Genome-wide Association Research Articles

Mining Candidate Genes for Maize Tassel Spindle Length Based on a Genome-Wide Association Analysis

Maize tassel spindle length is closely related to the number of pollen grains and the duration of the flowering stage, ultimately affecting maize yield and adaptations to stress conditions. In this study, 182 maize inbred lines were included in an association population. A genome-wide association study was conducted on maize tassel spindle length using the Q + K model. With p ≤ 1.0 × 10−4 applied as the significance threshold, 240 SNPs significantly associated with tassel spindle length were detected, which were associated with 99 quantitative trait loci (QTLs), with 21 QTLs detected in two or more environments. Moreover, 51 candidate genes were detected in 21 co-localized QTLs. A KEGG enrichment analysis and candidate gene expression analysis indicated that Zm00001d042312 affects plant hormone signal transduction and is highly expressed in maize tassels. A haplotype analysis of Zm00001d042312 revealed three main haplotypes, with significant differences between Hap1 and Hap2. In conclusion, we propose that Zm00001d042312 is a gene that regulates maize tassel spindle length. This study has further elucidated the genetic basis of maize tassel spindle length, while also providing excellent genetic targets and germplasm resources for the genetic improvement of maize tassel spindle length and yield.

Genome-Wide Association Study of Sweet Potato Storage Root Traits Using GWASpoly, a Gene Dosage-Sensitive Model

Sweet potato (Ipomoea batatas) is an important food crop that plays a pivotal role in preserving worldwide food security. Due to its polyploid genome, high heterogeneity, and phenotypic plasticity, sweet potato genetic characterization and breeding is challenging. Genome-wide association studies (GWASs) can provide important resources for breeders to improve breeding efficiency and effectiveness. GWASpoly was used to identify 28 single nucleotide polymorphisms (SNPs), comprising 21 unique genetic loci, associated with sweet potato storage root traits including dry matter (4 loci), subjective flesh color (5 loci), flesh hue angle (3 loci), and subjective skin color and skin hue angle (9 loci), in 384 accessions from the USDA sweet potato germplasm collection. The I. batatas ‘Beauregard’ and I. trifida reference genomes were utilized to identify candidate genes located within 100 kb from the SNPs that may affect the storage traits of dry matter, flesh color, and skin color. These candidate genes include transcription factors (especially Myb, bHLH, and WRKY family members), metabolite transporters, and metabolic enzymes and associated proteins involved in starch, carotenoid, and anthocyanin synthesis. A greater understanding of the genetic loci underlying sweet potato storage root traits will enable marker-assisted breeding of new varieties with desired traits. This study not only reinforces previous research findings on genes associated with dry matter and β-carotene content but also introduces novel genetic loci linked to these traits as well as other root characteristics.

Correlation between gut microbiota and pancreatitis: a bidirectional Mendelian randomization.

The causative role of gut microbiota in pancreatitis remains unknown. This study aimed to investigate potential causal associations between gut microbiota and pancreatitis, using bidirectional Mendelian randomization (MR) analysis. We analyzed genome-wide association study (GWAS) summary statistics for gut microbiota (211 taxa from gut microbiota, n = 18 340) and two types of pancreatitis, namely acute pancreatitis (AP, 5509 cases and 301 383 controls) and chronic pancreatitis (CP, 3002 cases and 301 383 controls). A reverse MR analysis was also performed to assess the possibility of reverse causation. Nine features (one family + eight genera) showed a causal association with AP. According to inverse-variance weighted (IVW) estimates, phylum Firmicutes (P = 4.10 × 10-2), genus Erysipelatoclostridium (P = 4.80 × 10-2), genus Flavonifractor (P = 4.10 × 10-2), genus Methanobrevibacter (P = 3.40 × 10-2), and genus Prevotella9 (P = 4.60 × 10-2) were found to have a protective effect on AP. Additionally, genus Eubacteriumeligensgroup (P = 4.10 × 10-2), genus Eubacteriumfissicatenagroup (P = 4.00 × 10-3), genus Coprococcus3 (P = 4.10 × 10-2), and genus Haemophilus (P = 4.60 × 10-2) exhibited a positive correlation with AP. Four features (two families + two genera) were causally associated with CP. IVW results also confirmed that family Clostridiaceae1 (P = 3.30 × 10-2), genus LachnospiraceaeFCS020group (P = 4.60 × 10-2), and genus Prevotella9 (P = 1.90 × 10-2) were protective factors for CP, whereas the presence of family Victivallaceae (P = 2.60 × 10-2) correlated with CP risk. No causal effects of pancreatitis (AP or CP) on these gut microbiota taxa were found in the reverse MR analysis. This study confirms a potential causal relationship between gut microbiota and pancreatitis, highlighting the gut microbiota-pancreas axis in the pathogenesis of pancreatitis.

Coffee and Risk of Pancreatic Cancer: Insights from Two-Sample and Multivariable Mendelian Randomization Analyses

Background: The association between coffee and pancreatic cancer risk has reported inconsistent results. Therefore, a Mendelian randomization (MR) study was undertaken to investigate the association between coffee and pancreatic cancer from a genetic perspective. Methods: In East Asian and European populations, independent genetic variants strongly associated with coffee were chosen as instrumental variables (IVs) from relevant genome-wide association studies (GWASs). GWAS data for pancreatic cancer were obtained from the JENGER (Japanese Encyclopedia of Genetic Associations by Riken) project and GWAS catalog database. Two-sample (TSMR) and multivariable Mendelian randomization (MVMR) analyses were conducted to investigate the genetically predicted causal relationship between coffee consumption and pancreatic cancer. A fixed-effect meta-analysis was employed to aggregate estimates from the two populations to reveal the overall association. Results: Both in East Asian and European populations, an increase in coffee intake of a cup per day was not associated with pancreatic cancer risk, regardless of coffee type (including caffeine drinks, instant coffee, decaffeinated coffee, ground coffee, etc.). The results aligned with the findings of the meta-analysis (OR = 1.100, 95%CI = 0.862–1.403, p = 0.450). Also, for coffee intake with positive results in the TSMR analysis (OR = 1.739, 95%CI 1.104–2.739, p = 0.017), consistent negative results were observed after adjusting for potential confounders (smoking traits, drinking, type 2 diabetes, body mass index) in the MVMR analyses. Conclusions: This study found no genetically predicted causal relationship between coffee consumption and pancreatic cancer risk.

Cooling lactating sows exposed to early summer heat wave alters circadian patterns of behavior and rhythms of respiration, rectal temperature, and saliva melatonin.

Heat stress (HS) exerts detrimental effects on animal production, with lactating sows being particularly vulnerable. Understanding the mechanisms involved in HS response could aid in developing effective strategies against the negative impacts on livestock. Recent genome wide association studies identified two core circadian clock genes as potential candidates in mediating HS response. The study aimed to investigate how cooling lactating sows under natural heat stress conditions impacted circadian patterns of respiration rate (RR), rectal temperature (RT), behavior, salivary melatonin and cortisol levels, and diurnal patterns of cytokines in saliva. Mixed parity lactating sows were assigned to one of two treatment groups: electronic cooling pad (C; n = 9) and heat-stressed (H; n = 9). The experiment spanned two 48 h periods of elevated ambient temperatures due to summer heat wave. In the first 48 h period, RR was recorded every 30 min, RT every 60 min, and behaviors (eating, standing, sitting, laying, sleeping, drinking, and nursing) every 5 min. In the second 48 h period, saliva samples were collected every 4 h. Cooling reduced RR and RT and altered circadian patterns (P < 0.05). Cooling did not affect amount of time engaged in any behavior over the 48 h period (P > 0.05), however, daily patterns of eating, standing and laying differed between the treatments (P < 0.05), with altered eating behavior related to RT increment in H sows (P < 0.05). Cooling increased and altered the circadian pattern of salivary melatonin (P < 0.05). Cooling also influenced the diurnal pattern of saliva cytokines. Cooling had no impact on saliva cortisol levels. In conclusion, cooling HS sows impacted circadian rhythms of physiology and behavior, supporting the need for further research to understand if circadian disruption underlies decreased production efficiency of HS animals.

Genetically predicted inflammatory cytokine levels and risk of retinitis pigmentosa

ABSTRACT Purpose This study aims to estimate the potential causal relationship between genetically predicted levels of inflammatory cytokine and retinitis pigmentosa (RP) by performing Mendelian randomization (MR). Methods Single nucleotide polymorphisms (SNPs) were identified as instrumental variables (IVs) from publicly available genome-wide association study datasets. Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were applied in this MR analysis. IVW and MR-Egger were used to confirm heterogeneity and pleiotropy of identified IVs. Leave-one-SNP-out analysis was used to identify SNPs with potential impact. Results IVW results revealed that elevated levels of Tumor Necrosis Factor Alpha (TNF-α), Macrophage Inflammatory Protein-1a (MIP1a), and Monokine Induced by Gamma Interferon (MIG) were associated with higher RP risk (OR = 2.358, p = 0.050; OR = 2.583, p = 0.013; OR = 1.851, p = 0.015), while elevated levels of Interleukin-16 (IL-16) were associated with reduced RP risk (OR = 0.723, p = 0.019). The results of heterogeneity and pleiotropy (p > 0.05) confirmed there was no pleiotropy and heterogeneity in our IVW analysis. The association of TNF-α, MIP1a, MIG and IL-16 with RP from sensitivity analyses using these two sets of restricted IVs remained stable. Conclusion Our study provides evidence of potential causal relationships between several circulating cytokine levels and RP. Elevated levels of TNF-α, MIP1a, and MIG are associated with a higher risk of RP, while elevated levels of IL-16 are associated with a lower risk of RP. These cytokines may be novel biomarkers and therapeutic targets for RP.

Associations between T-cell traits and narcolepsy type 1: new insights from a Mendelian randomization study

BackgroundNarcolepsy type 1 (NT1) is primarily caused by a malfunctioning immune system in which T-cells damage the hypothalamus. To elucidate the causal relationships between biomarkers in T-cells and NT1, we employed Mendelian randomization (MR) analysis.MethodsWe conducted a two-sample MR analysis utilizing genetically predicted T-cell traits to examine their effects on NT1. Genome-wide association study summary data were extracted from studies by Valeria (3,757 participants) for 211 T-cell traits, Ollila (6,073 cases and 84,856 controls) for NT1. The MR analysis was executed at two threshold levels. Inverse variance weighted, Wald ratio, weighted median, and MR-Egger regression methods were used for the MR analysis. Odds ratios (ORs) were calculated, and heterogeneity tests, as well as pleiotropy tests, were conducted.ResultsAfter Bonferroni correction at the significant level (p &amp;lt; 1.18 × 10−4), a higher ratio of naive CD4− CD8− T-cells was identified as a risk factor for NT1 (OR = 10.50; 95% CI: 6.98, 15.90, p = 3.89 ×10−29). Conversely, CD4 on HLA DR+ CD4+ T cells (mean fluorescence intensity, MFI) exhibited a negative correlation with NT1. At nominally significant levels (p &amp;lt; 0.05) for both threshold levels, HVEM (herpesvirus entry mediator) on naive CD8+ T cells (MFI) was suggested as a protective factor for NT1. Additionally, a higher ratio of CD25++ CD45RA− CD4 not regulatory T cells, CD127 on CD45RA− CD4 not regulatory T cells (MFI), CD127 on CD28+ CD4+ T cells (MFI), CD3 on HLA DR+ T cells (MFI), and CD3 on HLA DR+ CD4+ T cells (MFI) were suggested as risk factors for NT1.ConclusionThis study confirmed the causal effects of CD4+ and CD8+ T-cells on NT1 and found several novel T-cell-related characteristics.

Causal association between insulin sensitivity index and Alzheimer's disease.

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.

Genome-wide association studies of bundle and single fiber length traits reveal the genetic basis of within-sample variation in upland cotton fiber length

Within-sample variation in cotton fiber len,gth is a major factor influencing the production and quality of yarns. The textile industry has been searching for approaches of improving the long fiber fraction and minimizing the short fiber fraction within a cotton sample to produce superior fiber and yarn quality. USTER® High Volume Instrument (HVI) has been widely used for a rapid assessment of cotton fiber length traits from a fiber bundle. However, its effectiveness for genetic studies has been questioned due to the indirect estimations of the cotton fiber traits that cannot be measured from a fiber bundle. To overcome the limits of the HVI fiber length traits, we utilized the Advanced Fiber Information System (AFIS) measuring fiber length traits directly from individual fibers based on weight or number. Comparative fiber length analyses showed AFIS provided higher sensitivity in detecting the fiber length variations within and among cotton samples than HVI. The weight-based AFIS length traits were strongly correlated with the corresponding HVI lengths, whereas the number-based AFIS mean length showed a relatively weaker correlation with the HVI lengths. Integrations of the weight based-length traits with genome-wide association studies (GWAS) enabled classifying the QTLs specifically associated with long, mean, or short fiber length traits and identified a false positive associated with the indirectly estimated HVI short fiber trait. Unlike the weight based-AFIS length traits, the number-based AFIS length trait did not show a negative correlation with a weight related-HVI property, and identified a single QTL that was not detected by the corresponding HVI trait. These results suggested that integrating the AFIS method with GWAS helped discoveries of the genome loci involved in the within-sample variation in cotton fiber length and characterizations of the fiber length QTLs.

Association between dietary tea consumption and non-alcoholic fatty liver disease: a study based on Mendelian randomisation and National Health and Nutrition Examination Survey (2005-2018) association between tea and non-alcoholic fatty liver disease.

Tea can improve the progression of some metabolic diseases through anti-inflammatory and antioxidant effects, but its impact on non-alcoholic fatty liver disease (NAFLD) is still controversial. The aim of this paper is to identify the relationship between tea and NAFLD by Mendelian randomisation (MR) and complete clinical validation using National Health and Nutrition Examination Survey (NHANES) database. MR used data from Genome Wide Association Study, with inverse-variance weighted (IVW) as principal analytical methods. The reliability of the results was verified by a series of sensitivity and heterogeneity tests. Subsequently, clinical validation was conducted using NHANES (2005-2018), involving 22257 participants, grouped by the type of tea. Green tea drinkers were categorised into four groups (Q1-Q4) by quartiles of green tea intake, from lowest to highest (similar for black tea drinkers and other tea drinkers). Models were constructed by logistic regression to estimate the role of tea consumption (Q1-4) on NAFLD. Finally, using fibrosis-4 index (FIB-4) to evaluate the severity of hepatic fibrosis, the effect of tea consumption (Q1-4) on the degree of hepatic fibrosis was investigated by linear regression. IVW method (OR = 0·43, 95 % CI: 0·21, 0·85, P = 0·01) and weighted median method (OR = 0·35, 95 % CI: 0·14, 0·91, P = 0·03) revealed there was a causal relationship between tea and NAFLD. An array of sensitivity analyses validated the reliability of results. Analysis of NHANES indicated tea drinker present a slightly lower prevalence of NAFLD than non-tea drinker (green tea drinkers: 47·6 %, black tea drinkers: 46·3 %, other tea drinker: 43·2 %, non-tea drinkers: 48·1 %, P < 0·05). After adjusting for confounders, compared with the lowest black tea consumption (Q1), the population with the highest black tea consumption (Q4) was independently related to lower presence of NAFLD (Q4: OR = 0·69, 95 % CI: 0·50, 0·93, P < 0·05), such association remained stable in the overweight subgroup. As further analysed, Q4 also displayed a significant negative correlation with the level of hepatic fibrosis in patients with NAFLD (β = -0·073, 95 % CI: -0·126, -0·020, P < 0·01).Tea reduces the morbidity of NAFLD and ameliorates hepatic fibrosis degree in those already suffering from the disease.

Causal relationship between hypothyroidism and ulcerative colitis: a bidirectional Mendelian randomization study.

Ulcerative colitis (UC) and Hashimoto's thyroiditis frequently cooccur in patients with multiple autoimmune conditions, but the specific association between UC and hypothyroidism is unknown. We used Mendelian randomization (MR) methods to determine the causal relationship between UC and hypothyroidism. We obtained single nucleotide polymorphisms (SNPs) related to ulcerative colitis (UC) and hypothyroidism from genome-wide association studies (GWAS) available in the public database of the Integrated Epidemiology Unit (IEU). To assess the causal relationship between UC and hypothyroidism, we employed MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode methods. Sensitivity analyses were performed using Cochran's Q test, the horizontal pleiotropy test, and the leave-one-out (LOO) method to assess the reliability of the MR data. The genes corresponding to instrumental variables (IVs) were subjected to Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of the Genome (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis to explore the mechanisms behind the causal relationships at the gene level. Forward MR analysis indicated that hypothyroidism was associated with an increased risk of UC (IVW: P = 0.02, OR = 9.71, 95% confidence interval (CI) = 1.36-69.46). In contrast, reverse MR did not demonstrate a causal relationship between UC and hypothyroidism (IVW: P = 0.53). Sensitivity analysis proved the reliability of the results. The PPI network revealed CD247, CD80, and STAT4 as central genes. GO and KEGG analyses revealed significant enrichment of the T cell, gamma interferon (IFN-γ), and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways. Hypothyroidism was a risk factor for UC. The balance of T-cell differentiation played an important role in the process of hypothyroidism-induced UC, and IL-21 might be the key to finding a cure. Enrichment of PD-1/PD-L1 might attenuate inflammation by suppressing the immune action of T cells.

The Rolled Towel Method for Hormone Response Assays in Maize.

The rolled towel assay (RTA) is a soil-free method to evaluate juvenile phenotypes in crops such as maize and soybean. Here, we provide an updated RTA-based protocol to phenotype maize seedling responses to chemicals of interest. We exemplify the protocol with two synthetic auxin herbicides (2,4-dichlorophenoxyacetic acid and picloram), an auxin precursor (indole-3-butyric acid), and an auxin inhibitor (N-1-naphthylphthalamic acid), but the method can be used with other hormones or plant growth regulators that are soluble in growth media. We also include instructions on how to annotate root traits and analyze primary root length trait data. The protocol can be scaled up for use in genetic screens, preparing tissue for gene expression analyses, carrying out genome-wide association studies (GWASs), and quantitative trait locus (QTL) identification.

Inflammatory cytokines, metabolites, and rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint destruction. Although the roles of inflammatory cytokines and metabolites in RA pathogenesis have caught a lot of attention, there is a lack of systematic studies, and their causal relationships remain unclear. We conducted a two-step mendelian randomization analysis utilizing genetic data from genome-wide association studies (GWAS) of inflammatory cytokines, metabolites, and RA. The first step assessed the causal effect of 91 inflammatory cytokines and 1400 metabolites on RA risk using inverse variance weighted method, complemented by MR-Egger, weighted median, simple mode and MR-PRESSO to ensure robustness and assess pleiotropy. The second step evaluated the mediation effects of selected metabolites on the relationship between cytokines and RA. The analysis identified 9 inflammatory cytokines, including IL-1α and IL-10, which significantly increase RA risk, while TNF-β exhibited a protective effect. Additionally, 6 metabolites were associated with increased RA risk, including 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE and arachidonate (20:4n6). Conversely, 5 metabolites, such as docosatrienoate (22:3n3) and Cholesterol, were found to reduce RA risk. The mediation analysis revealed that TNF-β may exerts its protective effect through its influence on specific metabolites, and X-24949, which accounted for a -2.58% mediated effect in the TNF-β-RA causal pathway. This study explores the complex interplay between inflammatory cytokines, metabolites, and RA. The findings suggest potential biomarkers for early diagnosis and novel therapeutic targets, particularly those related to lipid metabolites and specific cytokines like TNF-β. Key message What is already known on this topic Inflammatory factors and metabolites are considered to be related to the onset and progression of RA. What this study adds We conducted a MR analysis to identify all inflammatory factors and metabolites associated with RA and calculated the mediation effect of inflammatory cytokines on RA through metabolites. This study contributes to a comprehensive understanding of the pathophysiological processes of RA. How this study might affect research, practice or policy This has laid the groundwork for developing early diagnosis methods and future treatments.

The causal relationship between trace element status and upper gastrointestinal ulcers: a Mendelian randomization study

BackgroundThis study aimed to investigate the bidirectional causal relationships between trace elements (such as zinc, magnesium, phosphate, and folate) and upper gastrointestinal ulcers (including gastric and duodenal ulcers). We utilized a two-sample Mendelian randomization (MR) analysis to achieve this.MethodsWe conducted a two-sample MR analysis using summary-level data from genome-wide association studies (GWAS) obtained from public genomics repositories. We utilized a range of MR methods, including inverse-variance weighted (IVW), MR-Egger, and weighted median methods, and conducted a meta-analysis to synthesize results across different datasets. To ensure the robustness of our findings, we performed extensive sensitivity analyses, including pleiotropy assessment, heterogeneity tests, and leave-one-out analysis.ResultsOur findings are significant, indicating a positive causal relationship between increased zinc levels and the risk of gastric ulcers. Moreover, magnesium and folate appear to offer potential protective effects against gastroduodenal ulcers (p &amp;lt; 0.05). The meta-analysis further supports the causal relationship between zinc and gastric ulcers (p &amp;lt; 0.05), confirming zinc’s significant causal impact on this condition.ConclusionThe study confirms a positive causal relationship between zinc and gastric ulcers and highlights the complexity of how trace elements regulate the progression of upper gastrointestinal ulcers. These results provide a scientific basis for dietary recommendations regarding trace element intake in clinical and public health practices. They also offer new insights into effective prevention and treatment strategies for gastric and duodenal ulcers.

Genome-Wide Association-Based Identification of Alleles, Genes and Haplotypes Influencing Yield in Rice (Oryza sativa L.) Under Low-Phosphorus Acidic Lowland Soils

Rice provides poor yields in acidic soils due to several nutrient deficiencies and metal toxicities. The low availability of phosphorus (P) in acidic soils offers a natural condition for screening genotypes for grain yield and phosphorus utilization efficiency (PUE). The objective of this study was to phenotype a subset of indica rice accessions from 3000 Rice Genome Project (3K-RGP) under acidic soils and find associated genes and alleles. A panel of 234 genotypes, along with checks, were grown under low-input acidic soils for two consecutive seasons, followed by a low-P-based hydroponic screening experiment. The heritability of the agro-morphological traits was high across seasons, and Ward’s clustering method identified 46 genotypes that can be used as low-P-tolerant donors in acidic soil conditions. Genotypes ARC10145, RPA5929, and K1559-4, with a higher grain yield than checks, were identified. Over 29 million SNPs were retrieved from the Rice SNP-Seek database, and after quality control, they were utilized for a genome-wide association study (GWAS) with seventeen traits. Ten quantitative trait nucleotides (QTNs) for three yield traits and five QTNs for PUE were identified. A set of 34 candidate genes for yield-related traits was also identified. An association study using this indica panel for an already reported 1.84 Mbp region on chromosome 2 identified genes Os02g09840 and Os02g08420 for yield and PUE, respectively. A haplotype analysis for the candidate genes identified favorable allelic combinations. Donors carrying the superior haplotypic combinations for the identified genes could be exploited in future breeding programs.

Accounting for genetic effect heterogeneity in fine-mapping and improving power to detect gene-environment interactions with SharePro

Classical gene-by-environment interaction (GxE) analysis can be used to characterize genetic effect heterogeneity but has a high multiple testing burden in the context of genome-wide association studies (GWAS). We adapt a colocalization method, SharePro, to account for effect heterogeneity in fine-mapping and identify candidates for GxE analysis with reduced multiple testing burden. SharePro demonstrates improved power for both fine-mapping and GxE analysis compared to existing methods as well as well-controlled false type I error in simulations. Using smoking status stratified GWAS summary statistics, we identify genetic effects on lung function modulated by smoking status that are not identified by existing methods. Additionally, using sex stratified GWAS summary statistics, we characterize sex differentiated genetic effects on fat distribution. In summary, we have developed an analytical framework to account for effect heterogeneity in fine-mapping and subsequently improve power for GxE analysis. The SharePro software for GxE analysis is openly available at https://github.com/zhwm/SharePro_gxe.

The causal role of gastroesophageal reflux disease in endometriosis: a bidirectional Mendelian randomization study

Observational studies have reported an association between gastroesophageal reflux disease (GERD) and endometriosis. We conducted a two-sample and bidirectional Mendelian randomization analysis to determine whether those associations are causal. Two-sample and bidirectional MR analyses were performed using summary statistics from the European Individual Genome-Wide Association Study (GWAS). The inverse variance weighting (IVW) method is used as the main analysis method to evaluate causality. Sensitivity analyses were performed to assess heterogeneity, horizontal versatility, and stability. The results showed no significant causal association between GERD in women with endometriosis in the UK Bank database [ratio (OR) ≈ 0, 95% adjusted interval (CI) 1.0007∼1.0044, P = 0.006] and Finn databases [ratio (OR) = 1.29, 95% adjusted interval (CI) 0.99∼1.67, P = 0.06]. However, when studying the Finn database only for endometriosis, which is confined to the uterus, a significant increase in GERD was limited to the risk of endometriosis in the uterus [ratio (OR) = 1.47, 95% adjusted interval (CI) 1.00∼2.17, P = 0.05]. Sensitivity analysis showed that the results were robust and did not detect multi efficacy or heterogeneity. Meanwhile, reverse MR analysis showed that endometriosis did not increase the risk of GERD. This MR study supports a causal relationship between GERD and an increased risk of endometriosis confined to the uterus. Therefore, patients with gastric esophageal reflux should be treated with gynecological examination to avoid and prevent the development of endometriosis.

Genomic predictors of fat mass response to the standardized exercise training.

To explore the genetic architecture underlying exercise-induced fat mass change, we performed a genome-wide association study with a Chinese cohort consisting of 442 physically inactive healthy adults in response to a 12-week exercise training (High-intensity Interval Training or Resistance Training). The inter-individual response showed an exercise-induced fat mass change and ten novel lead SNPs were associated with the response on the level of P<1×10-5. Four of them (rs7187742, rs1467243, rs28629770 and rs10848501) showed a consistent effect direction in the European ancestry. The Polygenic Predictor Score (PPS) derived from ten lead SNPs, sex, baseline body mass and exercise protocols explained 40.3% of the variance in fat mass response, meanwhile importantly the PPS had the greatest contribution. Of note, the subjects whose PPS was lower than -9.301 had the highest response in exercise-induced fat loss. Finally, we highlight a series of pathways and biological processes regarding the fat mass response to exercise, e.g. apelin signaling pathway, insulin secretion pathway and fat cell differentiation biological process.

Translational Insights From Cell Type Variation Across Amygdala Subnuclei in Rhesus Monkeys and Humans.

Theories of amygdala function are central to our understanding of psychiatric and neurodevelopmental disorders. However, limited knowledge of the molecular and cellular composition of the amygdala impedes translational research aimed at developing new treatments and interventions. The aim of this study was to characterize and compare the composition of amygdala cells to help bridge the gap between preclinical models and human psychiatric and neurodevelopmental disorders. Tissue was dissected from multiple amygdala subnuclei in both humans (N=3, male) and rhesus macaques (N=3, male). Single-nucleus RNA sequencing was performed to characterize the transcriptomes of individual nuclei. The results reveal substantial heterogeneity between regions, even when restricted to inhibitory or excitatory neurons. Consistent with previous work, the data highlight the complexities of individual marker genes for uniquely targeting specific cell types. Cross-species analyses suggest that the rhesus monkey model is well-suited to understanding the human amygdala, but also identify limitations. For example, a cell cluster in the ventral lateral nucleus of the amygdala (vLa) is enriched in humans relative to rhesus macaques. Additionally, the data describe specific cell clusters with relative enrichment of disorder-related genes. These analyses point to the human-enriched vLa cell cluster as relevant to autism spectrum disorder, potentially highlighting a vulnerability to neurodevelopmental disorders that has emerged in recent primate evolution. Further, a cluster of cells expressing markers for intercalated cells is enriched for genes reported in human genome-wide association studies of neuroticism, anxiety disorders, and depressive disorders. Together, these findings shed light on the composition of the amygdala and identify specific cell types that can be prioritized in basic science research to better understand human psychopathology and guide the development of potential treatments.

The role of digital device use on the risk of migraine: a univariable and multivariable Mendelian randomization study

BackgroundThe pervasive integration of digital devices into daily life has raised concerns about their potential health impacts. This study aimed to explore the causal relationships between digital device use and the risk of migraine using Mendelian randomization (MR).MethodsGenetic data on digital device use and migraines were sourced from large-scale genome-wide association studies conducted by the UK Biobank, the FinnGen study, and the International Headache Genetics Consortium. Univariable MR (UVMR), meta-analysis, and multivariable MR (MVMR) approaches were conducted to explore and verify the causal effects of digital device use (including mobile phone use, computer use, playing computer games, and watching television) on migraine risk. Sensitivity analyses were conducted using Cochran’s Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier, MR Radial, MR Steiger, and leave-one-out methods.ResultsUVMR analyses revealed that genetically predicted mobile phone use was significantly associated with an increased risk of overall migraine (odds ratio [OR] = 2.39, p = 9.78e-5) and migraine without aura (MO) (OR = 2.25, p = 0.024). Additionally, there were significant positive associations between genetically predicted television watching and the risk of overall migraine (OR = 1.63, p = 2.12e-5) and MO (OR = 2.10, p = 4.98e-5). These results were further supported by the meta-analysis and MVMR analysis. Sensitivity analysis indicated no heterogeneity or pleiotropy.ConclusionThis comprehensive MR study provides preliminary evidence for the causal impact of mobile phone use and television watching on the risk of migraines. Further studies are needed to explore these associations across different populations.