to the prevention of OP in patients with sTBI and provides genetic evidence supporting the theory that the nervous system regulates bone remodeling.

Humans↗