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Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Purpose: To investigate the causality between periodontitis and non-alcoholic fatty liver disease (NAFLD) using a two-sample bidirectional Mendelian randomisation (MR) analysis. Materials and Methods: Genetic variations in periodontitis and NAFLD were acquired from genome-wide association studies (GWAS) using the Gene-Lifestyle Interaction in Dental Endpoints, a large-scale meta-analysis, and FinnGen consortia. Data from the first two databases were used to explore the causal relationship between periodontitis and NAFLD (“discovery stage”), and the data from FinnGen was used to validate our results (“validation stage”). We initially performed MR analysis using 5 single nucleotide polymorphisms (SNPs) in the discovery samples and 18 in the replicate samples as genetic instruments for periodontitis to investigate the causative impact of periodontitis on NAFLD. We then conducted a reverse MR analysis using 6 SNPs in the discovery samples and 4 in the replicate samples as genetic instruments for NAFLD to assess the causative impact of NAFLD on periodontitis. We further implemented heterogeneity and sensitivity analyses to assess the reliability of the MR results. Results: Periodontitis was not causally related to NAFLD (odds ratio [OR] = 1.036, 95% CI: 0.914–1.175, p = 0.578 in the discovery stage; OR = 1.070, 95% CI: 0.935–1.224, p = 0.327 in the validation stage), and NAFLD was not causally linked with periodontitis (OR = 1.059, 95% CI: 0.916–1.225, p = 0.439 in the discovery stage; OR = 0.993, 95% CI: 0.896–1.102, p = 0.901 in the validation stage). No heterogeneity was observed among the selected SNPs. Sensitivity analyses demonstrated the absence of pleiotropy and the reliability of our MR results. Conclusion: The present MR analysis showed no genetic evidence for a cause-and-effect relationship between periodontitis and NAFLD. Periodontitis may not directly influence the development of NAFLD and vice versa. [ABSTRACT FROM AUTHOR]

Although commendable progress for combating malaria in endemic areas has been achieved and a dozen countries have been declared malaria-free since 2000 (1), increasing international travel has led to a [...]

Preventive measures and treatments for psychiatric disorders are limited. Circulating metabolites are potential candidates for biomarker and therapeutic target identification, given their measurability and essential roles in biological processes. Leveraging large-scale genome-wide association studies, we conducted Mendelian randomization analyses to assess the associations between circulating metabolite abundances and the risks of bipolar disorder, schizophrenia, and depression. Genetic instruments were selected for 94 metabolites measured in the Canadian Longitudinal Study on Aging cohort (N = 8299). We repeated Mendelian randomization analyses based on the UK Biobank, INTERVAL, and EPIC (European Prospective Investigation into Cancer)–Norfolk studies. After validating Mendelian randomization assumptions and colocalization evidence, we found that a 1 SD increase in genetically predicted circulating abundances of eicosapentaenoate and docosapentaenoate was associated with odds ratios of 0.72 (95% CI, 0.65–0.79) and 0.63 (95% CI, 0.55–0.72), respectively, for bipolar disorder. Genetically increased Ω -3 unsaturated fatty acids abundance and Ω -3-to-total fatty acids ratio, as well as genetically decreased Ω -6-to- Ω -3 ratio, were negatively associated with the risk of bipolar disorder in the UK Biobank. Genetically increased circulating abundances of 3 N -acetyl-amino acids were associated with an increased risk of schizophrenia with a maximum odds ratio of 1.31 (95% CI, 1.18–1.44) per 1 SD increase. Furthermore, a 1 SD increase in genetically predicted circulating abundance of hypotaurine was associated with an odds ratio of 0.85 (95% CI, 0.78–0.93) for depression. The biological mechanisms that underlie Ω -3 unsaturated fatty acids, NAT8-catalyzed N -acetyl-amino acids, and hypotaurine warrant exploration to identify new biomarkers and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Antisocial 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. This 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. LDSC 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. This 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. • There are genetic links between ASB and disorders like ADHD, MDD, SCZ, and PTSD. • The pleiotropic loci like FOXP2 and MDFIC at 7q31.1, linking ASB with psychiatric disorders. • There are causal links between ADHD, SCZ, MDD, and ASB. [ABSTRACT FROM AUTHOR]

Observational studies have shown that individual sleep traits habits are potential risk factors for major depression. However, it is not known whether there is a causal relationship between individual sleep traits habits such as continuous sleep duration, short sleep duration, short sleep duration, insomnia, nap during the day, snoring, and major depression. In this study, Mendelian randomization (MR) was used to predict major depressive disorder (MDD) in individuals sleep traits habits. Data were obtained from the genome-wide association study (GWAS). Nine MR analysis methods were used: Inverse Variance Weighted (IVW) [fixed effects/multiplicative random effects], simple mode, simple mode, weighted mode, simple median, weighted median, penalised weighted median, and MR-Egger, MR Egger (bootstrap). IVW was used as the main analysis method for the MR analysis of two samples, and the other methods were used as supplements. The results obtained through the IVW method supported a causal relationship between sleep duration and decreased risk of MDD (odds ratio, OR ivw : 0.998; 95 % CI: 0.996–0.999, P<0.001). Two-Sample MR, results showed that short sleep duration has a causal effect on the increased risk of MDD (odds ratio, OR ivw : 1.179; 95 % CI: 1.108–1.255, P<0.001). However, there were no sufficient evidence supported that long sleep duration has a causal effect on the decreased risk of MDD (odds ratio, OR ivw : 0.991; 95 % CI: 0.924–1.062, P = 0.793). A significant causal relationship between insomnia and increased risk of MDD was observed (OR: 1.233; 95 % CI: 1.214–1.253, P<0.001). Interestingly, our study also found that daytime napping has a causal effect on the increased risk of MDD (odds ratio, OR ivw : 1.519; 95 % CI: 1.376–1.678, P<0.001). The present results did not show a significant causal relationship between snoring and the risk of MDD (OR ivw : 1.000; 95 % CI: 0.998–1.002, P = 0.906). Obstructive sleep apnea (odds ratio, OR ivw : 1.021; 95 % CI: 0.972–1.072, P = 0.407) and morning person (odds ratio, OR ivw : 1.021; 95 % CI: 0.972–1.072, P = 0.407) have no causal effect on the increased risk of MDD. The study could not ascertain whether there were genetic differences among different ethnicities, nations, and regions, as it only included participants of European ancestry. In summary, our research provides genetic evidence for the relationship between individual sleep traits (short sleep duration, insomnia, daytime napping) and the increased risk of MDD. Interventions targeting lifestyle factors may reduce the risk of MDD. • This study explored the causality between lifestyle and major depressive disorder by Mendelian Randomization analysis. • This research provides genetic evidence supporting that sleep traits increase major depressive disorder risk. • The research primarily included European ancestry. The conclusions may not apply to other ethnic and regional groups. [ABSTRACT FROM AUTHOR]

Background: Recent genome-wide association studies (GWASs) in liver diseases have generated some polygenic risk scores (PRSs), but their predictive effectiveness on hepatocellular carcinoma (HCC) risk assessment remains unclear. Methods: Here, we constructed a novel combined polygenic risk score and evaluated its increment to the well-established risk model. We used 15 HCC-associated genetic loci from two PRSs and FinnGen GWAS data to calculate a PRS-combined score and to fit the related PRS model in the UK Biobank cohort (N = 436,162). The PRS-combined score was further assessed for risk stratification for HCC integrating with the recommended clinical risk scores. Results: The PRS-combined model achieved a better AUC (0.657) than that of PRS-HFC (0.637) and PRS-cirrhosis (0.645). The top 20% of the PRS-combined distribution had a 3.25 increased risk of HCC vs. the middle decile (45–55%). At the population level, the addition of PRS-combined to the CLivD score significantly increased the C-statistic (from 0.716 to 0.746) and provided a remarkable improvement in reclassification (NRI = 0.088) at the 10-year risk threshold of 0.2%. In clinic, additional assessment of PRS-combined would reclassify 34,647 intermediate-risk participants as high genetic risk, corresponding to an increase of 63.92% (62/97) of the HCC events classified at high risk using the Fibrosis-4 alone. Conclusions: The PRS may enhance HCC risk prediction effectiveness in the general population and refine risk stratification of the conventional clinical indicator. [ABSTRACT FROM AUTHOR]

Introduction Knowledge of the impact of smoking on health care costs is important for establishing the external effects of smoking and for evaluating policies intended to modify this behavior. Conventional analysis of this association is difficult because of omitted variable bias, reverse causality, and measurement error. Aims and Methods We approached these challenges using a Mendelian Randomization study design; genetic variants associated with smoking behaviors were used in instrumental variables models with inpatient hospital costs (calculated from electronic health records) as the outcome. We undertook genome-wide association studies to identify genetic variants associated with smoking initiation and a composite smoking index (reflecting cumulative health impacts of smoking) on up to 300 045 individuals (mean age: 57 years at baseline, range 39–72 years) in the UK Biobank. We followed individuals up for a mean of 6 years. Results Genetic liability to initiate smoking (ever vs. never smoking) was estimated to increase mean per-patient annual inpatient hospital costs by £477 (95% confidence interval (CI): £187 to £766). A one-unit change in genetic liability to the composite smoking index (range: 0–4.0) increased inpatient hospital costs by £204 (95% CI: £105 to £303) per unit increase in this index. There was some evidence that the composite smoking index causal models violated the instrumental variable assumptions, and all Mendelian Randomization models were estimated with considerable uncertainty. Models conditioning on risk tolerance were not robust to weak instrument bias. Conclusions Our findings have implications for the potential cost-effectiveness of smoking interventions. Implications We report the first Mendelian Randomization analysis of the causal effect of smoking on health care costs. Using two smoking phenotypes, we identified substantial impacts of smoking on inpatient hospital costs, although the causal models were associated with considerable uncertainty. These results could be used alongside other evidence on the impact of smoking to evaluate the cost-effectiveness of antismoking interventions and to understand the scale of externalities associated with this behavior. [ABSTRACT FROM AUTHOR]

Objective: Association between mitochondrial dysfunction and osteoarthritis (OA) has been consistently investigated, yet their genetic association remains obscure. In this study, mitochondrial-related genes were used as instrumental variables to proxy for mitochondrial dysfunction, and summary data of knee OA (KOA) were used as outcome to examine their genetic association. Methods: We obtained 1136 mitochondrial-related genes from the human MitoCarta3.0 database. Genetic proxy instruments for mitochondrial-related genes from studies of corresponding gene expression (n = 31,684) and protein (n = 35,559) quantitative trait locus (eQTLs and pQTLs), respectively. Aggregated data for KOA (62,497 KOA cases and 333,557 controls) were extracted from the largest OA genome-wide association study (GWAS). We integrated QTL data with KOA GWAS data to estimate their genetic association using summary data-based Mendelian randomization analysis (SMR). Additionally, we implemented Bayesian colocalization analysis to reveal whether suggestive mitochondrial-related genes and KOA were driven by a same genetic variant. Finally, to validate the primary findings, replication study (24,955 cases and 378,169 controls) and multi-SNP-based SMR (SMR-multi) test was performed. Results: Through SMR analysis, we found that the expression levels of 2 mitochondrial-related genes were associated with KOA risk. Specifically, elevated gene expression levels of the IMMP2L (odds ratio [OR] = 1.056; 95% confidence interval [CI] = 1.030–1.082; P-FDR = 0.004) increased the risk of KOA. Conversely, increased gene expression levels of AKAP10 decreased the risk of KOA (OR = 0.955; 95% CI, 0.934–0.977; P-FDR = 0.019). Colocalization analysis demonstrated that AKAP10 (PP.H4 = 0.84) and IMMP2L (PP.H4 = 0.91) shared the same genetic variant with KOA. In addition, consistent results were found in replication study and SMR-multi test, further demonstrating the reliability of our findings. Conclusions: In summary, our analyses revealed the genetic association between mitochondrial dysfunction proxied by mitochondrial-related genes and KOA, providing new insight into potential pathogenesis of KOA. Furthermore, these identified candidate genes offer the possibility of clinical drug target development for KOA. Key points • This is the first SMR study to explore the genetic association between mitochondrial dysfunction proxied by mitochondrial-related genes and KOA. • Sufficient evidence to support genetic association between the expression levels of AKAP10 and IMMP2L, and KOA • Our MR analysis may provide novel new insight into potential pathogenesis of KOA. • These identified candidate genes offer the possibility of clinical drug target development for KOA [ABSTRACT FROM AUTHOR]

To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals. Cross-sectional analysis. Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study). We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements. Proportion of patients with POAG after stratification according to the GRS. We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35–8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79–9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10–4) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10–6). The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Background: Temporomandibular joint disorder (TMD), a prevalent orofacial disorder with complex aetiologies and considerable socioeconomic costs. This underscores the critical importance of developing a comprehensive understanding of the risk factors associated with TMD, as existing research is hindered by deficiencies in establishing causal relationships and the limitations of traditional research methodologies. Objectives: This research explores the causal link between certain risk factors and temporomandibular joint disorder (TMD) through Mendelian randomization (MR), providing multidimensional perspectives in addressing this worldwide health issue. Methods: Utilizing instrumental variables, we applied advanced statistical methods, including the weighted median, inverse variance weighted (IVW) and MR‐Egger, to evaluate the impact of twelve potential risk factors on TMD. Results: Our results identified a significant positive association of TMD with malocclusion (p <.001), sleeping disorders (p =.006), anxiety (p =.002), major depression (p =.0002), daily cigarettes consumption (p =.029) and autoimmune diseases (p =.039). Conversely, a negative association was observed with educational attainment (p =.003). Conclusion: These findings suggest that malocclusion, sleeping disorders, anxiety, major depression, daily cigarettes consumption and autoimmune diseases, could potentially increase TMD risk while educational attainment might mitigate its increase. No direct causal relationships were established between serum 25‐hydroxyvitamin D levels, menopause, frequent alcohol consumption, coffee intake and severely worn dentition and TMD. [ABSTRACT FROM AUTHOR]

• The first use of MR to evaluate the association between neuroticism and IAs. • Using large GWAS data, with a large sample size, results are more reliable. • Further validate the reliability of the results using multiple databases. The aim of this study was to assess the potential causal relationship between neuroticism and 12 neuroticism items with intracranial aneurysms (IAs) and aneurysmal subarachnoid hemorrhage (aSAH) using a two-sample Mendelian randomization (MR) approach. Study data were obtained from the Genome-Wide Association Study (GWAS) pooled dataset, and we extracted summary statistics for neuroticism, 12 neuroticism items, and IAs, which were categorized into ruptured and unruptured aneurysms (IA), aSAH, and unruptured IAs (uIA). Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs) to explore the causal relationship between exposure and outcome using five Mendelian randomization methods, with Inverse variance weighted (IVW) as the primary study method. Horizontal multiple validity tests, sensitivity analyses, and inverse MR ensured the stability of the results. The two-sample MR showed a genetically predictive association between neuroticism and IA [odds ratio (OR) = 1.16; 95 % confidence interval (95 % CI): 1.04–1.30; p = 0.009], aSAH (OR = 1.17; 95 % CI: 1.03–1.33; p = 0.013) and uIA (OR = 1.30; 95 % CI: 1.07–1.59; p = 0.009) were all genetically predictive of association. Ivw showed a positive association between 5 neuroticism items and IA risk, 5 neuroticism items and aSAH risk as well as no genetically predictive association between neuroticism items and uIA. Sensitivity analysis and inverse MR confirmed the robustness of the results. Our Mendelian randomization analysis demonstrated genetic causality between neuroticism and neuroticism items with intracranial aneurysms, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysms, and further studies are needed to confirm these results and explore potential mechanisms of action. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is a genetically complex multifactorial trait. Over the past decade, population-based genome-wide association studies (GWAS) have identified more than 30 IgAN risk loci, providing novel perspectives on both the epidemiology of the disease and its underlying molecular mechanisms. In addition, the association between IgAN and galactose-deficient IgA1 (Gd-IgA1) presented another avenue for genetic exploration due to the heritability of the elevated serum Gd-IgA1 levels. These endeavors also yielded and enabled refinement of polygenic risk scores, which may help identify specific groups of individuals at significantly increased risks, leading to stratifications of medical treatments. In this review, we aim to explore the existing evidence for genetic causation in IgAN. We summarize the state of genetic research in IgAN and how it has led to the reformulation of the new pathogenesis model and novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common degenerative disease that affects millions of individuals worldwide. Objective: There is no conclusive epidemiological evidence regarding the relationship between OA, depression, and whole-body fat mass. In this study, we conducted a two-step Mendelian randomization analysis to determine the causal relationships between them. Design: The published summary-level data are from genome-wide association studies (GWAS). Our study included 357,957 samples and 10,828,862 SNPs. Finally, the outcome GWAS data for OA came from a GWAS on the genetic architecture of OA using UK Biobank data. This study included 50,508 samples and 15,845,511 SNPs. We used five different modes of analysis, including inverse variance weighted meta-analysis (IVW), MR-Egger regression, weighted median, simple mode, and weighted mode, to explore causal relationships. Results: We found a positive correlation between depression and body fat mass, with depression leading to body fat mass an increase in (IVW result: p = 3.39E-07, OR (95 % CI) =2.16 (1.61, 2.90)). We also found a positive correlation between body fat mass and OA, with body fat mass increasing the risk of OA (IVW result: p = 1.65E-33, OR (95 % CI) = 1.98 (1.77, 2.21). Body fat mass played an important role as a mediator in the causal relationship between depression and OA, with approximately 14 % of the risk of OA caused by depression being mediated by body fat mass. Conclusions: Our study offers reliable evidence that depression has a detrimental impact on the risk of OA. Future research can support these associations from improving depressed effect, including social, biological, and behavioral factors, to reduce the risk of chronic diseases such as osteoarthritis. And we identified high-risk variation of alleles which associated with OA and depression can be used to predict disease and provide a basis for clinical intervention and treatment of OA. • The study introduces an innovative approach in utilizing two-step and multivariable Mendelian Randomization (MR) for causal mediation analysis, catering to the exploration of the effect of body fat mass on Osteoarthritis (OA) through the mediating role of depression. • By sidestepping the requirement for individual-level data, this research efficiently leverages genome-wide association studies (GWAS) to gather population-scale data, enhancing the robustness and scope of its findings. • Approximately 14% of the risk of osteoarthritis caused by depression is mediated through body fat as a variable. • The study identified a series of susceptibility genes related to depression and osteoarthritis, providing new potential targets for the treatment of osteoarthritis [ABSTRACT FROM AUTHOR]

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post‐prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome‐wide significant (p < 5E‐08, primary analyses) and 61 suggestive (p < 1E‐05, secondary analyses) ISI genetic variants from large‐scale genome‐wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta‐analysis to combine MR estimates from two non‐overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68–0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82–0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR‐associated T2D and AD. [ABSTRACT FROM AUTHOR]

SUMMARY Plant height can be an indicator of plant health across environments and used to identify superior genotypes. Typically plant height is measured at a single timepoint when plants reach terminal height. Evaluating plant height using unoccupied aerial vehicles allows for measurements throughout the growing season, facilitating a better understanding of plant‐environment interactions and the genetic basis of this complex trait. To assess variation throughout development, plant height data was collected from planting until terminal height at anthesis (14 flights 2018, 27 in 2019, 12 in 2020, and 11 in 2021) for a panel of ~500 diverse maize inbred lines. The percent variance explained in plant height throughout the season was significantly explained by genotype (9–48%), year (4–52%), and genotype‐by‐year interactions (14–36%) to varying extents throughout development. Genome‐wide association studies revealed 717 significant single nucleotide polymorphisms associated with plant height and growth rate at different parts of the growing season specific to certain phases of vegetative growth. When plant height growth curves were compared to growth curves estimated from canopy cover, greater Fréchet distance stability was observed in plant height growth curves than for canopy cover. This indicated canopy cover may be more useful for understanding environmental modulation of overall plant growth and plant height better for understanding genotypic modulation of overall plant growth. This study demonstrated that substantial information can be gained from high temporal resolution data to understand how plants differentially interact with the environment and can enhance our understanding of the genetic basis of complex polygenic traits. [ABSTRACT FROM AUTHOR]

ABSTRACT Flowering time is a crucial rice trait that influences its adaptation to various environments, cropping schedules, and agronomic characteristics. Rice breeders have exploited spontaneous mutations in heading date genes to regulate the flowering time. In the present study, we investigated how breeders in Fukui Prefecture regulated days to heading while developing promising rice varieties. Genome‐wide association studies (GWAS) identified Hd1, Hd16, and Hd18 as the major genes controlling days to heading in the population. However, we suspected that this highly bred population might exhibit genomic stratification, which could lead to spurious or false correlations in the GWAS. Thus, we also conducted correlation and partial correlation analyses, which uncovered another key heading date gene, Hd17, that GWAS failed to detect because of its linkage disequilibrium with the major effect gene Hd16. Examination of haplotype frequencies across different breeding periods revealed that the early‐heading Hd16 (Hd16(E)) and late‐heading Hd17 (Hd17(L)) were increasingly co‐selected in the Hd1 functional population. Varieties carrying this Hd16(E)/Hd17(L) combination exhibited days to heading in the range of 70–80, which corresponds to the peak temperature and sunshine period and is also optimal for grain quality and yield components in the Fukui environment. The present study highlights that it is imperative to remain vigilant for Type I (false positives) and Type II (false negatives) errors when performing GWAS on highly bred populations and to implement appropriate countermeasures by accounting for gene‐by‐gene interactions established through the breeding process. We also discuss the effectiveness of Hd16(E), which is not used outside Japan for subtle days to heading control but is widely used in Japan at certain latitudes. [ABSTRACT FROM AUTHOR]

Genome-wide association studies typically considers epistatic interactions as a crucial factor in exploring complex diseases. However, the current methods primarily concentrate on the detection of two-order epistatic interactions, with flaws in accuracy. In this work, we introduce a novel method called Epi-SSA, which can be better utilized to detect high-order epistatic interactions. Epi-SSA draws inspiration from the sparrow search algorithm and optimizes the population based on multiple objective functions in each iteration, in order to be able to more precisely identify epistatic interactions. To evaluate its performance, we conducted a comprehensive comparison between Epi-SSA and seven other methods using five simulation datasets: DME 100, DNME 100, DME 1000, DNME 1000 and DNME3 100. The DME 100 dataset encompasses eight second-order epistasis disease models with marginal effects, each comprising 100 simulated data instances, featuring 100 SNPs per instance, alongside 800 case and 800 control samples. The DNME 100 encompasses eight second-order epistasis disease models without marginal effects and retains other properties consistent with DME 100. Experiments on the DME 100 and DNME 100 datasets were designed to evaluate the algorithms' capacity to detect epistasis across varying disease models. The DME 1000 and DNME 1000 datasets extend the complexity with 1000 SNPs per simulated data instance, while retaining other properties consistent with DME 100 and DNME 100. These experiments aimed to gauge the algorithms' adaptability in detecting epistasis as the number of SNPs in the data increases. The DNME3 100 dataset introduces a higher level of complexity with six third-order epistasis disease models, otherwise paralleling the structure of DNME 100, serving to test the algorithms' proficiency in identifying higher-order epistasis. The highest average F-measures achieved by the seven other existing methods on the five datasets are 0.86, 0.86, 0.41, 0.56, and 0.79 respectively, while the average F-measures of Epi-SSA on the five datasets are 0.92, 0.97, 0.79, 0.86, and 0.97 respectively. The experimental results demonstrate that the Epi-SSA algorithm outperforms other methods in a variety of epistasis detection tasks. As the number of SNPs in the data set increases and the order of epistasis rises, the advantages of the Epi-SSA algorithm become increasingly pronounced. In addition, we applied Epi-SSA to the analysis of the WTCCC dataset, uncovering numerous genes and gene pairs that might play a significant role in the pathogenesis of seven complex diseases. It is worthy of note that some of these genes have been relatedly reported in the Comparative Toxicogenomics Database (CTD). Epi-SSA is a potent tool for detecting epistatic interactions, which aids us in further comprehending the pathogenesis of common and complex diseases. The source code of Epi-SSA can be obtained at https://osf.io/6sqwj/. [ABSTRACT FROM AUTHOR]

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4bM220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone-shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4bM220T mice. At 24 h post-trauma, Pde4bM220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4bM220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests a potential causal association between lipid levels and facial aging. The aim of this study was to investigate the relationship between levels of specific lipids and facial aging via Mendelian randomization methods. Additionally, this study aimed to identify mediators and explore relevant genes and drug targets. Methods: In this study, genome-wide association data on plasma lipids from 7,174 Finnish individuals in the UK Biobank were used. Two-sample Mendelian randomization was applied to assess the causal effects of specific lipids on facial aging. Sensitivity and pleiotropy analyses were conducted to ensure the robustness and reliability of the results. Multivariate Mendelian randomization was conducted to account for the potential impact of confounding factors. Furthermore, summary-data-based Mendelian randomization was used to identify relevant genes, which were validated through multiomics data. Finally, drug‒gene interactions were explored via molecular docking techniques. Results: Two-sample Mendelian randomization analysis revealed a causal relationship between lipid levels and facial aging. According to the multivariate Mendelian randomization results, smoking was found to mediate this association, and these lipids remained significantly associated with facial aging, even after accounting for environmental confounders. Using summary-data-based Mendelian randomization, CYP21A2, CCND1, PSMA4, and MED1 were identified as potential gene targets, with MED1 further validated through pQTL and mQTL data. Additionally, the MED1 protein was found to bind spontaneously with astragalin, fenofibrate, and ginsenoside. Conclusions: The results revealed a causal relationship between lipid levels and facial aging, revealing key gene targets that were still significantly associated with facial aging after controlling for environmental confounders. Additionally, the interactions between MED1 and certain drugs may indicate potential pathways for therapeutic interventions related to facial aging. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of lung adenocarcinoma (LUAD), the most prevalent histological subtype of primary lung cancer, remains inadequate, with accurate prognostic assessment posing significant challenges. This study sought to elucidate the prognostic significance of mitochondrial-related genes in LUAD through an integrative multi-omics approach, aimed at developing personalized therapeutic strategies. Utilizing transcriptomic and single-cell RNA sequencing (scRNA-seq) data, alongside clinical information from publicly available databases, we first applied dimensionality reduction and clustering techniques to the LUAD single-cell dataset, focusing on the subclassification of fibroblasts, epithelial cells, and T cells. Mitochondrial-related prognostic genes were subsequently identified using TCGA-LUAD data, and LUAD cases were stratified into distinct molecular subtypes through consensus clustering, allowing for the exploration of gene expression profiles and clinical feature distributions across subtypes. By leveraging an ensemble of machine learning algorithms, we developed an Artificial Intelligence-Derived Prognostic Signature (AIDPS) model based on mitochondrial-related genes and validated its prognostic accuracy across multiple independent datasets. The AIDPS model demonstrated robust predictive power for LUAD patient outcomes, revealing significant differences in responses to immunotherapy and chemotherapy, as well as survival outcomes between risk groups. Furthermore, we conducted comprehensive analyses of tumor mutation burden (TMB), immune microenvironment characteristics, and genome-wide association study (GWAS) data, providing additional insights into the mechanistic roles of mitochondrial-related genes in LUAD pathogenesis. This study not only offers a novel approach to improving prognostic assessments in LUAD but also establishes a strong foundation for the development of personalized therapeutic interventions. [ABSTRACT FROM AUTHOR]

In recent observational studies, a potential link between prostatitis and prostate cancer (PCa) has been hinted at, yet the causality remains ambiguous. In our endeavor to scrutinize the conceivable causal nexus between prostatitis and PCa, we embarked upon a Mendelian randomization (MR) study. MR circumvents arbitrary groupings by employing genetic variations that have a strong association with the exposure as instrumental variables to infer causal relationships between exposures and outcomes. The etiology of PCa remains elusive. Given that prostatitis and prostate cancer occupy the same anatomical region, MR can more effectively delineate their relationship by mitigating confounding variables. This method can indirectly elucidate disease correlations, thereby contributing to cancer prevention strategies. FinnGen Consortium data were used for the prostatitis genome-wide association study (GWAS), including 74,658 participants. UK biobank baseline data (ncase = 3436, ncontrol = 459574), European Bioinformatics Institute Database (ncase = 79148, ncontrol = 61106), and IEU openGWAS database (ncase = 79148, ncontrol = 61106) were used for PCa outcomes, mostly for European population samples. Data from the GWSAs for prostatitis were compared with data from the three GWASs for PCa, respectively, in an analysis of an MR. Utilizing the inverse variance weighting (IVW) methodology as our primary analytical framework, we delved into a meticulous exploration of the conceivable causal association between prostatitis and PCa. Furthermore, we deployed supplementary methodologies, including Maximum Likelihood, MR-Egger, weighted median, and MR-PRESSO, to thoroughly assess and scrutinize the causality aspect comprehensively. Cochran's Q statistic is employed as a metric to quantify the heterogeneity inherent in instrumental variables. The inverse variance weighted analysis revealed no discernible effect of prostatitis on PCa in the three PCa GWAS databases (odds ratio [OR]: 1.001, 95% Confidence Interval [CI]: 0.999–1.002, p = 0.28), (OR: 1.015, 95% CI: 0.981–1.050, p = 0.40), (OR: 1.015, 95% CI: 0.981–1.050, p = 0.40). Similarly, employing MR-Egger did not yield substantial evidence (OR: 0.999, 95% CI: 0.999–1.002, p = 0.89), (OR: 1.103, 95% CI: 1.006–1.209, p = 0.07), (OR: 1.103, 95% CI: 1.006–1.209, p = 0.07). The weighted median analysis also failed to provide convincing support for the impact of prostatitis on the incidence of PCa (OR: 1.001, 95% CI: 1.000-1.002, p = 0.064), (OR: 0.989, 95% CI: 0.946–1.034, p = 0.64), (OR: 0.989, 95% CI: 0.945–1.036, p = 0.65). The results of the MR showed no causality from prostatitis to PCa. [ABSTRACT FROM AUTHOR]

SUMMARY Lotus (Nelumbo nucifera G.) is a perennial aquatic horticultural plant with diverse architectures. Distinct plant architecture (PA) has certain attractive and practical qualities, but its genetic morphogenesis in lotus remains elusive. In this study, we employ genome‐wide association analysis (GWAS) for the seven traits of petiole length (PLL), leaf length (LL), leaf width (LW), peduncle length (PLF), flower diameter (FD), petal length (PeL), and petal width (PeW) in 301 lotus accessions. A total of 90 loci are identified to associate with these traits across 4 years of trials. Meanwhile, we perform RNA sequencing (RNA‐seq) to analyze the differential expression of the gene (DEG) transcripts between large and small PA (LPA and SPA) of lotus stems (peduncles and petioles). As a result, eight key candidate genes are identified that are all primarily involved in plant cell wall remodeling significantly associated with PA traits by integrating the results of DEGs and GWAS. To verify this result, we compare the cell wall compositions and structures of LPA versus SPA in representative lotus germplasms. Intriguingly, compared with the SPA lotus, the LPA varieties have higher content of cellulose and hemicellulose, but less filling substrates of pectin and lignin. Additionally, we verified longer cellulose chains and higher cellulose crystallinity with less interference in LPA varieties. Taken together, our study illustrates how plant cell wall remodeling affects PA in lotus, shedding light on the genetic architecture of this significant ornamental trait and offering a priceless genetic resource for future genomic‐enabled breeding. [ABSTRACT FROM AUTHOR]

Introduction: The intricate roles of immune cells and inflammatory factors in cancer, particularly their association with the risk of bladder cancer, are not well understood. Methods: This study aimed to clarify potential causal relationships between these elements and the development of bladder cancer using genome-wide association study (GWAS) summary statistics for 731 immune cell phenotypes and 91 circulating inflammatory factors (cases=2,053; controls=287,137). The primary analytical approach was Inverse Variance Weighting (IVW), supplemented by MR-Egger regression, weighted median, and weighted mode analyses. Sensitivity analyses included Cochran Q test, MR-Egger intercept test, and Leave-one-out test. Results: The findings indicated that monocytes are positively correlated with an increased risk of bladder cancer. On the contrary, double-negative (DN) T cells, HLA DR+CD8br, and CD28 on CD28+CD45RA+CD8br T cells exhibited an inverse correlation, suggesting a possible protective effect. Furthermore, inflammatory factors IL-20, IL-22RA1, and Eotaxin were significantly associated with an increased risk of bladder cancer. Discussion: These results suggest that certain immune cell phenotypes and inflammatory factors may play a role in the development of bladder cancer and could serve as potential biomarkers for assessing tumor risk. The findings also offer new insights into the pathogenesis of bladder cancer, indicating a need for further investigation. [ABSTRACT FROM AUTHOR]

Background: Extensive observational data suggest a link between celiac disease (CeD) and osteoporosis, but the causality and mediating mechanism remain undetermined. Herein, we performed a Mendelian randomization (MR) study to address these concerns. Methods: We obtained the summary-level statistics for CeD from a large genome-wide association study (GWAS) comprising 4,533 cases and 10,750 controls of European ancestry. The GWAS data for osteoporosis-related traits and inflammatory cytokines were derived from the UK Biobank, FinnGen, IEU OpenGWAS database, or GWAS catalog. Two-sample MR with the inverse variance-weighted methods were employed to evaluate the genetic association between CeD and osteoporosis-related traits. The potential inflammatory mediators from CeD to osteoporosis were explored using twostep mediation analyses. Results: The primary MR analyses demonstrated causal associations between genetically predicted CeD and osteoporosis (odds ratio [OR]: 1.110, 95% confidence interval [CI]: 1.043-1.182, p=0.001), total body bone mineral density (β: -0.025, p=0.039), and osteoporotic fracture (OR: 1.124, 95% CI: 1.009-1.253, p=0.034). Extensive sensitivity analyses consolidated these findings. Among the candidate inflammatory cytokines, only interleukin-18 was observed to mediate the effects of CeD on osteoporosis, with an indirect OR of 1.020 (95% CI: 1.000-1.040, p=0.048) and a mediation proportion of 18.9%. The mediation effects of interleukin-18 could be validated in other datasets (OR: 1.015, 95% CI: 1.001-1.029, p=0.041). Bayesian colocalization analysis supported the role of interleukin-18 in osteoporosis. Conclusion: The present MR study reveals that CeD is associated with an increased risk of developing osteoporosis, which may be partly mediated by upregulation of interleukin-18. [ABSTRACT FROM AUTHOR]

Background: Coffee is a widely consumed beverage with potential benefits for various chronic diseases. Its effect on reducing erectile dysfunction (ED) risk is unclear. This Mendelian randomization (MR) study investigates the impact of coffee/caffeine consumption on ED. Methods: Two sets of coffee consumption-associated genetic variants at the genome-wide significance level were obtained from recent studies of coffee consumption. Taking into account other sources of caffeine, genetic variants associated with caffeine consumption from tea were also obtained. The inverse variance weighted (IVW) method was utilized as the primary analysis. Sensitivity analysis methods and meta-analysis methods were performed to confirm the robustness of the results, while the genetic variants associated with confounders, e.g., diabetes and hypertension, were excluded. Results: Genetically predicted coffee/caffeine consumption was unlikely to be associated with the risk of ED in the Bovijn datasets, with similar directional associations observed in the FinnGen datasets. The combined odds ratio for ED was 1.011 (95% CI 0.841-1.216, p=0.906) for coffee consumption from the genome-wide meta-analysis, 1.049 (95% CI 0.487-2.260, p=0.903) for coffee consumption from the genome-wide association study, and 1.061 (95% CI 0.682-1.651, p=0.793) for caffeine from tea. Conclusion: Using genetic data, this study found no association between coffee/caffeine consumption and the risk of ED. [ABSTRACT FROM AUTHOR]

Background: The relationship between gut microbiota and coagulation defects, purpura, and other hemorrhagic conditions (CPH) is currently unclear, with causal links yet to be firmly established. Objective: The causal relationships between gut microbiota and CPH, along with the potential mediating role of immune cells, were studied using Mendelian randomization analysis. Methods: Data on 412 gut microbiota species, 731 immune cell types, and CPH were methodologically compiled from genome-wide association studies and the FinnGen database. A 2-sample Mendelian randomization approach in 2 stages was used and the causal links between gut microbiota and CPH were statistically analyzed, assessing the potential mediation by immune cells. Sensitivity and reliability were ensured through heterogeneity and pleiotropy tests. Results: The abundance of Alistipes putredinis (odds ratio [OR]=0.77, 95% confidence interval [CI] 0.64-0.93, P=0.006) was negatively correlated with CPH, whereas the abundance of Bacteroides stercoris (OR=1.25, 95%CI 1.09-1.45, P=0.002) was positively correlated with the risk of CPH. There was no evidence of reverse causality or the potential mediating effects of 731 immune cell types. The abundance of Proteobacteria (OR=0.81, 95%CI 0.71-0.92, P=0.001) and Coprococcus sp. ART55/1 (OR=0.87, 95%CI 0.80-0.96, P=0.005) was negatively associated with the risk of CPH, whereas the abundance of Enterobacteriales/Enterobacteriaceae (OR=1.36, 95%CI 1.12-1.64, P=0.002) was positively correlated with the risk of CPH, with no evidence of reverse causality. Furthermore, CD38 levels on CD3-CD19 cells can serve as a mediating factor for the influence of Proteobacteria on the pathogenesis of CPH, with a mediating effect ratio of 7.26%. Conclusions: An increase in Proteobacteria abundance leads to a decrease in CD38 expression on CD3-CD19-cells, thereby reducing the risk of developing CPH. CD3 expression on naive CD4+ in mature T cells serves as a mediating factor for the influence of Enterobacteriales/Enterobacteriaceae on the pathogenesis of CPH, whereas IgD CD38br AC expression on B cells serves as a mediating factor for the influence of Coprococcus sp. ART55/1 on the pathogenesis of CPH. The mediating effect is opposite to the overall trend and has a relatively small impact. No significant heterogeneity or pleiotropy was observed. [ABSTRACT FROM AUTHOR]

Aim: An excessively activated or dysregulated complement system has been proven to be a vital contributor to the pathogenesis of periodontitis. It has been previously hypothesized that inhibiting the activity of complement component C5 by targeting the C5a receptor is a powerful candidate for treating periodontitis. Here, we apply the drug target instrumental variable (IV) approach to investigate the therapeutic effect of genetically proxied inhibition of C5 on periodontitis. Method: In our primary analysis, we used 26 independent 'cis' single nucleotide polymorphisms as IVs from the vicinity of the encoding locus of C5 that are associated with plasma C5 levels. In a secondary analysis, we assess the validity of our primary findings, exploring the involvement of alternative downstream biomarkers, interleukin 17 (IL-17), interleukin 1b (IL-1b), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1b, and TNF) were obtained from a genome-wide association study (GWAS) of 35,559 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis. Results: In our primary approach, inhibiting C5 reduced the risk of periodontitis (Odds ratio 0.89 per 1 standard deviation reduction in C5; 95% confidence Interval 0.80-0.98, p value=0.022). Our secondary analysis suggests an involvement of IL-17 within the potential causal pathway, but was inconclusive for other biomarkers. Conclusions: The findings from our study suggest that C5 inhibition may reduce the risk of periodontitis, prioritizing C5 inhibitors as a potential adjunctive therapeutic intervention in this disease. [ABSTRACT FROM AUTHOR]

Introduction: A potential link between venous thromboembolism and the risk of ovarian cancer has been identified in clinical practice. However, it is unclear whether there is a causal relationship between the two. In this study, we applied a univariate two-sample Mendelian randomization method to explain the possible link between venous thromboembolism and ovarian cancer pathogenesis at the genetic level, and pointed out that lipid metabolism and ovarian cancer pathogenesis have innovative basic experimental directions. Objective: This study explored the causal effect between a history of venous thromboembolism and the risk of ovarian cancer. Methods: Genome-Wide Association Study (GWAS) data of venous thromboembolism patients (n = 9176) of the same ethnicity were selected as study exposures, and GWAS data of ovarian cancer patients (n = 1218) of the same ethnicity were selected as study exposures. In this study, univariate two-sample Mendelian randomization analysis (UVMR) was performed separately using inverse variance weighted (IVW), MR-Egger regression, and weighted median (WM) to assess causal effects. In this study, Cochran's Q test, MR-Egger regression intercept term, MR-PRESSO, and leave-one-out method were used for sensitivity analysis to assess the stability and reliability of the results. Results: The GWAS data screened in this study were all European ethnicity data. In this study, we found that genetically predicted history of venous thromboembolism was associated with an upward trend in ovarian cancer incidence, and the results of Weighted median, Simple mode, Weighted mode, and MR Egger showed a similar trend (OR = 1.0006, 95% CI: 1.00007–1.0013, p < 0.05). There was no heterogeneity of results (p = 0.18) and no horizontal pleiotropy (p = 0.77). The instrumental variables selected for venous thromboembolism in this study were all strong instrumental variables (F = 669.7). The results of the sensitivity analysis remained consistent. Conclusion: The results of this study indicate that patients with a history of venous thromboembolism are at increased risk of developing ovarian cancer and point to possible associations between lipid metabolism genes, such as CYP4V2, and the development of ovarian cancer, which provide interesting directions for further basic research. [ABSTRACT FROM AUTHOR]

Rice tocopherols, vitamin E compounds with antioxidant activity, play essential roles in human health. Even though the key genes involved in vitamin E biosynthetic pathways have been identified in plants, the genetic architecture of vitamin E content in rice grain remains unclear. A genome-wide association study (GWAS) on 179 genotypically diverse rice accessions with 34,323 SNP markers was conducted to detect QTLs that define total and a-tocopherol contents in rice grains. Total and a-tocopherol contents had a strong positive correlation and varied greatly across the accessions, ranging from 0.230-31.76 and 0.011-30.83 (mg/g), respectively. A total of 13 QTLs were identified, which were spread across five of the rice chromosomes. Among the 13 QTLs, 11 were considered major with phenotypic variation explained (PVE) greater than 10%. Twelve transcription factor (TF) genes, one microprotein (miP), and a transposon were found to be associated with the QTLs with putative roles in controlling tocopherol contents. Moreover, intracellular transport proteins, ABC transporters, nonaspanins, and SNARE, were identified as associated genes on chromosomes 1 and 8. In the vicinity of seven QTLs, protein kinases were identified as key signaling factors. Haplotype analysis revealed the QTLs qAlph1.1, qTot1.1, qAlph2.1, qAlph6.1, qTot6.1, and qTot8.3 to have significant haplogroups. Quantitative RT-PCR validated the expression direction and magnitude of WRKY39 (Os02g0265200), PIP5Ks (Os08g0450800), and MADS59 (Os06g0347700) in defining the major tocopherol contents. This study provides insights for ongoing biofortification efforts to breed and/or engineer vitamin E and antioxidant levels in rice and other cereals. [ABSTRACT FROM AUTHOR]

Background: Endometrial carcinoma (EC) remain a malignancy with incompletely understood risk factors. To address this knowledge gap, we employed mendelian randomization study to investigate potential protective and risk elements associated with endometrial cancer. Methods: We conducted a two-sample Mendelian randomization (MR) study using genetic association data for overall EC and its subtypes from a large-scale genome-wide association study (GWAS). This GWAS encompassed 12,906 EC patients and 108,979 healthy controls. The EC cases were further categorized into 8758 endometrioid and 1230 non-endometrioid subtypes. To serve as instrumental variables, we identified independent genetic variants strongly associated with 5 lifestyle factors and 14 metabolic factors from relevant GWASs. Subsequently, we conducted univariable Mendelian randomization (MR) analyses. Results: Our study revealed the relationship among EC with lifetime smoking index (OR: 1.43; 95% CI 1.05–1.96), frequency of alcohol consumption (OR:1.23; 95% CI 1.04–1.45), body mass index (BMI) (OR:1.82; 95% CI 1.64–2.01), type 2 diabetes mellitus (T2DM) (OR:1.06; 95% CI 1.00–1.12), and fasting insulin (OR:1.97; 95% CI 1.30–2.98). Conversely, inverse associations with EC were observed for education level (OR:0.72, 95% CI 0.62–0.83), moderate-level physical exercise (OR 0.35, 95% CI 0.15–0.84), and low-density lipoproteins (LDL) (OR 0.91, 95% CI 0.84–0.99). Conclusions: Our findings underscore a causal association between genetically predicted lifetime smoking index, alcohol intake frequency, BMI, T2DM, and fasting insulin with EC risk. Furthermore, our study highlights the potential protective effects of a high education level, moderate-intensity physical exercise, and LDL reduction against EC risk. This MR analysis provided valuable insights into underlying EC risk mechanisms and paved new ways for EC prevention strategies. [ABSTRACT FROM AUTHOR]

Objective: Early identification of modifiable risk factors is crucial for the prevention of constipation. This study systematically investigated the relationship between genetically predicted modifiable risk factors and constipation. Methods: The inverse variance weighting (IVW) method was employed as the primary analytical approach. For similar exposure indicators, the multivariate Mendelian randomization (MVMR) method was used to adjust for potential biases in univariate MR analysis. The robustness of the results was further evaluated using the MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis. Bonferroni correction was applied to reduce the false positive rate in the results. Results: The IVW analysis indicated a significant causal association between genetically predicted gastroesophageal reflux disease [OR (95% CI) = 1.192 (1.079–1.315), P = 0.0005], atorvastatin use [OR (95% CI) = 16.995 (3.327–86.816), P = 0.0007], and constipation. Additionally, there was a potential causal association between education level [OR (95% CI) = 0.859 (0.767–0.964), P = 0.009], major depressive disorder [OR (95% CI) = 1.206 (1.041–1.399), P = 0.013], hypothyroidism [OR (95% CI) = 2.299 (1.327–3.985), P = 0.003], and aspirin use [OR (95% CI) = 4.872 (1.174–20.221), P = 0.029] with constipation. No causal associations were found for the other included indicators. Sensitivity analysis demonstrated the absence of evidence for heterogeneity and pleiotropy in any positive results. Conclusion: This study identified several risk factors that could be targeted for the prevention of constipation, offering valuable insights for public health policies. [ABSTRACT FROM AUTHOR]

Iron is an essential mineral that supports numerous biological functions. Studies have reported associations between iron dysregulation and certain cardiovascular and neurodegenerative diseases, but the direction of influence is not clear. Our goal was to use computational approaches to better understand the role of genetically predicted iron levels on disease risk. We meta-analyzed genome-wide association study summary statistics for serum iron levels from two cohorts and two previous meta-analyses. We then obtained summary statistics from 11 neurodegenerative, cerebrovascular, cardiovascular or lipid traits to assess global and regional genetic correlation between iron levels and these traits. We used two-sample Mendelian randomization (MR) to estimate causal effects. Sex-stratified analyses were also carried out to identify effects potentially differing by sex. Overall, we identified three significant global correlations between iron levels and (i) coronary heart disease, (ii) triglycerides, and (iii) high-density lipoprotein (HDL) cholesterol levels. A total of 194 genomic regions had significant (after correction for multiple testing) local correlations between iron levels and the 11 tested traits. MR analysis revealed two potential causal relationships, between genetically predicted iron levels and (i) total cholesterol or (ii) non-HDL cholesterol. Sex-stratified analyses suggested a potential protective effect of iron levels on Parkinson's disease risk in females, but not in males. Our results will contribute to a better understanding of the genetic basis underlying iron in cardiovascular and neurological health in aging, and to the eventual identification of new preventive interventions or therapeutic avenues for diseases which affect women and men worldwide. [ABSTRACT FROM AUTHOR]

Observational studies have shown some association between cannabis use disorder (CUD) and neurological disorders, but their causal relationship is unclear. In this study, we tested the potential causal relationship between CUD and three common neurological disorders using two-sample Mendelian randomization (TSMR) and multivariate MR (MVMR) methods. Thirty-two genetic loci were extracted as exposure factors from the largest genome-wide association study (GWAS) summary statistics for CUD to date. TSMR results showed that genetic prediction of CUD with all stroke, ischemic stroke, large-artery atherosclerotic stroke, migraine with aura, and Alzheimer's disease (AD) had a positive causal relationship (P < 0.05), which was not found in several other diseases. The association between CUD and stroke, ischemic stroke, and AD in the MVMR study may have been influenced by confounding factors (P > 0.05). Subgroup analyses highlighted a causal relationship between genetically predicted CUD and large-artery atherosclerotic stroke (OR = 1.169; 95%CI 1.030–1.328; P = 0.016) and migraine with aura (OR = 1.142; 95% 1.021–1.278; P = 0.020). Our further functional mapping and annotation enrichment analyses using FUMA suggest that the brain-gut axis may serve as another layer of explanation for the existence of an association between CUD and neurological disorders. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the potential causal relationships between coronary artery disease (CAD), myocardial infarction (MI), urate levels, and aortic aneurysm (AA), abdominal aortic aneurysm (AAA), thoracic aortic aneurysm(TAA), aortic dissection (AD) in individuals of European ancestry. To examine the potential causal relationships between CAD, MI, and urate levels with AA, AAA, TAA, AD, respectively, we performed a two-sample Mendelian randomization (MR) analysis. Genetic instruments that reached genome-wide significance (p < 5 × 10 − 8) for risk factors were obtained from genome-wide association studies(GWASs) conducted on individuals of European origin. On the other hand, genetic instruments of AA, AAA, TAA or AD were chosen from the FinnGen cohort. The primary analysis employed the inverse-variance weighted MR method, while sensitivity analyses were conducted using MR-Egger, weighted median MR, MR pleiotropy residual sum and outlier, and Phenoscanner searching. In addition, we performed the MR-Egger intercept analysis to identify potential pleiotropy and utilized Cochran's Q statistics to evaluate heterogeneity. Additionally, we conducted bidirectional Mendelian randomization experiments to mitigate the potential influence of reverse causation. According to the results of our study, there were statistically significant higher risks for AA in relation to CAD/MI(odds ratio (OR) with 95% confidence interval (CI): 1.309 (1.150–1.490), and 1.255 (1.147–1.373). Similarly, there were statistically significant higher risks for AAA in relation to CAD and MI (OR with 95% CI: 1.383 (1.189–1.609), and 1.352 (1.178–1.552). The sensitivity analysis demonstrated that the causative effects of CAD/MI, and AA /AAA, were robust. A positive causal link was observed between CAD/MI, and AA/AAA. Nevertheless, no causal link was found between CAD, MI, urate levels, and TAA. [ABSTRACT FROM AUTHOR]

Developing lettuce varieties with salt tolerance at the seed germination stage is essential since lettuce seeds are planted half an inch deep in soil where salt levels are often highest in the salinity-affected growing regions. Greater knowledge of genetics and genomics of salt tolerance in lettuce will facilitate breeding of improved lettuce varieties with salt tolerance. Accordingly, we conducted a genome-wide association study (GWAS) in lettuce to identify marker-trait association for salt tolerance at the seed germination stage. The study involved 445 diverse lettuce accessions and 56,820 single nucleotide polymorphism (SNP) markers obtained through genotype-by-sequencing technology using lettuce reference genome version v8. GWAS using two single-locus and three multi-locus models for germination rate (GR) under salinity stress, 5 days post seeding (GR5d_S) and a salinity susceptibility index (SSI) based on GR under salinity stress and control conditions, 5 days post seeding (SSI_GR5d) revealed 10 significant SNPs on lettuce chromosomes 2, 4, and 7. The 10 SNPs were associated with five novel QTLs for salt tolerance in lettuce, explaining phenotyping variations of 5.85%, 4.38%, 4.26%, 3.77%, and 1.80%, indicating the quantitative nature of these two salt tolerance-related traits. Using the basic local alignment search tool (BLAST) within 100 Kb upstream and downstream of each of the 10 SNPs, we identified 25 salt tolerance-related putative candidate genes including four genes encoding for major transcription factors. The 10 significant salt tolerance-related SNPs and the 25 candidate genes identified in the current study will be a valuable resource for molecular marker development and marker-assisted selection for breeding lettuce varieties with improved salt tolerance at the seed germination stage. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aβ) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies. [ABSTRACT FROM AUTHOR]

Background: Breast cancer remains a significant global health challenge. Understanding its etiological factors, particularly the role of immune system components, is crucial. This study leverages Mendelian randomization (MR) to investigate the causal relationship between various immune cell features and the risk of developing breast cancer. Methods: Utilizing two-sample MR analysis, we examined 731 immune cell features across 7 groups for their potential causal links to breast cancer. We analyzed genome-wide association studies (GWAS) data of 257,730 Europeans, comprising 17,389 cases and 240,341 controls, focusing on 24,133,589 single nucleotide polymorphisms (SNPs). Instrumental variables (IVs) were selected based on genetic associations, with rigorous statistical methods employed, including inverse variance weighting (IVW) and weighted median-based estimation. Results: Our analysis identified 20 immunophenotypes with significant causal associations with breast cancer risk. Notably, contain B cell, mature T cell, T + B + NK (TBNK) cells, regulatory T (Treg) cell, Classic dendritic cells (cDCs), Monocyte, and Myeloid cell group features displayed positive or negative correlations with breast cancer. For instance, specific B cell phenotypes were found to have both positive and negative causal relationships with breast cancer. Additionally, reverse MR analysis revealed no significant causal effects of breast cancer on these immune characteristics. Conclusions: This study underscores the complex interplay between various immune cell phenotypes and breast cancer risk. The identified immunophenotypes could be potential biomarkers or targets for future therapeutic interventions. Our findings contribute to a deeper understanding of the immunological dimensions of breast cancer etiology. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a complex disease influenced by well-established environmental exposures (most notably, cigarette smoking) and incompletely defined genetic factors. The chromosome 4q region harbors multiple genetic risk loci for COPD, including signals near HHIP, FAM13A, GSTCD, TET2, and BTC. Leveraging RNA-Seq data from lung tissue in COPD cases and controls, we estimated the co-expression network for genes in the 4q region bounded by HHIP and BTC (~70MB), through partial correlations informed by protein-protein interactions. We identified several co-expressed gene pairs based on partial correlations, including NPNT-HHIP, BTC-NPNT and FAM13A-TET2, which were replicated in independent lung tissue cohorts. Upon clustering the co-expression network, we observed that four genes previously associated to COPD: BTC, HHIP, NPNT and PPM1K appeared in the same network community. Finally, we discovered a sub-network of genes differentially co-expressed between COPD vs controls (including FAM13A, PPA2, PPM1K and TET2). Many of these genes were previously implicated in cell-based knock-out experiments, including the knocking out of SPP1 which belongs to the same genomic region and could be a potential local key regulatory gene. These analyses identify chromosome 4q as a region enriched for COPD genetic susceptibility and differential co-expression. Author summary: Complex diseases, such as chronic obstructive pulmonary disease (COPD), are characterized by multifactorial causes, including multiple genetic variants and a variety of molecular functions. A 70 megabase genomic region on chromosome 4 harbors some of the strongest genetic associations to COPD based on genome-wide association studies (GWAS). In this work we study the co-expression patterns of genes located in this genomic region. We developed a new approach to compute partial correlations between pairs of expressed genes, using prior information regarding the mediating genes from protein-protein interaction networks. We identified potential biological connections between several of the COPD-related GWAS genes in this region, including BTC, NPNT, PPM1K and HHIP, suggesting possible functional co-regulation. Furthermore, by comparing COPD cases and control subjects, we found multiple network edges whose co-expression changed between health and disease, particularly the edge between CXCL10 and CXCL11. Some of these genes were previously implicated in cell-based knock-out experiments, suggesting a common regulator, namely SPP1. These analyses provide insight into regional gene regulation of GWAS genes that may be related to COPD pathogenesis. [ABSTRACT FROM AUTHOR]

Enteritis caused by Vibrio is a highly die-off disease that severely impeded substantial production in seahorse aquaculture. In the present study, challenged with LD50 of concentration of Vibrio harveyi, a total of 161 of susceptible and 166 of resistant individuals were allocated into binary survival phenotypes, thus, to firstly investigate the genetic architecture by genome-wide association study (GWAS) analysis, as well as to evaluate the feasibility of genomic selection (GS) in enteritis disease resistance trait of the lined seahorse Hippocampus erectus. Results indicated that the heritability for resistance to Vibrio harveyi was estimated to be 0.10. And a set of 10 significant/suggestive SNPs in a multiple chromosomes localization were identified, explaining 7.76% to 13.28% of genetic variance. Associated 82 of candidate genes were clustered into signal transduction, cell proliferation, response of external stress, bacteria defence, and antiinflammatory processes. Moreover, the potential performance of genomic selection (GS) in application in selective breeding for enteritis disease resistance seahorses was assessed by genomic prediction (GP). In general, the predictive accuracy of the genomic estimated breeding value (GEBV) of BayesC exceeded the rrBLUP, BayesA, RKHS, and SVM models while with no significant difference. And the GWAS-informative SNPs was significantly superior in efficience than random selected markers by comparison of predictive performance on different selection strategies of SNPs. Overall, the genetic basis of enteritis disease resistance trait in the lined seahorse is a polygenic genetic architecture. SNPs associated with the important genes of cathepsin L1-like previously reported with respect to disease resistance are consider as potential molecular markers of genetic breeding. Furthermore, GS approach is an appropriate, effective, and less-cost application in breeding enteritis disease-resistant seahorses. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is a major microvascular complication of diabetes and a leading cause of blindness worldwide. The pathogenesis of DR involves complex interactions between metabolic disturbances, immune cells, and proteolytic enzymes such as cathepsins (CATs). Despite various studies, the precise roles of different CATs, metabolites, and vitamins in DR remain unclear. Method: In this study, we employed Mendelian Randomization (MR) to assess causal relationships using genetic instruments selected based on genome-wide association studies (GWAS). We employed two-sample and mediation MR to explore the causal effects between nine CATs, immune cells, metabolites, vitamins, and DR. Additionally, the study also incorporated data from the NHANES survey to explore the associated relationship between vitamins and DR. We utilized cross-sectional data from the NHANES to analyze the association between vitamin intake and diabetic retinopathy (DR), adjusting for potential confounders to strengthen the validity of our findings. Results: The MR analysis identified CAT H as a significant risk factor for both NPDR and PDR, with no evidence of reverse causality. Additionally, 62 immune cell traits were found to have causal relationships with NPDR and 49 with PDR. Enrichment analysis revealed that metabolic pathways such as sphingolipid metabolism are crucial in DR progression. Vitamins B6 and E were significantly associated with a reduced risk of PDR. Cross-sectional data indicated that vitamins B1, B2, B6, B12, and E progressively decreased with DR severity. Conclusion: This study is the first to identify CAT H as a key risk factor for DR, while vitamins B6 and E showed significant protective effects, particularly against PDR. These findings suggest that CAT H, along with vitamins B6 and E, could serve as therapeutic targets for DR. Further validation through larger, multi-center studies is recommended to enhance the accuracy and applicability of these findings. [ABSTRACT FROM AUTHOR]

Background: Yam production in sub-Saharan African countries faces challenges due to susceptibility to yam mosaic virus (YMV) disease, leading to significant yield losses. Dioscorea praehensilis, a semi-cultivated yam species known for its high yield and resistance to YMV, can be utilized as a new variety and a gene source to enhance tuber yield and YMV resistance of White Guinea yam. Investigating the genetic basis of tuber yield-related traits and YMV resistance in D. praehensilis through association mapping will facilitate the traits discovery and deployment into the yam breeding program. Methodology: A total of 132 D. praehensilis genotypes were evaluated in 2022 and 2023 seasons for tuber yield per plant, tuber size ratio and for mosaic virus severity response. The genotypes were sequenced using SNP markers generated from Diversity Array Technology Platform. The trait association analysis was conducted using mixed linear model implemented in GWASpoly package followed for putative genes analysis. Results: Population structure and phylogeny analyses using 4,525 single nucleotide polymorphism (SNP) markers grouped the 132 D. praehensilis genotypes into three clusters. Using multiple gene action models which include dominant, additive, and general models, 27 SNP markers were significantly identified to be associated with the tuber yield, tuber size ratio and yam mosaic virus severity. Of these 27 SNPs, we identified three and two SNP markers for tuber yield and yam mosaic virus severity, respectively as stable markers across years. Using gene annotation, we identified 10 putative genes such as Serine/threonine-/dual specificity protein kinase, catalytic domain involved in starch biosynthesis and Ribosomal protein L5 involved in defense signaling against virus diseases. The marker effect revealed that alleles CC and TT were associated with high tuber yield, while AA and AC were linked with low tuber yield. For YMV severity response, alleles CC and CT were linked with low YMV severity, while TT was associated high YMV severity prediction. Conclusion: The results of this study offer valuable insights into comprehending the functional networks involved in developing strategies to enhance tuber yield and resistance to yam mosaic virus in Dioscorea spp. The markers and candidate genes discovered in this research will serve as crucial genomic resources for selection of D. praehensilis and other yam species. [ABSTRACT FROM AUTHOR]

Background: Chronic Kidney Disease (CKD) impacts over 10% of the global population, and recent advancements in high-throughput analytical technologies are uncovering the complex physiology underlying this condition. By integrating Genome-Wide Association Studies (GWAS), RNA sequencing (RNA-seq/RNA array), and single-cell RNA sequencing (scRNA-seq) data, our study aimed to explore the genes and cell types relevant to CKD traits. Methods: GWAS summary data for end-stage renal failure (ESRD) and decreased eGFR (CKD) with or without diabetes and (micro)proteinuria were obtained from the GWAS Catalog and the UK Biobank (UKB) database. Two gene Expression Omnibus (GEO) transcriptome datasets were used to establish glomerular and tubular gene expression differences between CKD patients and healthy individuals. Two scRNA-seq datasets were utilized to obtain the expression of key genes at the single-cell level. The expression profile, differentially expressed genes (DEGs), gene-gene interaction, and pathway enrichment were analysed for these CKD risk genes. Results: A total of 779 distinct SNPs were identified from GWAS across different CKD traits, involving 681 genes. While many of these risk genes are specific to the CKD traits of renal failure, decreased eGFR, and (micro)proteinuria, they share common pathways, including extracellular matrix (ECM). ECM modeling was enriched in upregulated glomerular and tubular DEGs from CKD kidneys compared to healthy controls, with the expression of relevant collagen genes, such as COL1A2, prevalent in fibroblasts/myofibroblasts. Additionally, immune responses, including T cell differentiation, were dysregulated in CKD kidneys. The late podocyte signature gene THSD7A was enriched in podocytes but downregulated in CKD. We also highlighted that the regulated risk genes of CKD are mainly expressed in tubular cells and immune cells in the kidney. Conclusions: Our integrated analysis highlight the genes, pathways, and relevant cell types associational with the pathogenesis of kidney traits, as a basis for further mechanistic studies to understand the pathogenesis of CKD. [ABSTRACT FROM AUTHOR]

Fusarium head blight (FHB) is a devastating disease of wheat, causing yield losses, reduced grain quality, and mycotoxin contamination. Breeding can mitigate the severity of FHB epidemics, especially with genomics-assisted methods. The mechanisms underlying resistance to FHB in wheat have been extensively studied, including phenological traits and genome-wide markers associated with FHB severity. Here, we aimed to improve genomic prediction for FHB resistance across breeding programs by incorporating FHB-correlated traits and FHB-associated loci as model covariates. We combined phenotypic data on FHB severity, anthesis date, and plant height with genome-wide marker data from five Central European winter wheat breeding programs for genome-wide association studies (GWAS) and genomic prediction. Within all populations, FHB was correlated with anthesis date and/or plant height, and a marker linked to the semi-dwarfing locus Rht-D1 was detected with GWAS for FHB. Including the Rht-D1 marker, anthesis date, and/or plant height as covariates in genomic prediction modeling improved prediction accuracy not only within populations but also in cross-population scenarios. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the causal relationship between cervical carcinoma in situ and antibody-mediated immune responses, providing a scientific basis for the prevention and treatment of cervical carcinoma in situ. Methods: A bidirectional Mendelian Randomization (MR) approach was utilized, leveraging two Genome-Wide Association Studies (GWAS) related to cervical carcinoma in situ and antibody-mediated immune responses to collect Single Nucleotide Polymorphism (SNP) data. Multiple statistical methods, including the inverse-variance weighted (IVW) method, MR-Egger regression, weighted median, and weighted mode, were utilized. Antibody-mediated immune response-related SNPs were used as instrumental variables (IVs) for a forward MR analysis of cervical carcinoma in situ, while cervical carcinoma in situ-related SNPs served as IVs for a reverse MR analysis of antibody-mediated immune responses. Results: The forward MR analysis revealed significant causal associations between two SNPs, GCST90006901 (P = 0.012, OR (95%CI) = 1.167(1.034–1.317)) and GCST90006909 (P < 0.001, OR (95%CI) = 1.805(1.320–2.467)), within antibody-mediated immune responses and the occurrence of cervical carcinoma in situ. The reverse MR analysis demonstrated that cervical carcinoma in situ exerts influence on multiple SNPs associated with antibody-mediated immune responses. Specifically, GCST90006891 (P = 0.018, OR (95%CI) = 1.164(1.027–1.319)) and GCST90006894 (P = 0.048, OR (95%CI) = 1.074 (1.001–1.153)) showed positive effects, while GCST90006899 (P = 0.022, OR (95%CI) = 0.935(0.882–0.990)) and GCST90006911 (P = 0.0193, OR (95%CI) = 1.226(1.034–1.454)) exhibited distinct trends of influence. Conclusion: The Mendelian Randomization analysis indicates a clear causal relationship between antibody-mediated immune responses and the prevalence of cervical carcinoma in situ, with cervical carcinoma in situ also exerting a certain degree of influence on antibody-mediated immune responses. This finding provides important insights into the interaction mechanism between the two and suggests avenues for developing effective prevention and control strategies. [ABSTRACT FROM AUTHOR]

The etiology of primary open angle glaucoma is constituted by both intraocular pressure-dependent and intraocular pressure-independent mechanisms. However, GWASs of traits affecting primary open angle glaucoma through mechanisms independent of intraocular pressure remains limited. Here, we address this gap by subtracting the genetic effects of a GWAS for intraocular pressure from a GWAS for primary open angle glaucoma to reveal the genetic contribution to primary open angle glaucoma via intraocular pressure-independent mechanisms. Seventeen independent genome-wide significant SNPs were associated with the intraocular pressure-independent component of primary open angle glaucoma. Of these, 7 are located outside known normal tension glaucoma loci, 11 are located outside known intraocular pressure loci, and 2 are novel primary open angle glaucoma loci. The intraocular pressure-independent genetic component of primary open angle glaucoma is associated with glaucoma endophenotypes, while the intraocular pressure-dependent component is associated with blood pressure and vascular permeability. A genetic risk score for the intraocular pressure-independent component of primary open angle glaucoma is associated with 26 different retinal micro-vascular features, which contrasts with the genetic risk score for the intraocular pressure-dependent component. Increased understanding of these intraocular pressure-dependent and intraocular pressure-independent components provides insights into the pathogenesis of glaucoma. The mechanisms connecting intraocular pressure to glaucoma remain unclear. Here, the authors use GWAS by subtraction to reveal intraocular pressure-independent aspects of glaucoma. [ABSTRACT FROM AUTHOR]

Objectives: Thyroid dysfunction is commonly associated with the risk of infertility in both females and males. However, recent randomized controlled trials have demonstrated that thyroid function levels in females are not significantly related to infertility, and evidence on the association between male thyroid function and infertility is limited. We aim to investigate the association between thyroid function levels and infertility in both females and males. Method: A two-sample Mendelian randomization study was conducted using four methods, with the inverse variance weighted method (IVW) as the primary approach. Data on thyroid function as the exposure were obtained from the ThyroidOmics Consortium and UK Biobank, including over 700,000 individuals from a large meta-analysis of genome-wide association studies for thyroid function and dysfunction. The outcome data for infertility in both sex encompassed more than 70,000 individuals from the FinnGen Consortium. All participants were adults of European ancestry. The MR Egger regression intercept and Cochran's Q test were employed to evaluate directional pleiotropy and heterogeneity. Results: The results indicated no causal effect of thyroid-stimulating hormone (TSH) and free tetraiodothyronine (fT4) on female and male infertility. Furthermore, no causal association between hypo- and hyperthyroidism and infertility were identified. Notably, we observed a causal relationship between high TSH and endometriosis-related infertility (OR=0.82, 95% CI: 0.74-0.91, P = 1.49E-04). Conclusions: This study did not find evidence for casual relationship between thyroid function levels and risk of infertility. The findings suggest that overall thyroid function levels may not be a significant predictor of infertility risk. [ABSTRACT FROM AUTHOR]

Northern corn leaf blight (NCLB), caused by Setosphaeria turcica, is a major fungal disease affecting maize production in sub-Saharan Africa. Utilizing host plant resistance to mitigate yield losses associated with NCLB can serve as a costeffective strategy. In this study, we conducted a high-resolution genome-wide association study (GWAS) in an association mapping panel and linkage mapping with three doubled haploid (DH) and three F3 populations of tropical maize. These populations were phenotyped for NCLB resistance across six hotspot environments in Kenya. Across environments and genotypes, NCLB scores ranged from 2.12 to 5.17 (on a scale of 1-9). NCLB disease severity scores exhibited significant genotypic variance and moderate-to-high heritability. From the six biparental populations, 23 quantitative trait loci (QTLs) were identified, each explaining between 2.7% and 15.8% of the observed phenotypic variance. Collectively, the detected QTLs explained 34.28%, 51.37%, 41.12%, 12.46%, 12.11%, and 14.66% of the total phenotypic variance in DH populations 1, 2, and 3 and F3 populations 4, 5, and 6, respectively. GWAS, using 337,110 highquality single nucleotide polymorphisms (SNPs), identified 15 marker-trait associations and several putative candidate genes linked to NCLB resistance in maize. Joint linkage association mapping (JLAM) identified 37 QTLs for NCLB resistance. Using linkage mapping, JLAM, and GWAS, several QTLs were identified within the genomic region spanning 4 to 15 Mbp on chromosome 2. This genomic region represents a promising target for enhancing NCLB resistance via marker-assisted breeding. Genome-wide predictions revealed moderate correlations with mean values of 0.45, 0.44, 0.55, and 0.42 for within GWAS panel, DH pop1, DH pop2, and DH pop3, respectively. Prediction by incorporating marker-by-environment interactions did not show much improvement. Overall, our findings indicate that NCLB resistance is quantitative in nature and is controlled by few major-effect and many minor-effect QTLs. We conclude that genomic regions consistently detected across mapping approaches and populations should be prioritized for improving NCLB resistance, while genome-wide prediction results can help incorporate both major- and minor-effect genes. This study contributes to a deeper understanding of the genetic and molecular mechanisms driving maize resistance to NCLB. [ABSTRACT FROM AUTHOR]

Since the turn of the 21st century, genome-wide association study (GWAS) have successfully identified genetic signals associated with a myriad of common complex traits and diseases. As we transition from establishing robust genetic associations with diverse phenotypes, the central challenge is now focused on characterizing the underlying functional mechanisms driving these signals. Previous GWAS efforts have revealed multiple variants, each conferring relatively subtle susceptibility, collectively contributing to the pathogenesis of various common diseases. Such variants can further exhibit associations with multiple other traits and differ across ancestries, plus disentangling causal variants from non-causal due to linkage disequilibrium complexities can lead to challenges in drawing direct biological conclusions. Combined with cellular context considerations, such challenges can reduce the capacity to definitively elucidate the biological significance of GWAS signals, limiting the potential to define mechanistic insights. This review will detail current and anticipated approaches for functional interpretation of GWAS signals, both in terms of characterizing the underlying causal variants and the corresponding effector genes. [ABSTRACT FROM AUTHOR]