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Results for “Genetic Pleiotropy”

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PubMed2025

Possible linking and treatment between Parkinson's disease and inflammatory bowel disease: a study of Mendelian randomization based on gut-brain axis.

BACKGROUND: Mounting evidence suggests that Parkinson's disease (PD) and inflammatory bowel disease (IBD) are closely associated and becoming global health burdens. However, the causal relationships and common pathogeneses between them are uncertain. Furthermore, they are uncurable. Thus, we aimed to identify the causal relationships and novel therapeutic targets shared between them based on their common pathophysiological mechanisms in gut-brain-axis (GBA). METHODS: A meta-analysis on bidirectional Mendelian randomization (MR) utilizing various datasets was performed to estimate their causal relationship. Then, pleiotropic analysis under the composite null hypothesis (PLACO) with functional mapping combined with annotation of genetic associations (FUMA) analysis were conducted to identify pleiotropic genes. Next, blood, brain and intestine expression quantitative trait locus (eQTL) were taken to perform drug-target MR finding common causal genes in two diseases. Colocalization analysis ensured the eQTLs of corresponding gene colocalized with disease. Enrichment analysis and protein‒protein interaction (PPI) network were done to explore common pathogenesis pathways. Genes passed all analysis were regarded as drug targets. RESULTS: Our MR meta-analysis revealed the bidirectional causal relationship between diseases, with combined ORs for PD on IBD, CD, UC (1.050 [95% CI 1.014-1.086], 1.044 [95% CI 0.995-1.095], 1.063 [95% CI 1.016-1.120]); for IBD, CD, UC on PD (1.003 [95% CI 0.973-1.034], 1.035 [95% CI 1.004-1.067], 1.008 [95% CI 0.977-1.040]). Overall, 277, 216 and 201 genes were identified as pleiotropic genes between PD and IBD, CD, UC. Total of 733 genes were classified as tier 3 (found in only one tissue) druggable targets, 57 as tier 2 (found in two tissues, 51 protein-coding genes) and 9 as tier 3 (found in three tissues). Among 60 protein-coding druggable targets over tier 2, 18 overlapped with pleiotropic genes and enriched in mitochondria, antigen presentation, processing and immune cell regulation pathways. Three druggable genes (LRRK2, RAB29 and HLA-DQA2) passed colocalization analysis. LRRK2 and RAB29 were reported to be pleiotropic genes, and RAB29 and HLA-DQA2 were reported for the first time as potential drug targets. CONCLUSIONS: This study established a reliable causal relationship, possible shared drug targets and common pathogenesis pathways of two diseases, which had important implications for intervention and treatment of two diseases simultaneously.

Humans↗

PubMed2004

Bivariate linkage between acylation-stimulating protein and BMI and high-density lipoproteins.

OBJECTIVE: Given the importance of visceral adiposity in the metabolic syndrome, whether levels of adipokines have shared genetic effects (pleiotropy) with aspects of the metabolic syndrome should be addressed. Acylation-stimulating protein (ASP), an adipose-derived protein, influences lipid metabolism, obesity, and glucose use. Therefore, our objective was to examine the genetic regulation of ASP and associated pleiotropic effects. RESEARCH METHODS AND PROCEDURES: We assayed serum ASP levels in 435 Mexican Americans participating in the San Antonio Family Heart Study and performed univariate and bivariate variance components analysis. RESULTS: Additive genetic heritability of ASP was 26% (p = 0.0004). Bivariate genetic analysis detected significant genetic correlations between ASP and several lipid measures but not between ASP and adiposity or diabetes measures. We detected two potential quantitative trait loci influencing ASP levels. The strongest signal was on chromosome 17 near marker D17S1303 [log of the odds ratio (LOD) = 2.7]. The signal on chromosome 15 reached its peak near marker D15S641 (LOD = 2.1). Both signals localize in regions reported to harbor quantitative trait loci influencing obesity and lipid phenotypes in this population. Bivariate linkage analysis yielded LODs of 4.7 for ASP and BMI on chromosome 17 and 3.2 for ASP and high-density lipoprotein2a on chromosome 15. DISCUSSION: Given these findings, there seems to be a significant genetic contribution to variation in circulating levels of ASP and an interesting pattern of genetic correlation (i.e., pleiotropy) with other risk factors associated with the metabolic syndrome.

Adolescent↗

PubMed1997

Exploiting pleiotropy to map genes for oligogenic phenotypes using extended pedigree data.

We investigated the utility of two approaches for exploiting pleiotropy to search for genes influencing related traits. To do this we first assessed the genetic correlations among a set of five closely related quantitative traits (Q1, Q2, Q3, Q4, Q5). We then used the genetic correlations among these five traits both to remove the common genetic effects of the four remaining traits, thereby identifying the unique genetic contribution to each trait, and to extract a synthetic phenotype which exploits the shared genetic information (pleiotropy) among these five traits. After obtaining these conditional traits, we then searched for evidence of quantitative trait loci (QTLs) (using variance component linkage) influencing the unique residual genetic component for each trait as well as those influencing the expression of the synthetic traits. From this work, we conclude that the removal of the common genetic effects of other traits in a group may be of greater utility when the majority of the pleiotropy initially detected between traits is attributable to the shared additive effects of polygenes, rather than to those of major loci. By contrast, decomposition of the genetic covariance matrix to its principal components is a greater utility when the majority of pleiotropy is attributable to major loci.

Chromosome Mapping↗

PubMed2025

Exploiting pleiotropy to enhance variant discovery with functional false discovery rates.

The cost of recruiting participants for genome-wide association studies (GWASs) can limit sample sizes and hinder the discovery of genetic variants. Here we introduce the surrogate functional false discovery rate (sfFDR) framework that integrates summary statistics of related traits to increase power. The sfFDR framework provides estimates of FDR quantities such as the functional local FDR and q value, and uses these estimates to derive a functional P value for type I error rate control and a functional local Bayes' factor for post-GWAS analyses. Compared with a standard analysis, sfFDR substantially increased power (equivalent to a 52% increase in sample size) in a study of obesity-related traits from the UK Biobank and discovered eight additional lead SNPs near genes linked to immune-related responses in a rare disease GWAS of eosinophilic granulomatosis with polyangiitis. Collectively, these results highlight the utility of exploiting related traits in both small and large studies.

Humans↗

PubMed2000

A population genetics model for multiple quantitative traits exhibiting pleiotropy and epistasis.

We study a population genetics model of an organism with a genome of L(tot)loci that determine the values of T quantitative traits. Each trait is controlled by a subset of L loci assigned randomly from the genome. There is an optimum value for each trait, and stabilizing selection acts on the phenotype as a whole to maintain actual trait values close to their optima. The model contains pleiotropic effects (loci can affect more than one trait) and epistasis in fitness. We use adaptive walk simulations to find high-fitness genotypes and to study the way these genotypes are distributed in sequence space. We then simulate the evolution of haploid and diploid populations on these fitness landscapes and show that the genotypes of populations are able to drift through sequence space despite stabilizing selection on the phenotype. We study the way the rate of drift and the extent of the accessible region of sequence space is affected by mutation rate, selection strength, population size, recombination rate, and the parameters L and T that control the landscape shape. There are three regimes of the model. If LT< >L(tot), there are many small peaks that can be spread over a wide region of sequence space. Compensatory neutral mutations are important in the population dynamics in this case.

Animals↗

PubMed1996

Genetic and environmental correlations among hormone levels and measures of body fat accumulation and topography.

In this study we partition the phenotypic correlations between body fat measures and serum levels of hormones with known, or suspected, lipolytic effects into their genetic and environmental components. Using variance decomposition techniques, we are able to estimate the pleiotropic effects of genes and/or shared environmental factors that give rise to the phenotypic correlations previously reported between these traits. We used data from a large sample of randomly ascertained Mexican-American families living in San Antonio, TX. Data were available for 582 individuals in 26 pedigrees. Levels of sex hormone-binding globulin, dehydroepiandrosterone sulfate, insulin, insulin-like growth factor I, total T4, and total T3 were assayed. The measures of body fat accumulation and topography included body mass index, subscapular/triceps ratio, and relative fat patterning index. The results of this analysis demonstrate that significant phenotypic correlations among these traits can arise from three underlying conditions: 1) entirely from shared genetic effects (pleiotropy), 2) entirely from shared random environmental effects, or 3) a combination of both effects. However, we also show that it is possible for significant genetic and environmental correlations to interact in such a way as to produce a phenotypic correlation that itself would not be considered significant.

Adipose Tissue↗

PubMed2003

Identification of putative QTL that underlie yield in interspecific soybean backcross populations.

Glycine soja, the wild progenitor of soybean, is a potential source of useful genetic variation in soybean improvement. The objective of our study was to map quantitative trait loci (QTL) from G. soja that could improve the crop. Five populations of BC(2)F(4)-derived lines were developed using the Glycine max cultivar IA2008 as a recurrent parent and the G. soja plant introduction (PI) 468916 as a donor parent. There were between 57 and 112 BC(2)F(4)-derived lines in each population and a total of 468 lines for the five populations. The lines were evaluated with simple sequence repeat markers and in field tests for yield, maturity, plant height, and lodging. The field testing was done over 2 years and at two locations each year. Marker data were analyzed for linkage and combined with field data to identify QTL. Using an experimentwise significance threshold of P=0.05, four yield QTL were identified across environments on linkage groups C2, E, K, and M. For these yield QTL, the IA2008 marker allele was associated with significantly greater yield than the marker allele from G. soja. In addition, one lodging QTL, four maturity QTL, and five QTL for plant height were identified across environments. Of the 14 QTL identified, eight mapped to regions where QTL with similar effects were previously mapped. Many regions carrying the yield QTL were also significant for other traits, such as plant height and lodging. When the significance threshold was reduced and the data were analyzed with simple linear regression, four QTL with a positive allele for yield from G. soja were mapped. One epistatic interaction between two genetic regions was identified for yield using an experimentwise significance threshold of P=0.05. Additional research is needed to establish whether multiple trait associations are the result of pleiotropy or genetic linkage and to retest QTL with a positive effect from G. soja.

Analysis of Variance↗

PubMed2011

Adaptation to climate across the Arabidopsis thaliana genome.

Understanding the genetic bases and modes of adaptation to current climatic conditions is essential to accurately predict responses to future environmental change. We conducted a genome-wide scan to identify climate-adaptive genetic loci and pathways in the plant Arabidopsis thaliana. Amino acid-changing variants were significantly enriched among the loci strongly correlated with climate, suggesting that our scan effectively detects adaptive alleles. Moreover, from our results, we successfully predicted relative fitness among a set of geographically diverse A. thaliana accessions when grown together in a common environment. Our results provide a set of candidates for dissecting the molecular bases of climate adaptations, as well as insights about the prevalence of selective sweeps, which has implications for predicting the rate of adaptation.

Acclimatization↗

PubMed2025

Decoding missense variants pleiotropy in the immune GPCR P2RY8.

G protein-coupled receptors (GPCRs) form the largest family of cell surface receptors and remain a central focus in pharmacology and drug discovery. Despite extensive structural and pharmacological studies, the functional impact of missense variation across GPCRs remains poorly understood, particularly for receptors involved in immune regulation. In this issue of Cell Genomics, LaFlam et al.1 systematically map P2RY8 variant functions using deep mutational scanning (DMS) combined with structural biology approaches, revealing pleiotropy and mechanisms linking GPCR variation to B cell confinement and lymphoma.

Humans↗

PubMed2004

Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid.

BACKGROUND: Monoamine neurotransmitters (serotonin, dopamine, and norepinephrine) are associated with several psychiatric disorders. Limited evidence suggests that monoamine levels are heritable, but no information concerning genetic relationships among monoamines is available. Further genetic analysis can help explain phenotypic correlations among monoamine levels and might eventually help identify genes involved in response to therapy or risk of psychopathology. METHODS: Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-hydroxy-4-methoxyphenylglycol (MHPG) were measured in cerebrospinal fluid from 271 baboons (Papio hamadryas). Variance components methods were used to estimate heritabilities, and multivariate analyses were used to estimate genetic correlations (pleiotropy) and environmental correlations between metabolites. RESULTS: Each metabolite exhibited significant heritability in baboons (5-HIAA: h(2) =.30 +/-.17; MHPG: h(2) =.36 +/-.16; HVA: h(2) =.50 +/-.19). Multivariate analyses revealed genetic correlations between 5-HIAA and HVA and between HVA and MHPG. Environmental correlations were found between 5-HIAA and HVA and between 5-HIAA and MHPG. CONCLUSIONS: Overlapping, nonidentical sets of genes influence individual variation in 5-HIAA, MHPG, and HVA levels among baboons. The phenotypic correlation between 5-HIAA and HVA observed in nonhuman primates and humans is likely due to both shared genetic and environmental factors. Genetic analyses of monoamine levels in primates can provide novel information concerning the genetics of variation among humans.

Analysis of Variance↗

PubMed2003

Directional selection has shaped the oral jaws of Lake Malawi cichlid fishes.

East African cichlid fishes represent one of the most striking examples of rapid and convergent evolutionary radiation among vertebrates. Models of ecological speciation would suggest that functional divergence in feeding morphology has contributed to the origin and maintenance of cichlid species diversity. However, definitive evidence for the action of natural selection has been missing. Here we use quantitative genetics to identify regions of the cichlid genome responsible for functionally important shape differences in the oral jaw apparatus. The consistent direction of effects for individual quantitative trait loci suggest that cichlid jaws and teeth evolved in response to strong, divergent selection. Moreover, several chromosomal regions contain a disproportionate number of quantitative trait loci, indicating a prominent role for pleiotropy or genetic linkage in the divergence of this character complex. Of particular interest are genomic intervals with concerted effects on both the length and height of the lower jaw. Coordinated changes in this area of the oral jaw apparatus are predicted to have direct consequences for the speed and strength of jaw movement. Taken together, our results imply that the rapid and replicative nature of cichlid trophic evolution is the result of directional selection on chromosomal packages that encode functionally linked aspects of the craniofacial skeleton.

Animals↗

PubMed2005

Genetic determination and correlation of body mass index and bone mineral density at the spine and hip in Chinese Han ethnicity.

The purpose of the present study was to evaluate the magnitude of genetic determination of spine and hip bone mineral density (BMD) and body mass index (BMI), and to explore the genetic, environmental, and phenotypic correlations among the above phenotypes in Chinese Han ethnicity. The sample was composed of at least 217 complete nuclear families in Chinese Han ethnicity. BMD at the spine and hip was measured using a dual-energy X-ray absorptiometry scanner. The heritability (h2) of BMI and BMD at the spine and hip, the genetic correlation (rhoG) and environmental correlation (rhoE) among the three phenotypes were evaluated via variance analysis, with age, sex, and age-by-sex interaction as covariates. The phenotypic correlation (rhoP) and the bivariate heritability rhoG2 were also calculated. The heritability for BMD and BMI was approximately 0.70 and approximately 0.50, respectively (p<0.0001). The common environment shared by household members (household effect) is significant for BMI variation (p=0.0004). Significant genetic, environmental, and phenotypic correlation was observed. The rhoG2 values were 0.13 for BMI/spine BMD, 0.18 for BMI/hip BMD, and 0.58 for the spine BMD/hip BMD. While BMD at the spine and hip have significant genetic determination, BMI is more likely to be affected by environmental factors than BMD. In addition, BMD at the spine and hip shares more genetic effect (pleiotropy) than BMI and BMD do in Chinese Han ethnicity, though the effects are significant for both.

Adult↗

PubMed2026

Multi-omics uncovers the pleiotropic genetic mechanisms linking MASLD and cardiometabolic syndromes.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome are interrelated conditions with shared pathophysiological features; however, the genetic architecture underlying their relationship has not been fully elucidated. Deciphering this shared genetic basis holds promise for advancing mechanistic insights and therapeutic discovery. METHODS: We performed an integrated genome-wide cross-trait analysis using GWAS summary statistics for MASLD and 38 CKM traits. Our analysis estimated genetic correlations, inferred causal relationships, and identified pleiotropic variants. Candidate causal genes and druggable targets were subsequently prioritized through integrating multi-omics data. RESULTS: MASLD exhibited significant genetic correlations with 16 CKM traits, especially metabolic and cardiovascular conditions. Bidirectional causal relationships were observed between MASLD and T2D, adiposity, and lipid traits. We discovered 116 pleiotropic loci, including 65 shared causal variants such as rs429358 near APOE, which exerted influence across multiple traits. Gene-based analyses prioritized 152 unique candidate pleiotropic genes, enriched in lipid and cholesterol metabolism, and highly expressed in the liver, adipose, and immune-related cell types, such as macrophages and endothelial cells. Multi-omics integration validated 131 genes using eQTL and pQTL data from multiple tissues and cohorts. Notably, FTO and APOE emerged as central pleiotropic hubs, and druggability evaluation highlighted APOE, LPL, PPARG, and GPBAR1 as established therapeutic targets for metabolic diseases. CONCLUSION: This study provides a comprehensive map of the shared genetic architecture between MASLD and CKM syndrome, reveals novel causal genes and repurposable drug targets, and offers insights into precision medicine approaches for cardiometabolic and liver diseases.

Humans↗

PubMed2005

Genetic influences on peripheral blood cell counts: a study in baboons.

Interperson differences in peripheral blood cell counts in healthy individuals result from genetic and environmental influences. We used multivariate genetic analyses to assess the relative impact of genes and environment on baseline blood cell counts and indices using a pedigreed colony of baboons, an animal with well-documented analogies to human blood physiology. After accounting for age, sex, and weight, we found that genetic influences explain a significant proportion of the remaining variability, ranging from a low of 13.7% for mean corpuscular hemoglobin concentration (MCHC) to a high of 72.4% for red blood cell (RBC) number. Genes influence 38.5% of the variation in baseline white blood cell (WBC) count, a characteristic that correlates with mortality in both the general human population and clinically defined subgroups such as individuals with sickle-cell disease. We examined the interaction between pairs of traits and identified those that share common genetic influences (pleiotropy). We unexpectedly observed that the same gene or group of genes influences both WBC count and mean platelet volume (MPV). We anticipate that this approach will ultimately lead to discovery of novel insights into the biology of related traits, and ultimately identify important genes that affect hematopoiesis.

Animals↗

PubMed2025

Phenotypic pleiotropy of missense variants in human B cell confinement receptor P2RY8.

Missense variants can have pleiotropic effects on protein function, and predicting these effects can be difficult. We performed near-saturation deep mutational scanning of P2RY8, a G protein-coupled receptor that promotes germinal center B cell confinement. We assayed the effect of each variant on surface expression, migration, and proliferation. We delineated variants that affected both expression and function, affected function independently of expression, and discrepantly affected migration and proliferation. We also used cryo-electron microscopy to determine the structure of activated, ligand-bound P2RY8, providing structural insights into the effects of variants on ligand binding and signal transmission. We applied the deep mutational scanning results to both improve computational variant effect predictions and to characterize the phenotype of germline variants and lymphoma-associated variants. Together, our results demonstrate the power of integrating deep mutational scanning, structure determination, and in silico prediction to advance the understanding of a receptor important in human health.

Humans↗

PubMed2026

Eating Disorders and Parkinson's Disease-2: Genetic Epidemiology and Shared Genomics.

OBJECTIVE: Individuals with anorexia nervosa (AN) share premorbid traits with Parkinson's Disease (PD) (e.g., anxiety) and exhibit a two-fold relative risk of a reported family history of PD. Published estimates of intra- and inter-disorder genetic architecture were extracted and compared prior to conducting novel analyses to provide evidence for cross-disorder genetic risk. METHODS: National register or meta-analytic familial, twin, and common variant genome-wide studies were searched; estimates and findings were extracted and compared. Novel cross-disorder conditional and conjunctional false discovery rate analyses were performed. RESULTS: Sibling relative risks and additive genetic estimates of the two disorders were similar. AN had greater common variant heritability than PD whether measured via infinitesimal model (linkage disequilibrium score regression, LDSC) or causal mixture model (MiXeR). AN had greater polygenicity than PD (mean (SD) 2.50E-03 (1.64E-04) versus 2.72E-4 (1.47E-05), p < 0.001), but lower discoverability than PD (4.20E-05 (2.69E-06) versus 1.40E-04 (6.95E-06), p < 0.001). Global genetic correlation was significant (e.g., bivariate LDSC rg = 0.10, p = 0.0033). Novel analyses identified cross-disorder enrichment, and cross-disorder risk at chr3p21.31. CONCLUSIONS: Cross-disorder AN and PD research identified shared risk variants at chr3p21.31, genes and mechanisms (e.g., conditioning, fear, and reward) linked to a shared endophenotype.

Parkinson's disease↗

PubMed2026

Genetic overlap between depression and C-reactive protein levels: Evidence from a cross-trait analysis.

Inflammation and depression have been consistently associated, with elevated C-reactive protein (CRP) levels observed in a significant subset of affected individuals. However, the genetic mechanisms underlying this association remain poorly understood. We integrated results from large-scale genome-wide association studies (GWAS) of depression and CRP levels in a cross-trait analysis specifically focusing on identifying horizontally pleiotropic loci. Identified variants were stratified as concordant versus discordant based on their direction of effects on the two traits and followed up using functional annotation, gene set enrichment, and colocalization analyses. We also explored causal relationships using Mendelian Randomization (MR) analysis with extensive sensitivity analyses, including adjustment for body mass index (BMI). We identified 9 novel loci. Functional analyses revealed that concordant loci were enriched in genes linked to immune and inflammatory processes, while discordant loci mostly mapped to metabolic pathways, including lipid regulation. MR provided strong evidence for body mass index driving a causal relationship between the genetic liability of depression on CRP levels. Our findings suggest that the association between depression and CRP levels is partly driven by shared genetic influences, pointing to different biological pathways depending on whether genetic effects are concordant or discordant. These results underscore the importance of considering effect direction when assessing the genetic overlap between depression and inflammatory processes. In addition, they highlight BMI as a key factor in the causal relationship between depression and systemic inflammation.

C-Reactive Protein↗

PubMed2026

Shared genetic architecture between major depression and intrinsic brain functional connectome organization.

BACKGROUND: Major depression (MD) is increasingly understood as a disorder characterized by widespread abnormalities in intrinsic brain functional network organization. Although both MD and brain functional connectome architecture are highly heritable, the genetic architecture underlying their relationship remains poorly characterized. METHODS: We integrated genome-wide association studies of MD with 191 ICA-based resting-state functional connectome traits to investigate their shared genetic architecture. These traits captured intrinsic connectome organization across amplitude, functional connectivity, and global connectivity domains. Cross-trait genetic analyses were used to assess pleiotropic overlap between traits. Locus-level and gene-based analyses integrating multi-omics evidence were performed to characterize the biological relevance of shared genetic signals. RESULTS: We identified significant genetic overlap between MD and 148 of 191 brain functional connectome traits. Cross-trait analyses revealed widespread shared genetic signals organized into 627 genomic loci across amplitude, functional connectivity, and global connectivity measures. Among these, 193 loci showed evidence consistent with shared causal variants based on colocalization analyses. Gene-level integration mapped these loci to 1459 protein-coding genes (390 unique genes). Multi-layer prioritization identified 17 high-confidence genes supported by convergent genomic, transcriptomic, and proteomic evidence, with enrichment in neurodevelopmental and lipid-related metabolism pathways. CONCLUSIONS: This study provides a multi-scale characterization of the shared genetic architecture between MD and intrinsic brain functional connectome organization, revealing that shared genetic signals between MD and brain functional systems are distributed across multiple functional levels and converge at the molecular level.

Connectome↗