Genome-wide Association Research Articles

New insights into the increased risk of migraines from COVID-19 infection and vaccination: a Mendelian randomization study

IntroductionMigraine is a prevalent neurological disorder characterized by recurrent attacks, leading to a substantial global disease burden. Recent observational studies have reported the onset and worsening of migraine following COVID-19 infection and vaccination. However, traditional observational study designs have limitations in controlling for confounding factors, potentially resulting in biased and inconsistent conclusions. To address this, we applied Mendelian randomization (MR) to investigate the causal relationship between COVID-19 infection and vaccination with migraine.MethodsThis study utilized summary-level genome-wide association study (GWAS) data from the GWAS catalog and FinnGen database to evaluate the effects of varying degrees of COVID-19 infection and vaccination on migraine. We employed inverse variance weighted (IVW) fixed-effect and random-effect models as the primary methods for MR analysis, with MR-Egger and other approaches as complementary methods. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept regression, and MR-PRESSO, were conducted to ensure robustness of the results.ResultsOur MR analysis revealed no significant causal association between COVID-19 infection and migraine. However, a significant causal association was found between COVID-19 vaccination and migraine (beta = 0.071, P = 0.034). The results were confirmed through a series of sensitivity tests, demonstrating the robustness of the findings.DiscussionThis study provides novel evidence of a significant causal link between COVID-19 vaccination and migraine, while no such association was observed with COVID-19 infection. These findings may have important implications for clinical practice, particularly in planning treatment adjustments and optimizing patient care for individuals with migraines in the context of COVID-19 vaccination.

Association of serum lipidomic profiles with risk of intracranial aneurysm: A Mendelian randomization study.

A two-sample Mendelian randomization (MR) analysis was utilized to assess the causal relationship between lipidomic profiles and the risk of intracranial aneurysms (IAs). Genetic variants related to lipidomic profiles (227 components) and IA [IA, aneurysmal subarachnoid hemorrhage (aSAH) only, unruptured IA (uIA) only] were obtained from published genome-wide association studies (GWASs) or the IEU Open GWAS project and used as instrumental variables for MR analysis. The inverse-variance weighted method was used in the primary analyses to derive causality estimates and was expressed as odds ratio (OR) with 95% confidence interval (CI). Of these 227 lipidomic profiles, only genetically predicted high levels of cholesterol to total lipids ratio in very small very-low-density lipoproteins (VLDL) [OR = 0.629 (95% CI, 0.504-0.786)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.637 (95% CI, 0.509-0.797)], ratio of docosahexaenoic acid to total fatty acids [OR = 0.691 (95% CI, 0.582-0.820)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.630 (95% CI, 0.522-0.760)] reduced the risk of aSAH, whereas genetically predicted high ratio of monounsaturated fatty acids to total fatty acids [OR = 1.471 (95% CI, 1.215-1.781)] increased the risk of aSAH. Moreover, genetically predicted high levels of cholesterol to total lipids ratio in very small VLDL [OR = 0.657 (95% CI, 0.542-0.798)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.663 (95% CI, 0.548-0.803)], free cholesterol to total lipids ratio in small VLDL [OR = 0.682 (95% CI, 0.560-0.832)], phospholipids to total lipids ratio in small VLDL [OR = 0.674 (95% CI, 0.548-0.830)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.678 (95% CI, 0.569-0.808)] reduced the risk of IA. The results of multivariable MR demonstrated that these causal associations persisted after adjusting for systolic blood pressure and cigarettes smoked per day. The effect of serum lipids on IA and aSAH may be mainly caused by subclasses of lipids such as VLDL.

Esophageal cancer risk is influenced by genetically determined blood metabolites.

It remains unclear what causes esophageal cancer (EC), but blood metabolites have been connected to it. Our study performed a Mendelian randomization (MR) analysis to assess the causality from genetically proxied 1400 blood metabolites to EC level. A two-sample MR analysis was employed to evaluate the causal relationship between 1400 blood metabolites and EC. Initially, the EC genome-wide association study (GWAS) data (from Jiang L et al) were examined, leading to the identification of certain metabolites. Subsequently, another set of EC GWAS data from FINNGEN was utilized to validate the findings. Causality was primarily determined through inverse variance weighting, with additional support from the MR-Egger, weighted median, and MR-PRESSO models. Heterogeneity was assessed using the MR Cochran Q test. The MR-Egger intercept and MR-PRESSO global methods were employed to detect multicollinearity. In this study, Bonferroni corrected P value was used for significance threshold. We found 2 metabolites with overlaps, which are lipids. Docosatrienoate (22:3n3) was found to be causally associated with a decreased risk of EC, as evidenced by the EC GWAS data (from Jiang et al) (odds ratio [OR] = 0.620, 95% confidence interval [CI] = 0.390-0.986, P = .044) and the EC GWAS data (from FINNGEN) (OR = 0.77, 95% CI = 0.6-0.99, P = .042), these results were consistent across both data sets. Another overlapping metabolite, glycosyl-N-(2-hydroxyneuramoyl)-sphingosine, was associated with the risk of ES, with EC GWAS data (from Jiang L et al) (OR = 1.536, 95% CI = 1.000-2.360, P = .049), while EC GWAS data (from FINNGEN) (OR = 0.733, 95% CI = 0.574-0.937, P = .013), the 2 data had opposite conclusions. The findings of this study indicate a potential association between lipid metabolites (Docosatrienoate (22:3n3) and glycosyl-N-(2-hydroxynervonoyl)-sphingosine (d18:1/24:1 (2OH))) and the risk of esophageal carcinogenesis.

First report of ergot caused by Claviceps clavispora in switchgrass (Panicum virgatum L.) in Georgia, USA.

Switchgrass (Panicum virgatum L.) is a North American grass species with biofuel potential. Claviceps spp. is known to infect the florets of various grass species, initially characterized by a sticky honeydew exudate and later as sclerotium replacing the seed in the infected ovary (Tanaka et al 2023). Since 2019, from July to October, switchgrass panicles in Georgia have been observed with honeydew and black sclerotia. The disease was first noted on some of the 285 accessions of the genome-wide association study (GWAS) panels at the University of Georgia's Iron Horse Farm in Watkinsville and Gibbs Farm in Tifton, GA. In Watkinsville, GA, ergot incidence was 5%, 6%, 65% and 54% in 2019, 2020, 2021 and 2022, respectively. Symptomatic panicles with honeydew and sclerotia were collected in 2021 (sample Scl) and 2023 (samples Cla_M and ATH20cl) from Watkinsville, GA. Under microcopy, panicles with honeydew symptoms had mycelium and conidia (9 μm long [range of 5-13 μm] and 4 μm wide [3-5 μm]) consistent with Claviceps spp. (Tooley et al. 2001). Sclerotia were 1.5 mm long (range 1-3 mm). Sclerotia were surface sterilized for 3 minutes in 5% NaOCl, followed by 70% ethanol then rinsed three times in distilled water. Sterilized sclerotia were plated on potato dextrose agar and placed on bench top with a 12-hour day/night cycle at room temperature (22°C) (Singh 1976). After 2 months, the sclerotia produced sterile apothecia. For molecular identification, genomic DNA was extracted from three honeydew samples following the protocol of Doyle and Doyle (1987). The internal transcribed spacer (ITS) region and RNA polymerase second largest subunit (RPB2) gene were amplified using ITS4/ITS5 (White et al. 1990) and 5F2/7CR (Liu et al. 1999) primer sets. The ITS region of ATH20cl, Cla_M, and Scl (GenBank nos. PP546317- PP546319) showed 92.83-97.48% identity to C. clavispora (NR_163506.1). The RPB2 region of ATH20cl, Cla_M, and Scl (GenBank nos. PP573916- PP573918) showed 97.46-97.72% identity to C. clavispora (LT216566.1). The maximum likelihood tree constructed in MEGA-X (Kumar et al. 2018) using concatenated ITS (539 bp) and RPB2 (792 bp) gene sequences from this study and eleven reference sequences from Tanaka et al. (2023), revealed close relatedness of ATH20cl, Cla_M, and Scl to C. clavispora under section Pusillae. The pathogenicity test for samples ATH20cl and Cla_M was conducted in the greenhouse on switchgrass cultivar 'Alamo' grown in injection molded pots containing Sungro professional growing mix. Three replicates plants at reproductive (R3) growth stage were inoculated by immersing panicles in 105 spores/ml suspension for 5 minutes and bagged for 3 days (Tooley et al. 2001). Control plants were immersed in distilled water. Honeydew symptoms and sclerotia appeared within 7- and 90-days post-inoculation, respectively, whereas control plants remained symptom-free. The honeydew collected from the infected Alamo panicles were reconfirmed to produce similar spores to those collected from the field. This is the first report of ergot caused by C. clavispora in switchgrass. Ergot was also observed since 2019 on some accessions from the same GWAS panel planted at the University of Tennessee Plant Sciences Farm in Knoxville, TN. This information will be beneficial to determine the effect of ergot on biomass production and seed quality of switchgrass in the southeastern U.S.

Causal relationships between allergic and autoimmune diseases with chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a prevalent inflammatory airway disease affecting over 10% of the global population, leading to considerable socio-economic impacts, especially in developing countries. The pathogenesis of CRS is multifactorial, involving potential contributions from both genetic and environmental factors. While the influence of allergic and autoimmune diseases on CRS has been observed, the causal relationships between these diseases and CRS remain unclear. We extracted data from large-scale genome-wide association studies (GWAS) and utilized a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationships between CRS and ten autoimmune and allergic diseases, including asthma, allergic rhinitis (AR), atopic dermatitis (AD), psoriasis, type 1 diabetes (T1D), hypothyroidism, celiac disease (CeD), multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Additionally, we conducted colocalization analysis to determine whether the allergic/autoimmune diseases showing statistical causal relationships with CRS are driven by the same genetic variants. The MR analysis identified that AR (OR = 1.30; 95% CI = 1.21–1.40; P = 3.26E−13), asthma (OR = 1.35; 95% CI = 1.25–1.45; P = 1.35E−14), and AD (OR = 1.17; 95% CI = 1.06–1.30; P = 0.003) were significantly associated with an increased risk of developing CRS. Interestingly, psoriasis (OR = 0.05; 95% CI = 0.01–0.37; P = 0.004) appeared to have a protective effect against CRS. Associations for T1D and hypothyroidism were also suggestive as potential risk factors for CRS. No significant associations in the reverse MR analysis, suggesting a one-directional relationship. Colocalization analysis indicated that asthma (PP.H4 = 0.99) shared the same genetic variant (IL-33 rs3939286) with CRS. In conclusion, our study confirmed the causal relationships between allergic and autoimmune diseases (AR, asthma, AD, and psoriasis) and CRS. Notably, we identified a shared genetic variant, rs3939286 in the IL-33 gene, between asthma and CRS, suggesting that targeting the IL-33 pathway may provide a therapeutic strategy for both diseases.

Exploring the potential link between gut microbiota and chronic kidney disease in causality: A 2-sample Mendelian randomization study.

Increasing evidence indicates a significant correlation between gut microbiota (GM) and susceptibility to chronic kidney disease (CKD). However, causal relationship presence remains uncertain. Mendelian randomization (MR) was applied to evaluate potential causal relation from GM to CKD. Genomic association analysis aggregates publicly online databases, utilizing Genome-Wide Association Study (GWAS) database focused on GM and CKD. For examination of potential causal connection from GM to CKD, a 2-way, 2-sample Mendelian randomization (MR) method was applied. Sensitivity analyses were utilized to scrutinize for heterogeneity, horizontal pleiotropy, MR outcomes resilience. Result from inverse variance weighting (IVW) method revealed that 10 microbiotas such as Porphyromonadaceae (OR = 1.351, 95% CI: 1.114-1.638, P = .002), Dorea (OR = 1.236, 95% CI: 1.040-1.468, P = .016), Ruminococcus torques group (OR = 1.290, 95% CI: 1.035-1.608, P = .024) are potential CKD risk factors. Five microbiotas, including the Prevotellaceae (OR = 0.814, 95% CI: 0.719-0.922, P = .001) are potential CKD protective factors. Sensitivity analyses reveal no horizontal pleiotropy or heterogeneity. Additionally, reverse MR results unveiled potential relation between CKD and disorders in 3 microbiotas, including Senegalimassilia. According to the investigation, MR method was employed to delve into reciprocal causal connection from GM to CKD. Our findings identified 15 types of GM causally linked to CKD, as well as CKD demonstrating causal associations with 3 types of GM. Further exploration of these associated GM types is hopeful to raise novel insights, for CKD preventing and early monitoring.

Common epidermal growth factor receptor mutations in north Indian patients with non-small cell lung carcinoma: evidence from real-time polymerase chain reaction.

Lung carcinoma was the ace cause of cancer deaths globally in 2022, with non-small cell lung carcinoma (NSCLC) accounting for 81% of the burden. Due to promising tyrosine kinase inhibitor (TKI) trials, NSCLC patients harboring epidermal growth factor receptor (EGFR) gene mutations are of interest. Our aim was to determine EGFR mutation prevalence in north India and its histologic and demographic correlations. We investigated the frequency of EGFR mutations in 40 patients with histologically confirmed NSCLC using real-time polymerase chain reaction. A 15% mutation frequency was observed in the study sample, involving 32 males and 8 females with a median age of 59 years. Squamous cell carcinoma (SCC) patients had only EXON20 (T790M, exon20 insertion) mutations, while adenocarcinoma patients had mutations in both EXON20 (T790M) and 21 (L858R) with mutation frequencies of 22% and 10%, respectively. 28% of the SCC patients were non-smokers, and 60% of these non-smokers had an EGFR mutation. South Indian and Asian studies have identified EXON19 (19-Del) and EXON21 (L858R) mutations as "common mutations" that account for nearly 80-90% of all mutations and respond well to TKIs. Interestingly, "common mutations" were found seldom in our study population, while the uncommon variants constitute 83% of all mutations, which we assume is due to diverse Indian genetics and ethnicity and co-existing signature mutations that involve the tyrosine kinase domain of EXON20. We suggest future genome-wide association studies to identify plausible genetic polymorphisms responsible for interethnic differences in EGFR mutation, which will contribute to better treatment and prevention of NSCLCs.

Causal relationship between amino acids and ovarian cancer in the European population: A bidirectional Mendelian randomization study and meta-analysis.

In recent years, an increasing number of observational studies have reported the impact of amino acids on ovarian cancer. However, Mendelian randomization studies have not yet been conducted to explore the causal relationship between them in the context of ovarian cancer. This study conducted Mendelian randomization (MR) analysis of 20 amino acids in relation to ovarian cancer data from 2 different sources within the European population, using a two-sample MR approach. The primary results from the inverse variance weighting analysis were then subjected to a meta-analysis, followed by multiple testing correction for the meta-analysis thresholds. Finally, reverse causality testing was performed on the positively associated amino acids and ovarian cancer. MR analyses were conducted for 20 amino acids with ovarian cancer data from both the Finngen R10 and Open genome-wide association study databases. The inverse variance weighted results from these 2 analyses were then combined through meta-analysis, with multiple corrections applied to the significance thresholds of the meta-analysis results. The findings showed that only cysteine had a significant association with ovarian cancer, with an (odds ratio) odds ratio value of 0.507 (95% confidence interval: 0.335-0.767, P = .025). The P-value of the combined MR and meta-analysis, after multiple testing correction, was 0.025, indicating statistical significance (P < .05). Additionally, cysteine did not show a reverse causal relationship with ovarian cancer in either data source. Cysteine is a protective factor for ovarian cancer, potentially reducing the risk of ovarian cancer and slowing the progression of the disease.

Gestational diabetes and future cardiovascular diseases: associations by sex-specific genetic data.

Observational studies have highlighted that gestational diabetes mellitus is associated with a higher risk of cardiovascular diseases, but the causality remains unclear. Herein, the causality between genetic predisposition to gestational diabetes mellitus and the risk of cardiovascular diseases was investigated using sex-specific Mendelian randomization analysis. Linkage disequilibrium score regression analysis and two-sample Mendelian randomization analysis were applied to infer the genetic correlation and causality, respectively. Mediation analysis was conducted using a two-step Mendelian randomization approach. Sensitivity analyses were performed to differentiate causality from pleiotropy. The genome-wide association study summary statistics for gestational diabetes mellitus were obtained from FinnGen consortium, while for cardiovascular diseases were generated based on individual-level genetic data from the UK Biobank. Linkage disequilibrium score regression analyses revealed that gestational diabetes mellitus had a significant genetic correlation with coronary artery disease and myocardial infarction after Benjamini-Hochberg correction in ever-pregnant women. In Mendelian randomization analyses, odds ratios (95% confidence interval) for coronary artery disease and myocardial infarction were 1.09 (1.01-1.17) and 1.12 (.96-1.31) per unit increase in the log-odds of genetic predisposition to gestational diabetes mellitus in ever-pregnant women, respectively. Further, Type 2 diabetes and hypertension were identified as mediators for the causality of genetic predisposition to gestational diabetes mellitus on coronary artery disease. In sensitivity analyses, the direction of odds ratio for the association between instrumental variables with gestational diabetes mellitus-predominant effects and the risk of coronary artery disease was consistent with the primary results in ever-pregnant women, although not statistically significant. This study demonstrated a suggestive causal relationship between genetic predisposition to gestational diabetes mellitus and the risk of coronary artery disease, which was mainly mediated by Type 2 diabetes and hypertension. These findings highlight targeting modifiable cardiometabolic risk factors may reduce the risk of coronary artery disease in women with a history of gestational diabetes mellitus.

Genome-wide association study reveals effect of nsSNPs on candidate genes in rice during iron deficiency.

Resource-poor areas with moisture deficit lands following aerobic and direct seeded rice (DSR) methods of cultivation face severe problems of iron deficiency. In this study, Bengal and Assam Aus rice panel was phenotyped at the seedling stage using an iron-deprived hydroponic medium for various shoot and root traits. A novel iron deficiency scoring scale was used to classify the tolerance reaction and could range anywhere between 0 and 9, indicating the most tolerant and susceptible, respectively. The GWAS results identified four putative candidate genes; OsFLA for number of leaves and shoot length, OsBIDK1 for root traits; average diameter, volume, biomass, projected area, and surface area, OsHPL3 for chlorophyll index of the third leaf and AKR2B (XBOS252) was for Fe score, (which was earlier reported in relation to Xa21). The nsSNP (nsSNPs) variations in these gene sequences were used to group the panel and identify superior haplotypes and donors. BR16 was identified as a superior donor, with higher chlorophyll index and shoot length than RA23, also higher values for root traits like root average diameter, root volume, root projected area and root surface area followed by Shete Bhado. The impact of identified nsSNPs on protein structure and stability was investigated. The conserved domains detected in the mutated proteins of the superior haplotypes are very informative, highlighting that natural selection favors abiotic stress tolerant variants in resource poor areas. Thus, justifying our choice of Aus landraces for association mapping of Fe deficiency tolerant genes in rice.

A novel functional IKBKE variant activating NFAT in a patient with polyarthritis and a remittent fever

BackgroundIKBKE is a negative regulator of T cell activation and one of the key activators of type I interferon (IFN) and NFκB signaling via non-classical pathways. The upstream single nucleotide polymorphism of IKBKE (rs2297550-G) is a genome-wide association study risk variant of systemic lupus erythematosus, and is associated with decreased IKBKE expression in T cells by expression quantitative trait locus analysis.Case presentationA 48-year-old female had a remittent fever, arthritis, and oral ulcers for 20 years. She had a poor response to corticosteroids or disease-modifying antirheumatic drugs, including the tumor necrosis factor-α antagonist, etanercept, and the anti-interleukin-6 receptor antibody, tocilizumab.MethodShe participated in the Initiative on Rare and Undiagnosed Disease (IRUD), and whole-exome sequencing (WES) was performed. Functional analyses were conducted by transfecting the identified variants into reporter cells to assess the activation of NFAT and NFκB signaling. Additionally, peripheral blood RNA- sequencing (RNA-seq) data were compared with those from healthy individuals to evaluate the gene expression profiles of immune cells.ResultWES identified a novel heterozygous c.1877G&amp;gt;A, p(Cys626Tyr) variant in IKBKE. Functional analysis indicated that this variant led to increased activity of NFAT (p = 0.015) and decreased activity of NFκB and type I IFN (p = 0.00068 and 0.00044, respectively). The patient had a remarkably low proportion of Naïve CD4 T cells. RNA-seq of peripheral blood immune cell subsets revealed significant differences in gene expression, especially in T cells.ConclusionA novel functional heterozygous variant in IKBKE is described in a patient with a remittent fever and arthritis. The data suggest that IKBKE is an important negative regulator of inflammation, particularly in T cells, and this IKBKE variant might be the underlying cause of a novel autoinflammatory pathology.

Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study

Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using GWAS summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [ORSD] = 0.97; 95% confidence interval [CI]: 0.95–0.99, p = 0.006), methionine (ORSD= 0.97; 95%CI: 0.94-1.00, p = 0.031), stearic acid (ORSD= 0.93; 95%CI: 0.87–0.99, p = 0.027), carnitine = (ORSD=1.01; 95% CI: 1.00-1.03, p = 0.027), hippuric acid (ORSD= 1.02; 95%CI: 1.00-1.04, p = 0.038) and 3-methylhistidine (ORSD= 1.05; 95%CI: 1.01–1.10, p = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78–0.99, p = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80–0.96, p = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis.

Genome-wide association studies for milk production traits and persistency of first calving Holstein cattle in Türkiye

The study presents a comprehensive investigation into the genetic determinants of 100-day milk yield (100DMY), 305-day milk yield (305DMY), total milk yield (TMY), and persistency using first lactation records of 374 Holstein heifers reared in a private farm at Çanakkale province of Türkiye, employing a genome-wide association study (GWAS) approach. The research underscores the substantial genetic component underlying these economically important traits through detailed descriptive statistics and heritability estimations. The estimated moderate to high heritabilities (0.32–0.54) for milk production traits suggest the feasibility of targeted genetic improvement strategies. By leveraging GWAS, the study identifies many significant and suggestively significant single nucleotide polymorphisms (SNP) associated with studied traits. Noteworthy genes have identified in this analysis include BCAS3, MALRD1, CTNND2, DOCK1, TMEM132C, NRP1, CNTNAP2, GPRIN2, PLEKHA5, GLRA1, SCN7A, HHEX, KTM2C, RAB40C, RAB11FIP3, and FXYD6. These findings provide valuable understandings of the genetic background of milk production and persistency in Holstein cattle, shedding light on specific genomic regions and candidate genes playing pivotal roles in these traits. This research contributes valuable knowledge to the field of dairy cattle genetics and informs future breeding efforts to improve milk production sustainability and efficiency in Holstein cattle populations.

Mendelian Randomization Study of the Causal Relationship between PM2.5 and Neurodegenerative Diseases

Background: In recent years, a large number of studies have evaluated the relationship between particulate matter 2.5 (PM2.5) and the incidence rate and mortality of neurodegenerative diseases (NDDs), but the conclusion is controversial. Methods: The publicly available statistical data from genome-wide association studies were used for two sample MR. Inverse variance weighted is used as the main analysis, MR Egger regression, maximum likelihood, simple median, and weighted median are used for supplementary validation. Results: MR analysis results indicate that for every standard deviation increase in PM2.5 exposure, the risk of Alzheimer's disease (AD) increases by 41% (95% CI: 1.10～1.82, P=0.008). However, there is no causal association between PM2.5 and NDDs such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Dementia with Lewy bodies. Sensitivity analysis did not detect heterogeneity and pleiotropy, indicating that the analysis results are robust. Conclusion: There is a causal relationship between PM2.5 and the risk of AD, and reducing PM2.5 exposure may be of great significance for the prevention of AD.

Estimating Causal Effects on a Disease Progression Trait Using Bivariate Mendelian Randomisation.

Genome-wide association studies (GWAS) have provided large numbers of genetic markers that can be used as instrumental variables in a Mendelian Randomisation (MR) analysis to assess the causal effect of a risk factor on an outcome. An extension of MR analysis, multivariable MR, has been proposed to handle multiple risk factors. However, adjusting or stratifying the outcome on a variable that is associated with it may induce collider bias. For an outcome that represents progression of a disease, conditioning by selecting only the cases may cause a biased MR estimation of the causal effect of the risk factor of interest on the progression outcome. Recently, we developed instrument effect regression and corrected weighted least squares (CWLS) to adjust for collider bias in observational associations. In this paper, we highlight the importance of adjusting for collider bias in MR with a risk factor of interest and disease progression as the outcome. A generalised version of the instrument effect regression and CWLS adjustment is proposed based on a multivariable MR model. We highlight the assumptions required for this approach and demonstrate its utility for bias reduction. We give an illustrative application to the effect of smoking initiation and smoking cessation on Crohn's disease prognosis, finding no evidence to support a causal effect.

Studies of genetic diversity and genome-wide association for vitamin C content in lettuce (Lactuca sativa L.) using high-throughput SNP arrays.

Lettuce (Lactuca sativa L.) is a source of beneficial compounds though they are generally present in low quantities. We used 40K Axiom and 9K Infinium SNP (single nucleotide polymorphism) arrays to (i) explore the genetic variability in 21 varieties and (ii) carry out genome-wide association studies (GWAS) of vitamin C content in21 varieties and a population of 205 plants from the richest variety in vitamin C ('Lechuga del Pirineo'). Structure and phylogenetic analyses showed that the group formed mainly by traditional varieties was the most diverse, whereas the red commercial varieties clustered together and very distinguishably apart from the rest. GWAS consistently detected, in a region of chromosome 2, several SNPs related to dehydroascorbic acid (a form of vitamin C) content using three different methods to assess population structure, subpopulation membership coefficients, multidimensional scaling, and principal component analysis. The latter detected the highest number of SNPs (17) and the most significantly associated, 12 of them showing a high linkage disequilibrium with the lead SNP. Among the 84 genes in the region, some have been reported to be related to vitamin C content or antioxidant status in other crops either directly, like those encoding long non-coding RNA, several F-box proteins, and a pectinesterase/pectinesterase inhibitor, or indirectly, like extensin-1-like protein and endoglucanase 2 genes. The involvement of other genes identified within the region in vitamin C levels needs to be further studied. Understanding the genetic control of such an important quality trait in lettuce becomes very relevant from a breeding perspective.

Genome-wide study of drought tolerance traits in wild jujube

BackgroundWild jujube trees in Ningxia, China, demonstrate exceptional drought tolerance. The identification of quantitative trait loci (QTLs) associated with drought resistance and linked genes could significantly enhance molecular breeding efforts for this species. This study involved the measurement of nine drought resistance indicators were measured in 150 wild jujube trees from five regions in Ningxia. Genome-wide association studies (GWAS) were carried out using a range of mixed linear models to pinpoint SNP markers linked to drought resistance.ResultsThe coefficients of variation for the nine leaf traits in wild jujube trees ranged from 14.76 to 62.17%, with broad-sense heritability estimates falling between 0.84 and 0.99. Through GWAS analysis, a total of 12 significant SNPs and 162 potential genes associated with drought resistance were detected. This SNPs explained phenotypic variance ranging from 20.74 to 50.37%. Gene Ontology (GO) functional annotation highlighted five crucial candidate genes‒ZjMYB44, ZjUCLOC, ZjDnaJ50, ZjUCHL22 and ZjHSFB‒linked to drought tolerance in wild jujube. These genes demonstrated a positive correlation with drought tolerance within the wild jujube population.ConclusionsOur findings indicate that these five genes likely play a pivotal role in conferring drought tolerance in wild jujubes. This study offers new insights to support the development of drought-resistant jujube varieties, thereby contributing to sustainable agricultural practices and bolstering food security in arid regions.

Association between vegetable intake and major depressive disorder: results from National Health and Nutrition Examination Survey 2005-2018 and bidirectional two-sample Mendelian randomisation.

This study aimed to evaluate the association between vegetable intake and major depressive disorder (MDD) through cross-sectional analysis and bidirectional two-sample Mendelian randomisation (MR). Cross-sectional analysis was conducted on National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018 and the corresponding Food Patterns Equivalents Database (FPED). Genome-wide association study (GWAS) data were obtained from UK Biobank and Psychiatric Genomics Consortium (PGC) dataset. Logistic regression analysis was performed after calculating the weights of the samples. Inverse variance weighted, MR-Egger and weighted median methods were used to evaluate the causal effects. A Patient Health Questionnaire-9 score ≥ 10 was considered to indicate MDD. Low vegetable intake was defined as < 2 cups of vegetables per day. 30 861 U.S. adults from NHANES. The GWAS data sample size related to vegetable intake were comprised 448 651 and 435 435 cases respectively, while the GWAS data sample size associated with MDD encompassed 500 199 cases. There were 23 249 (75·33 %) participants with low vegetable intake. The relationship between vegetable intake and MDD was nonlinear. In the multivariate model adjusted for sex, age, education, marital status, poverty income ratio, ethnicity and BMI, participants with low vegetable intake were associated with an increased risk of MDD (OR = 1·53, 95 % CI (1·32, 1·77), P < 0·001). Bidirectional MR showed no causal effects between vegetable intake and MDD. Cross-sectional analysis identified a significant relationship between vegetable intake and MDD, whereas the results from bidirectional two-sample MR did not support a causal role.

Mapping the locus for ocular melanosis in Cairn Terriers.

To map the disease locus for familial ocular melanosis (OM) in the Cairn Terrier. Cairn Terriers with OM and normal control dogs. A genome-wide association study (GWAS) was performed using 63 OM-affected and 31 control Cairn Terriers, followed by haplotype analysis. A significantly associated single-nucleotide polymorphism was genotyped in a larger group of OM-affected and control Cairn Terriers. The coding and splice-site regions of genes mapping within the confidence interval were sequenced. A ~9.2 Mb region of chromosome 11 was significantly associated with OM. Haplotype analysis narrowed the region to 1.49 Mb. Genotyping of a SNP within the region showed 86% of OM-affected dogs were homozygous or heterozygous for the risk allele, whereas 78% of unaffected dogs were homozygous for the nonrisk allele. Sequencing of the coding regions and splice sites of four genes (c9orf72, IFNK, the 5' end of MOB3B, and the 3' end of LINGO2) and of a microRNA (MIR876) did not detect any genetic variants unique to OM-affected dogs. OM in Cairn Terriers maps to a 1.49 Mb region of chromosome 11. This accounts for 86% of OM cases in our DNA bank. A second locus may account for the OM phenotype in the remaining 14% of cases. Sequencing of coding regions and splice sites of positional candidate genes and a microRNA did not reveal any genetic variants unique to affected dogs. Further studies are required to elucidate the DNA variant causal for OM in Cairn Terriers and to understand the disease mechanism.

Genome-wide association and functional genomic analyses for body conformation traits in North American Holstein cattle

Genome-wide association and functional genomic analyses for body conformation traits in North American Holstein cattle