Linkage Disequilibrium Score Regression Research Articles

Genetically predicted 486 blood metabolites in relation to risk of esophageal cancer: a Mendelian randomization study

Background and ObjectiveEnhancing therapy choices for varying stages of esophageal cancer and improving patient survival depend on timely and precise diagnosis. Blood metabolites may play a role in either causing or preventing esophageal cancer, but further research is needed to determine whether blood metabolites constitute a genetic risk factor for the disease. In order to tackle these problems, we evaluated the causal association between esophageal cancer and 486 blood metabolites that functioned as genetic proxies using a two-sample Mendelian randomization (MR) study.MethodsWe utilized two-sample MR analyses to evaluate the causal links between blood metabolites and esophageal cancer. For the exposure, we used a genome-wide association study (GWAS) of 486 metabolites, and a GWAS study on esophageal cancer from Sakaue et al. was used for preliminary analyses. Causal analyses employed randomized inverse variance weighted (IVW) as the main method, supplemented by MR-Egger and weighted median (WM) analyses. Sensitivity analyses included the MR-Egger intercept test, Cochran Q test, MR-PRESSO, and leave-one-out analysis. Additionally, independent esophageal cancer GWAS data were utilized for replication and meta-analysis. FDR correction was applied to discern features with causal relationships. For conclusive metabolite identification, we conducted Steiger tests, linkage disequilibrium score regression, and colocalization analyses. Moreover, we utilized the program MetaboAnalyst 5.0 to analyze metabolic pathways.ResultsThis study found an important association between esophageal cancer and three metabolites: 1-linoleoylglycerophosphoethanolamine* [odds ratio (OR) = 3.21, 95% confidence interval (CI): 1.42–7.26, p < 0.01], pyroglutamine* (OR = 1.92, 95% CI: 1.17–3.17, p < 0.01), and laurate (12:0) (OR = 3.06, 95% CI: 1.38–6.78, p < 0.01).ConclusionThis study establishes a causal link between three defined blood metabolites and esophageal cancer, offering fresh insights into its pathogenesis.

Genetic liability to higher frailty index may increase the risk of ophthalmic disease.

Frailty and age-related eye diseases are common in older people; however, whether there is a causal link remains unknown. We aimed to explore the causal associations between the frailty index (FI) and ophthalmic traits and identify modifiable mediators. Linkage disequilibrium score regression and two-sample Mendelian randomization were applied to identify genetic correlations and causal associations between FI and ophthalmic traits. Summary data for FI was obtained from a genome-wide association study that included 175,226 individuals of European ancestry. Summary-level statistics for ophthalmic traits were obtained from relative GWASs. Summary-level data for cardiovascular risk factors, inflammatory biomarkers, and the central nervous system were used to identify the possible mediators. FI had a significant genetic correlation with 10 ophthalmic traits. Per SD increment of FI, the odds ratio was 1.329 (95% CI, 1.123, 1.573; P = 9.5 × 10-4) for cataracts, 1.825 (95% CI, 1.115, 2.986; P = 0.016) for keratitis, 1.798 (95% CI, 1.039, 3.11; P = 0.036) for disorders of vitreous body and 1.478 (95% CI, 1.005, 2.173; P = 0.046) for disorders of sclera, cornea, iris and ciliary body. The MR effect estimates of FI on ophthalmic traits were attenuated after adjusting for mental disorders, type 2 diabetes, triglyceride, and interleukin-8 (IL-8) levels. This study reports a genetic correlation and causal association between FI and ophthalmic traits, in which mental disorders, type 2 diabetes, triglycerides, and IL-8 may play a mediating role. These findings highlight a possible method to reduce the risk of FI-related ophthalmic diseases.

Causal effects of serum calcium, phosphate, and 25-hydroxyvitamin D on kidney function: a genetic correlation, pleiotropic analysis, and Mendelian randomization study

BackgroundExisting studies investigating the impact of serum calcium (Ca), phosphate (P), 25 hydroxyvitamin D (25[OH]D), and parathyroid hormone (PTH) levels on kidney function have produced inconsistent results. Further research is needed to establish the direct causal relationship between these factors and kidney function.MethodsThe study used genome-wide association study datasets for exposure and outcome, mainly derived from the UK Biobank and CKDGen Consortium, with sample sizes ranging from 3,310 to 480,699 individuals of European ancestry. Heritability and genetic correlations among these phenotypes were assessed using linkage disequilibrium score regression (LDSC) and phenotypes with a heritability z-score <4 were excluded from further analyses. Pleiotropic analyses were performed to identify potential horizontal pleiotropic variants at gene and LD-independent locus levels. Mendelian randomization (MR) analysis, using instrumental variables (IVs) based on two distinct selection criteria, was conducted to investigate the potential causal relationships between serum Ca, P, 25(OH)D, PTH, and kidney function.ResultsPTH was excluded from further analysis due to a heritability z-score < 4. Genetic correlations were observed between serum Ca and urine albumin-to-creatinine ratio (UACR) (rg = 0.202, P-value = 5.0E−04), between serum 25(OH)D and estimated glomerular filtration rate using serum creatinine (eGFRcrea) (rg = -0.094; P-value = 1.4E−05), and between serum 25(OH)D and blood urea nitrogen (BUN) (rg = 0.127; P-value = 1.7E−06). In univariable MR analysis using IVs based on two different selection criteria, it consistently demonstrated that genetically predicted serum Ca consistently showed an increase in UACR (beta 0.11, P-value 2.0E−03; beta 0.13, P-value 2.0E−04). Similarly, serum P was associated with a decrease in eGFRcrea (beta −0.01, P-value 2.0E−04; beta −0.005, P-value 2.0E−03) and an increase in BUN (beta 0.02, P-value 3.0E−03; beta 0.02, P-value 7.5E−07). The influence of serum P on kidney function was further supported in multivariable MR analysis. However, genetically predicted 25(OH)D did not have a significant impact on kidney function.ConclusionsElevated serum Ca or P levels could both impair kidney function, whereas 25(OH)D has no impact on renal function.

Investigating the uncertain causal link between gut microbiota and glaucoma: A genetic correlation and Mendelian randomisation study.

Glaucoma is the most common cause of irreversible blindness, and gut microbiota (GM) is associated with glaucoma. Whether this association represents a causal role remains unknown. This study aims to assess the potential association and causal link between GM and various forms of glaucoma, emphasising the need for cautious interpretation of the strength of these associations. Employing a two-sample bidirectional Mendelian randomisation (MR) framework with false discovery rate correction and various sensitivity analyses, supplemented by genetic correlation analysis via linkage disequilibrium score regression (LDSC) and colocalisation for European summary-level data between MiBioGen consortium and FinnGen Study, we sought to explore the relationship between GM and glaucoma. While certain microbial taxa showed potential associations with glaucoma subtypes (e.g., Erysipelotrichaceae with primary angle closure glaucoma, Senegalimassilia with exfoliation glaucoma), the overall findings suggest a complex and not definitively causal relationship between GM and glaucoma. Notably, reverse MR analysis did not establish a significant causal effect of glaucoma on GM composition, and no consistent genetic correlations were observed between GM and glaucoma. While our study provides some evidence of associations between specific GM taxa and glaucoma, the results underscore the complexity of these relationships and the need for further research to clarify the potential causal links. The findings highlight the importance of interpreting the gut-eye axis with caution and suggest that while GM may play a role in glaucoma, it is unlikely to be a predominant causal factor.

Investigating the shared genetic basis of inflammatory bowel disease and systemic lupus erythematosus using genetic overlap analysis

BackgroundInflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) are autoimmune diseases that often coexist clinically. This phenomenon might be due to shared genetic components.MethodsGenome-wide association study (GWAS) data for IBD and SLE were analyzed to determine both global and local genetic correlations using three methodologies: linkage disequilibrium score regression (LDSC), genetic covariance analyzer (GNOVA), and SUPERGNOVA. The genetic overlap and risk loci were subsequently examined using the conditional/conjunctional false discovery rate (cond/conjFDR) statistical framework. Furthermore, a multi-trait analysis of MTAG was employed to validate the loci, followed by an LDSC analysis focusing on tissue-specific gene expression.ResultsGWAS findings demonstrated a marked global genetic correlation between IBD (including Crohn’s disease and ulcerative colitis) and SLE. Locally, SLE showed a strong association with IBD and Crohn’s disease on chromosomes 10, 19, and 22. ConjFDR analysis confirmed the genetic overlap and identified relevant genetic risk loci. MTAG further validated several shared susceptibility genes. Additionally, the LDSC-SEG analysis results indicate that IBD (including CD and UC) and SLE are jointly enriched in the tissues of Spleen and Whole Blood.ConclusionThis study confirms a genetic overlap between IBD and SLE, identifying marked comorbid genes and offering new insights for treating these diseases.

Causal association between blood metabolites and abdominal aortic calcification: A bidirectional Mendelian randomization study.

Previous studies have reported correlations between metabolic factors and abdominal aortic calcification (AAC). However, the causal relationship between blood metabolites and AAC remains to be fully explored. We employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationships between 486 blood metabolites and AAC. The inverse variance weighted method was primarily utilized for MR analysis, and the MR-Egger, weighted median, and Robust Adjusted Profile Score methods were used for supplementary analysis. Sensitivity analyses were conducted using Radial MR, MR-PRESSO, Cochran Q test, MR-Egger intercept, and leave-one-out analysis to evaluate the heterogeneity and pleiotropy. Furthermore, the Steiger test and linkage disequilibrium score regression were used to assess genetic correlation and directionality. Multivariable MR analysis was performed to evaluate the direct effect of metabolites on AAC. Through rigorous screening, we identified 6 metabolites with presumed causal effects on AAC: 4-methyl-2-oxopentanoate (effect size [ES] 0.46, 95% confidence interval [CI]: 0.10-0.82), erythrose (ES -0.35, 95% CI: -0.59 to -0.11), 10-undecenoate (11:1n1) (ES 0.14, 95% CI: 0.03-0.25), 1-myristoylglycerophosphocholine (ES 0.31, 95% CI: 0.11-0.50), glycerol 2-phosphate (ES 0.20, 95% CI: 0.04-0.37), and the unidentified metabolite X-11469 (ES 0.19, 95% CI: 0.08-0.30). Multivariable MR analysis revealed that genetically predicted erythrose, 10-undecenoate, 1-myristoylglycerophosphocholine, and X-11469 could directly affect AAC independent of other metabolites. Reverse MR analysis revealed an alteration in 12 blood metabolites due to AAC, including caffeine, 1,7-dimethylurate, arachidonic acid, and 1-arachidonoylglycerophosphocholine. This study provides evidence supporting a causal relationship between metabolites and AAC. These findings help elucidate the underlying biological mechanisms of AAC and may offer insights into screening, prevention, and treatment approaches.

Genetic association and causal effects between inflammatory bowel disease and conjunctivitis.

Inflammatory bowel disease (IBD) is often clinically associated with conjunctivitis, which may result from genetic associations and causal effects. Genetic correlations were investigated through the genome-wide association study (GWAS) data on IBD and conjunctivitis using the linkage disequilibrium score regression (LDSC) and heritability estimated in summary statistics (HESS). The causal effect analysis was performed using four methods of Mendelian randomization (MR) and the genetic risk loci common to both diseases were identified by the statistical method of conditional/conjoint false discovery rate (cond/conjFDR), followed by genetic overlap analysis. Finally, a multi-trait GWAS analysis (MTAG) was performed to validate the identified shared loci. IBD (including CD and UC) and conjunctivitis showed a significant overall correlation at the genomic level; however, the local correlation of IBD and CD with conjunctivitis was significant and limited to chromosome 11. MR analysis suggested a significant positive and non-significant negative correlation between IBD (including CD and UC) and conjunctivitis. The conjFDR analysis confirmed the genetic overlap between the two diseases. Additionally, MTAG was employed to identify and validate multiple genetic risk loci. The present study provides evidence of genetic structure and causal effects for the co-morbidity between IBD (both CD and UC) and conjunctivitis, expanding the epidemiologic understanding of the two diseases.

Causal association among glaucoma, cerebral cortical structures, and Alzheimer's disease: insights from genetic correlation and Mendelian randomization.

Glaucoma and Alzheimer's disease are critical degenerative neuropathies with global impact. Previous studies have indicated that glaucomatous damage could extend beyond ocular structures, leading to brain alterations potentially associated with Alzheimer's disease risk. This study aimed to explore the causal associations among glaucoma, brain alterations, and Alzheimer's disease. We conducted a comprehensive investigation into the genetic correlation and causality between glaucoma, glaucoma endophenotypes, cerebral cortical surficial area and thickness, and Alzheimer's disease (including late-onset Alzheimer's disease, cognitive performance, and reaction time) using linkage disequilibrium score regression and Mendelian randomization. This study showed suggestive genetic correlations between glaucoma, cortical structures, and Alzheimer's disease. The genetically predicted all-caused glaucoma was nominally associated with a decreased risk of Alzheimer's disease (OR = 0.96, 95% CI: 0.93-0.99, P = 0.013). We found evidence for suggestive causality between glaucoma (endophenotypes) and 20 cortical regions and between 29 cortical regions and Alzheimer's disease (endophenotypes). Four cortical regions were causally associated with cognitive performance or reaction time at a significant threshold (P < 6.2E-04). Thirteen shared cortical regions between glaucoma (endophenotypes) and Alzheimer's disease (endophenotypes) were identified. Our findings complex causal relationships among glaucoma, cerebral cortical structures, and Alzheimer's disease. More studies are required to clarify the mediation effect of cortical alterations in the relationship between glaucoma and Alzheimer's disease.

Shared genetic architecture between gastro-esophageal reflux disease, asthma, and allergic diseases

The aim is to investigate the evidence for shared genetic architecture between each of asthma, allergic rhinitis and eczema with gastro-esophageal reflux disease (GERD). Structural equation models (SEM) and polygenic risk score (PRS) analyses are applied to three Swedish twin cohorts (n = 46,582) and reveal a modest genetic correlation between GERD and asthma of 0.18 and bidirectional PRS and phenotypic associations ranging between OR 1.09-1.14 and no correlations for eczema and allergic rhinitis. Linkage disequilibrium score regression is applied to summary statistics of recently published GERD and asthma/allergic disease genome wide association studies and reveals a genetic correlation of 0.48 for asthma and GERD, and Genomic SEM supports a single latent factor. A gene-/gene-set analysis using MAGMA reveals six pleiotropic genes (two at 12q13.2) associated with asthma and GERD. This study provides evidence that there is a common genetic architecture unique to asthma and GERD that may explain comorbidity and requires further investigation.

Causality of Genetically Determined Metabolites on Chronic Kidney Disease: A Two-Sample Mendelian Randomization Study In Silico.

Introduction: Chronic kidney disease (CKD) is associated with metabolic disorders. However, the evidence for the causality of circulating metabolites to promote or prevent CKD is still lacking. Methods: The two-sample Mendelian randomization (MR) analysis was conducted to evaluate the latent causal relationship between the genetically proxied 486 blood metabolites and CKD. Genome-wide association study (GWAS) data for exposures were derived from 7824 European GWAS on metabolite levels, which have been extensively utilized in the medical field to elucidate the mechanisms underlying disease onset and progression. The random inverse variance weighted (IVW) is the primary analysis for causality analysis while MR-Egger and weighted median as complementary analyses. For the further identification of metabolites, reverse MR and linkage disequilibrium score regression were performed for further evaluation. The drug target for N-acetylornithine was subsequently supplemented into the analysis, with MR and colocalization analysis being utilized. Key metabolic pathways were identified via MetaboAnalyst 4.0 (https://www.metaboanalyst.ca/) online website. Results: N-acetylornithine was identified as a reliable metabolite that increases the susceptibility to estimated glomerular filtration rate (eGFR) decrease (β = 0.047; 95% confidence interval: -0.068 to -0.026; PIVW = 1.5E-5). The "glyoxylate and dicarboxylate metabolism" pathway showed significant relevance to CKD development (P = 6E-4), whereas the "glycine, serine, and threonine metabolism" pathway was also recognized as associated with CKD by general practitioners (P = 7E-4). Colocalization analysis revealed a robust genetic link between N-acetylornithine and both CKD and eGFR, with 85.1% and 99.4% colocalization rates, respectively. IVW-MR analysis substantiated these findings with a significant positive association for CKD (odds ratio = 1.43, P = 4.7E-5) and a negative correlation with eGFR (b = -0.04, P = 1.13E-31). Conclusions: MR was utilized to explore the potential causal links between 61 genetic serum metabolites and CKD. N-acetylornithine and NAT8 were further explored as a potential therapeutic target for CKD treatment.

Causal association between epilepsy and its DNA methylation profile and atrial fibrillation

BackgroundThe "epileptic heart" concept is emerging, but the causal relationship between epilepsy and atrial fibrillation (AF) remains unclarified. ObjectiveThis study explores the genetic correlations and bidirectional causality between various epilepsy phenotypes and AF. MethodsGenome-wide association study (GWAS) statistics for 10 epilepsy subtypes (29,944 cases, 52,538 controls) and AF (60,620 cases, 970,216 controls) were sourced from the International League Against Epilepsy (ILAE) and HGRI-EBI Catalog-GWAS, respectively. Linkage disequilibrium score regression (LDSC) and genome-wide Mendelian Randomization (MR) evaluated genetic correlations and bidirectional causal relationships. Epilepsy-related DNA methylation data (N= ∼800) from EWAS catalog were analyzed to identify causal CpG sites influencing AF risk through epigenetic MR. ResultsLDSC revealed significant genetic correlations between four epilepsy subtypes and AF (rg from 0.116 to 0.241). Forward MR suggested a significant causal effect of focal epilepsy with hippocampal sclerosis (FE with HS) on AF risk (IVW and MR-PRESSO: OR = 1.046, P ≤ 0.004), with results robust against heterogeneity, horizontal pleiotropy, and outliers. Epigenetic MR indicated that lower methylation at cg06222062 (OR = 0.994, P = 3.16E-04) mapped to PLA2G5 and cg08461451 mapped to SPPL2B gene (OR = 0.954, P = 1.19E-03), and higher cg10541930 in the C10orf143 promoter (OR = 1.043, P = 4.18E-22) increases AF risk. Sensitivity analyses affirmed no pleiotropic bias. ConclusionFE with HS significantly increases AF risk, highlighting the natural neural-cardiac connection and the need for cardiac monitoring in epilepsy patients. Specific methylated CpG sites may serve as biomarkers and preventive targets for AF susceptibility.

Unraveling the shared genetics of common epilepsies and general cognitive ability.

PurposeCognitive impairment is prevalent among individuals with epilepsy, and increasing evidence indicates that genetic factors can underlie this relationship. However, the extent to which epilepsy subtypes differ in their genetic relationship with cognitive function, and information about the specific genetic variants involved remain largely unknown. MethodsWe investigated the genetic relationship between epilepsies and general cognitive ability (COG) using complementary statistical tools, including linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR). We analyzed genome-wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes ‘all epilepsy’, focal epilepsies and genetic generalized epilepsies (GGE), as well as specific subtypes. We functionally annotated the identified loci using several biological resources and validated the results in independent samples. ResultsUsing MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than ‘all epilepsy’, GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k – 2.9k variants). The other epilepsy phenotypes were insufficiently powered for MiXeR analysis. We quantified extensive genetic overlap between COG and epilepsy types, but with varying negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and ‘all epilepsy’, and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), ‘all epilepsy’ (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 3.62 × 10-7; ‘all epilepsy’: p = 2.58 × 10-3). ConclusionOur study further dissects the substantial genetic basis shared between epilepsies and COG and identifies novel shared loci. An improved understanding of the genetic relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.

Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia

BackgroundClinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear. MethodsThis work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes. ResultsCombining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70–3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06–3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88–3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %. ConclusionOur study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.

Exploring the shared genetic basis of major depressive disorder and frailty

BackgroundMajor depressive disorder (MDD) and frailty impose substantial health and economic burdens. MDD is recognized as a significant risk factor for frailty, but the genetic associations between these conditions remain unclear. This study investigates the genetic correlation, shared pleiotropic loci, causal relationships, and comorbid genes between MDD and frailty. MethodsThe genetic correlation between MDD and frailty was assessed using linkage disequilibrium score regression (LDSC) based on data from genome-wide association studies (GWAS). A detailed analysis was performed to identify shared pleiotropic loci and causal relationships through cross-phenotype association tests and Mendelian randomization. Additionally, tissue enrichment analysis was conducted using stratified LDSC, gene-based associations with both conditions were assessed using Multimarker Analysis of Genomic Annotation (MAGMA), and pathway analysis of comorbid genes was performed using the g: GOSt tool. ResultsOur findings revealed a significant positive genetic correlation between MDD and frailty (rg = 0.65, P = 1.49E-219). We identified 57 shared risk SNPs between the two conditions, including 6 novel SNPs. Mendelian randomization analyses indicated robust causal effects of MDD on frailty and vice versa. Furthermore, we observed tissue-specific heritability enrichment in 9 brain tissues. By combining MAGMA and CPASSOC analyses, we identified 10 comorbid genes associated with both MDD and frailty, primarily involved in synapse formation, modulation, plasticity, and desaturase activity. ConclusionThis study provides strong evidence for a shared genetic basis between MDD and frailty. The identification of comorbid genes offers new insights into the mechanisms underlying the relationship between these conditions.

The shared genetic etiology of antisocial behavior and psychiatric disorders: Insights from pleiotropy and causality analysis

BackgroundAntisocial behavior (ASB) infringes on the rights of others and significantly disrupts social order. Studies have shown that ASB is phenotypically associated with various psychiatric disorders. However, these studies often neglected the importance of genetic foundations. MethodsThis study utilized genome-wide association studies and pleiotropy analysis to explore the genetic correlation between ASB and psychiatric disorders. Linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods were employed to assess genetic correlations, and the PLACO method was used for pleiotropy analysis. Functional annotation and biological pathway analysis of identified pleiotropic genes were performed using enrichment analysis. Furthermore, Mendelian randomization (MR) analysis was conducted to validate these causal relationships. ResultsLDSC and HDL analysis showed that significant positive genetic correlations were between ASB and attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Multiple potential pleiotropic genetic loci were identified, particularly the FOXP2 and MDFIC genes located at the 7q31.1 locus. Enrichment analysis showed that these pleiotropic genes are highly expressed in several brain regions (such as the hypothalamus, cerebellar hemisphere, cortex, and amygdala) and immune-related cells. MR analysis further confirmed the causal effects ADHD, SCZ, and MDD on ASB risk. ConclusionThis study reveals significant genetic correlations and potential causal mechanisms between ASB and various psychiatric disorders. The MR analysis confirmed the causal effects of psychiatric disorders on ASB. These findings deepen our understanding of the genetic architecture of psychiatric disorders and ASB.

Unraveling the Genetic Susceptibility of Irritable Bowel Syndrome: integrative genome-wide analyses in 845,492 individuals: a diagnostic study.

Irritable bowel syndrome (IBS) significantly impacts individuals due to its prevalence and negative effect on quality of life. Current genome-wide association studies (GWAS) have only identified a small number of crucial single nucleotide polymorphisms (SNPs), not fully elucidating IBS's pathogenesis. To identify genomic loci at which common genetic variation influence IBS susceptibility. Combining independent cohorts that in total comprise 65,840 cases of IBS and 788,652 controls, we performed a meta-analysis of genome-wide association studies (GWAS) of IBS. We also carried out gene mapping and pathway enrichment to gain insights into the underlying genes and pathways through which the associated loci contribute to disease susceptibility. Furthermore, we performed transcriptome analysis to deepen our understanding. IBS risk models were developed by combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. We detect the phenotype association for IBS utilizing PRS-based phenome-wide association (PheWAS) analyses, linkage disequilibrium score regression, and Mendelian randomization. The GWAS meta-analysis identified 10 IBS risk loci, seven of which were novel (rs12755507, rs34209273, rs34365748, rs67427799, rs2587363, rs13321176, rs1546559). Multiple methods identified nine promising IBS candidate gene (PRRC2A, COP1, CADM2, LRP1B, SUGT1, MED12L, P2RY14, PHF2, SHISA6) at 10 GWAS loci. Transcriptome validation also revealed differential expression of these genes. Phenome-wide associations between PRS-IBS and nine traits (neuroticism, diaphragmatic hernia, asthma, diverticulosis, cholelithiasis, depression, insomnia, COPD, and BMI) were identified. The six diseases (asthma, diaphragmatic hernia, diverticulosis, insomnia major depressive disorder and neuroticism) were found to show genetic association with IBS and only major depressive disorder and neuroticism were found to show causality with IBS. We identified seven novel risk loci for IBS and highlight the substantial influence on genetic risk harboured. Our findings offer novel insights into aetiology and phenotypic association of IBS and lay the foundation for therapeutic targets and interventional strategies.

Genetic relations between type 1 diabetes, coronary artery disease and leukocyte counts.

Type 1 diabetes is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of haematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between type 1 diabetes, CAD and leukocyte counts. Genome-wide association study summary statistics were used to perform pairwise linkage disequilibrium score regression and heritability estimation from summary statistics (ρ-HESS) to respectively estimate the genome-wide and local genetic correlations, and two-sample Mendelian randomisation to estimate the causal relationships between leukocyte counts (335,855 healthy individuals), type 1 diabetes (18,942 cases, 501,638 control individuals) and CAD (122,733 cases, 424,528 control individuals). A latent causal variable (LCV) model was performed to estimate the genetic causality proportion of the genetic correlation between type 1 diabetes and CAD. There was significant genome-wide genetic correlation (rg) between type 1 diabetes and CAD (rg=0.088, p=8.60 × 10-3) and both diseases shared significant genome-wide genetic determinants with eosinophil count (rg for type 1 diabetes [rg(T1D)]=0.093, p=7.20 × 10-3, rg for CAD [rg(CAD)]=0.092, p=3.68 × 10-6) and lymphocyte count (rg(T1D)=-0.052, p=2.76 × 10-2, rg(CAD)=0.176, p=1.82 × 10-15). Sixteen independent loci showed stringent Bonferroni significant local genetic correlations between leukocyte counts, type 1 diabetes and/or CAD. Cis-genetic regulation of the expression levels of genes within shared loci between type 1 diabetes and CAD was associated with both diseases as well as leukocyte counts, including SH2B3, CTSH, MORF4L1, CTRB1, CTRB2, CFDP1 and IFIH1. Genetically predicted lymphocyte, neutrophil and eosinophil counts were associated with type 1 diabetes and CAD (lymphocyte OR for type 1 diabetes [ORT1D]=0.67, p=2.02-19, ORCAD=1.09, p=2.67 × 10-6; neutrophil ORT1D=0.82, p=5.63 × 10-5, ORCAD=1.17, p=5.02 × 10-14; and eosinophil ORT1D=1.67, p=5.45 × 10-25, ORCAD=1.07, p=2.03 × 10-4. The genetic causality proportion between type 1 diabetes and CAD was 0.36 ± 0.16 (pLCV=1.30 × 10-2), suggesting a possible intermediary causal variable. This study sheds light on shared genetic mechanisms underlying type 1 diabetes and CAD, which may contribute to their co-occurrence through regulation of gene expression and leukocyte counts and identifies cellular and molecular targets for further investigation for disease prediction and potential drug discovery.

No bidirectional association between serum 25-hydroxyvitamin D and erectile dysfunction: Mendelian randomization and genetic association studies

Abstract Background The causal relationship between the level of serum 25-hydroxyvitamin D [25(OH)D] and the risk of erectile dysfunction (ED) is still unclear. Aim We tried to determine the causal relationship between the level of serum 25(OH)D and ED risk. Methods In this study, we used genome-wide association study data from the UK Biobank to analyse the relationship between serum 25(OH)D (as the exposure) and ED (as the outcome). Linkage disequilibrium score regression (LDSC) was used to assess the genetic correlation between 2 traits. The CAUSE (Causal Analysis using Summary Effect estimates) method and Mendelian randomization (MR) were employed to evaluate the bidirectional causal relationship. The MRlap method was utilized to assess the impact of sample overlap on the results. To assess potential heterogeneity and horizontal pleiotropy, we utilized methods such as MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier), weighted median, and others. Outcomes The primary outcome was defined as self or physician-reported ED, or using oral ED medication, or a history of surgery related to ED. Results The LDSC analysis did not reveal a significant genetic correlation between serum 25(OH)D and ED (rg = 0.2787, P = .3536). Additionally, the CAUSE (P value testing that the causal model is a better fit &amp;gt;.05) and MR analyses (odds ratio, 0.8951; 95% confidence interval, 0.7480-1.0710; P = .2260) did not support a causal relationship between 25(OH)D and ED, and our study did not detect any heterogeneity and pleiotropy. Clinical implications This study provides evidence on whether vitamin D needs to be ingested to prevent or treat ED. Strengths and limitations We used LDSC and MR to avoid bias. However, the population in this study was limited to European ancestry. Conclusion No causal relationship was found between 25(OH)D and ED.

Exploring the Genetic Risk of Childhood Daytime Urinary Incontinence: A Genome-Wide Association Study.

Childhood incontinence is stigmatized and underprioritized, and a basic understanding of its pathogenesis is missing. Our goal was to identify risk-conferring genetic variants in daytime urinary incontinence (DUI). We conducted a genome-wide association study in the Danish iPSYCH2015 cohort. Cases (3024) were identified through DUI diagnosis codes and redeemed prescriptions for DUI medication in children aged 5 to 20. Controls (30,240), selected from the same sample, were matched to cases on sex and psychiatric diagnoses, if any, and down-sampled to a 1:10 case:control ratio. Replication was performed in the Icelandic deCODE cohort (5475 cases/287,773 controls). Single-nucleotide polymorphism heritability was calculated using the genome-based restricted maximum likelihood method. Cross-trait genetic correlation was estimated using linkage disequilibrium score regression. Polygenic risk scores generated with LDpred2-auto and BOLT-LMM were assessed for association. Variants on chromosome 6 (rs12210989, OR = 1.24 [95% CI: 1.17-1.32], P = 3.21 × 10-12) and 20 (rs4809801, OR = 1.18 [95% CI: 1.11-1.25], P = 3.66 × 10-8) reached genome-wide significance and implicated the PRDM13 and RIPOR3 genes. Chromosome 6 findings were replicated (P = .024, OR = 1.09 [95% CI: 1.01-1.16]). Liability scale heritability ranged from 10.20% (95% CI: 6.40%-14.00%) to 15.30% (95% CI: 9.66%-20.94%). DUI and nocturnal enuresis showed positive genetic correlation (rg = 1.28 ± 0.38, P = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR = 1.098 [95% CI: 1.046-1.152], P < .0001) and body mass index (OR = 1.129 [95% CI: 1.081-1.178], P < .0001) polygenic risk. Common genetic variants contribute to the risk of childhood DUI and genes important in neuronal development and detrusor smooth muscle activity were implicated. These findings may help guide identification of new treatment targets.

Elucidating the role of genetically determined metabolites in Diabetic Retinopathy: insights from a mendelian randomization analysis.

Diabetic retinopathy (DR) results from complex genetic and metabolic interactions. Unraveling the links between blood metabolites and DR can advance risk prediction and therapy. Leveraging Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC), we analyzed 10,413 DR cases and 308,633 controls. Data was sourced from the Metabolomics GWAS server and the FinnGen project. Our research conducted a comprehensive MR analysis across 486 serum metabolites to investigate their causal role in DR. After stringent selection and validation of instrumental variables, we focused on 480 metabolites for analysis. Our findings revealed 38 metabolites potentially causally associated with DR. Specifically, 4-androsten-3beta,17beta-diol disulfate 2 was identified as significantly associated with a reduced risk of DR (OR = 0.471, 95% CI = 0.324-0.684, p = 7.87 × 10- 5), even after rigorous adjustments for multiple testing. Sensitivity analyses further validated the robustness of this association, and linkage disequilibrium score regression analyses showed no significant genetic correlation between this metabolite and DR, suggesting a specific protective effect against DR. Our study identifies 4-androsten-3beta,17beta-diol disulfate 2, a metabolite of androgens, as a significant protective factor against diabetic retinopathy, suggesting androgens as potential therapeutic targets.