Association Analysis Research Articles

DNA Methylation Participates in Drought Stress Memory and Response to Drought in Medicago ruthenica

Background: Drought is currently a global environmental problem, which inhibits plant growth and development and seriously restricts crop yields. Many plants exposed to drought stress can generate stress memory, which provides some advantages for resisting recurrent drought. DNA methylation is a mechanism involved in stress memory formation, and many plants can alter methylation levels to form stress memories; however, it remains unclear whether Medicago ruthenica exhibits drought stress memory, as the epigenetic molecular mechanisms underlying this process have not been described in this species. Methods: We conducted methylome and transcriptome sequencing to identify gene methylation and expression changes in plants with a history of two drought stress exposures. Results: Methylation analysis showed that drought stress resulted in an approximately 4.41% decrease in M. ruthenica genome methylation levels. The highest methylation levels were in CG dinucleotide contexts, followed by CHG contexts, with CHH contexts having the lowest levels. Analysis of associations between methylation and transcript levels showed that most DNA methylation was negatively correlated with gene expression except methylation within CHH motifs in gene promoter regions. Genes were divided into four categories according to the relationship between methylation and gene expression; the up-regulation of hypo-methylated gene expression accounted for the vast majority (692 genes) and included genes encoding factors key for abscisic acid (ABA) and proline synthesis. The hypo-methylation of the promoter and body regions of these two gene groups induced increased gene transcription levels. Conclusions: In conclusion, DNA methylation may contribute to drought stress memory formation and maintenance in M. ruthenica by increasing the transcription levels of genes key for ABA and proline biosynthesis.

Reduced antiviral gene expression and elevated CXCL8 expression in peripheral blood are associated with severe hypoxemia in RSV-infected children

The pathology of respiratory syncytial virus (RSV) infection remains unclear. An unbalanced immune response to RSV infection can lead to immunopathology, causing airway damage and impaired exchange of oxygen and carbon dioxide between the air and the bloodstream. We aimed to evaluate the association of the expression of inflammatory and antiviral genes in peripheral blood with severe hypoxemia in children with RSV infection seen in the hospital emergency room. We conducted a cross-sectional study on 121 RSV-infected children seen in hospital emergency rooms between 2015 and 2023. Total RNA was extracted from whole blood samples, and gene expression (IL-6, TNFα, CXCL8, ISG15, IFIT1, RIGI, IFNβ, CCL5, and CXCL10) was quantified using quantitative RT-PCR. The outcome variable was having severe hypoxemia (SpO2 ≤ 90%). The association analysis was performed using a volcano plot, adjusted logistic regression, and orthogonal partial least squares discriminant analysis (OPLS-DA). We found that 26 of 121 children had severe hypoxemia (SpO2 ≤ 90%). CXCL8 was overexpressed [fold changes (FC) > 2; q-value < 0.05], and ISG15, IFIT1, RIGI, IFNβ, CCL5, and CXCL10 were underexpressed (FC <0.5; q-value <0.05) in children with severe hypoxemia. These associations were ratified using adjusted logistic regression. The OPLS-DA showed that the gene expressions of CXCL8, ISG15, IFIT1, RIGI, and CXCL10 had values of variable importance in projection (VIP) ≥1, being the most relevant features. In conclusion, an imbalance favoring inflammation over antiviral defense may contribute to the pathogenesis of severe hypoxemia in RSV-infected children. These findings provide valuable insights into the pathology of RSV infection.

Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome.

Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (nobserved = 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS.

Genetic variability, character association and path coefficient analysis in okra

A study was conducted to investigate the genetic architecture of different lines for fruit yield and its associated traits in okra. Fourteen parents, consisting of twelve lines and two testers, were crossed using a Line × Tester mating design in the spring-summer season of 2019-20 at Vegetable Research Farm, CCSHAU, Hisar. The resulting twenty-four hybrids were cultivated in a randomized block design with three replications during the rainy season of 2020-21. Fruit yield/hectare showed a significant range from 87.86 to 150.18 quintals with an average of 117.73 quintals. The phenotypic coefficient of variation ranged from 3.91% (test weight) to 20.23% (Number of branches per plant), slightly surpassing the genotypic coefficient of variation which ranged from 1.98% (test weight) to 12.15% (fruit yield) with high estimate of PCV for the number of branches per plant (20.23%) and a moderate estimate of both PCV and GCV for fruit yield (14.67%, 12.15%), number of fruits per plant (14.34%, 12.06%), respectively. This suggests that the traits studied were more influenced by genetic factors than environmental factors. High heritability coupled with high genetic advance as percentage of mean for traits such as number of fruits/plant (70.74%, 20.89%) and fruit yield/hectare (68.65%, 20.74%) suggested that additive genes play a major role in determining these traits respectively. This indicates that it is possible to select high-yielding genotypes by selecting parents with desirable traits. Fruit yield/hectare displayed positive and significant associations with most of the traits like number of fruits per plant (0.95) and plant height (0.36) at phenotypic levels. The number of fruits per plant, 1000 seeds test weight, fruit diameter, and number of branches per plant had the most significant positive effect on fruit yield. Ultimately, such analysis has the potential to assist breeders in formulating their selection strategies aimed at enhancing fruit yield.

Genetic Variability, Character Association and Path Analysis for Yield and Yield Components in Foxtail Millet [Setaria italica (L.) P. Beauv.] Accessions under Multi Environments in Foothills of Nagaland

Background: Foxtail millet cultivation inIndia’s North Eastern Hill regionholds promise due to its adaptation to diverse environments and high-quality grain. The objective of this study was to assess the amount of variability present among the genotypes, association of traits and find out foxtail millet genotypes that produce high yield in diverse environments. Methods: The investigation was carried out during July 2022 to May 2023 in four different dates of sowing. Two environments maintained under rainfed condition and the remaining two environments are maintained under irrigated condition. The experiment was conducted in randomized complete block design with three replications in all environments. Result: Analysis of variance revealed statistically significant differences (at 5%) among the 30 genotypes for all yield variables under evaluation. Genotype ‘G1’ exhibited superior performance for both yield and yield-related traits. The present study revealed considerable genetic variation among the yield traits, with all traits demonstrating high heritability except for harvest index.Traits such as fodder yield per plant, panicle length, biological yield, flag leaf width, peduncle length, panicle width and grain yield per plant show high heritability coupled with high genetic advance. A strong correlation was observed between grain yield per plant and several traits including days to 50% flowering, days to maturity, plant height, panicle length, flag leaf length, peduncle length, biological yield and fodder yield per plant. This correlation was consistent at both the genotypic and phenotypic levels. Biological yield exhibited the strongest direct influence on grain yield per plant, followed by harvest index, flag leaf width and number of base tillers on genotypic and phenotypic levels.

Delineation of Selection Criterion Using Correlation and Path Analysis in Forage Pearl Millet (Pennisetum glaucum (L.) R. Br.) in North Gujarat Condition

Knowledge of genetic and phenotypic association among economic traits helps plant breeders in outlying efficient breeding strategies for development of high yielding forage pearl millet variety. An experiment was conducted at the research farm of Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, Gujarat to evaluate plant characteristics associated with green forage yield and its attributes in forage pearl millet [Pennisetum glaucum (L.) R. Br.] genotypes in north Gujarat condition through correlation and path analyses during 2023. Twelve independent and 1 dependent variables were evaluated for the character association analysis of the 30 forage pearl millet genotypes. The evaluation was performed in a Randomized Complete Block Design with three replications. Data collection was done from 5 randomly selected plants and this data was used for analysis using R Studio. The green forage yield per plant had positive and significant correlation with plant height, number of tiller per plant, stem thickness, leaf length, leaf width, and dry fodder yield per plant at both genotypic and phenotypic level. Path analysis revealed the importance of leaf width and dry fodder yield per plant by showing high and positive direct effects towards green forage yield per plant. These characters also exhibited significant and positive association with green forage yield per plant at the genotypic and phenotypic. Hence, these traits could be considered as the vital component characters for development of high yielding genotypes in forage pearl millet.

Causal relationship between plasma lipidome and four types of pancreatitis: a bidirectional Mendelian randomization study

BackgroundPancreatitis is a serious and complex inflammatory disease that imposes a severe effect on quality of life. Links between plasma lipidome and pancreatitis have been reported, some of which have not yet been clearly elucidated.MethodsTherefore, our study aimed to investigate the causal relationships between plasma lipidome and four types of pancreatitis by conducting a bidirectional, two-sample Mendelian randomization (MR) analysis. We obtained genetic variants associated with 179 lipid species from a Genome-wide association analysis of plasma lipidome. The aggregated statistical data of acute pancreatitis (AP), alcohol-induced acute pancreatitis (AAP), chronic pancreatitis (CP), and alcohol-induced chronic pancreatitis (ACP) from the FinnGen consortium were exploited as the outcome. The inverse variance weighted (IVW) technique as the main method was used for MR analysis and sensitivity analyses were used to evaluate heterogeneity and pleiotropy.ResultsAfter FDR correction, SE (27:1/20:4) (OR = 0.938, 95%CI = 0.906-0.972, P = 4.38 × 10-4, PFDR = 0.039) was identified to be significantly associated with AP risk. Eight lipid species were identified to be significantly associated with CP risk: SE (27:1/20:4) (OR = 0.911, 95%CI = 0.869-0.954, P = 8.89 × 10-5, PFDR = 0.016), LPC (20:4) (OR = 0.892, 95%CI = 0.843-0.945, P = 9.74 × 10-5, PFDR = 0.009), PC (16:0_22:5) (OR = 0.880, 95%CI = 0.818-0.947, P = 6.29 × 10-4, PFDR = 0.028), PC (17:0_20:4) (OR = 0.893, 95%CI = 0.842-0.948, P = 1.76 × 10-4, PFDR = 0.010), PC (18:0_20:4) (OR = 0.920, 95%CI = 0.874-0.969, P = 1.70 × 10-3, PFDR = 0.038), PC (O-16:0/20:4) (OR = 0.871, 95%CI = 0.804-0.943, P = 6.95 × 10-4, PFDR = 0.025), PC (O-16:1/20:4) (OR = 0.890, 95%CI = 0.832-0.953, P = 7.85 × 10-4, PFDR = 0.023), and PE (O-18:1/20:4) (OR = 0.866, 95%CI = 0.791-0.947, P = 1.61 × 10-3, PFDR = 0.041). Furthermore, genetically predicted increased LPC (20:4) (OR = 0.862, 95%CI = 0.796-0.934, P = 3.00 × 10-4, PFDR = 0.027) and SM (34:2;O2) (OR = 0.753, 95%CI = 0.659-0.860, P = 2.97 × 10-5, PFDR = 0.005) levels were associated with decreased risk of ACP.ConclusionsOur findings provide evidence of causal associations between the specific types of lipidome and pancreatitis, offering new insights into future clinical research.

Differences between uncapping and removal behaviors in Apis cerana from the perspective of long non-coding RNAs

BackgroundHygienic behavior, a specialized form of immune response evolved in social insects, plays a crucial role in safeguarding colonies from disease spread. In honeybee colonies, such behavior typically entails the dual steps of uncapping and removal of unhealthy and deceased brood. Although in recent years, numerous studies have examined the development of hygienic behavior, the mechanisms underlying the division in the performance of uncapping and removal have yet to be sufficiently elucidated. In this regard, long non-coding RNAs (lncRNAs) have been evidenced to be engaged in regulating the physiological activities of honeybees; however, whether lncRNAs are likewise involved in the uncapping and removal tasks has not been clarified.ResultsIn this study, the strong hygienic Apis cerana worker bees were used and the processes of uncapping and removal behaviors in three colonies were assayed with freeze-killed brood in the field. We then sequenced the antennal RNAs of honeybees to identify differentially expressed lncRNAs and performed lncRNA-mRNA association analysis to establish the differences between uncapping and removal. We detected 1,323 differentially expressed lncRNAs in the antennae, and the findings of lncRNA-mRNA association analyses revealed that the target genes of differentially expressed lncRNAs between uncapping and removal worker bees were predominantly linked to response to stimulus, receptor activity, and synapse. Notably, among the lncRNAs enriched in cellular response to stimulus, XR_001766094.2 was exclusively expressed in the uncapping worker bees. Based on these findings, we hypothesize that XR_001766094.2 plays a key role in distinguishing uncapping from removal behaviors by responding to external stimulus, thereby suggesting that the division of hygienic behaviors is governed by differential thresholds of responsiveness to environmental cues.ConclusionWe characterized differences in the uncapping and removal behaviors of worker bees from a perspective of lncRNAs. Uncapping bees may be equipped with a more rapid stimulatory response and more acute olfactory sensitivity, contributing to the rapid hygienic behavior in honeybee colonies. Our results thus establish a foundation for potential lncRNA-mediated gene expression regulation in hygienic behavior.

Integrating genetic analysis of germplasm wealth for enhanced selection and improvement in olive (Olea europaea L.): insights from leaves.

High-throughput next-generation sequencing of 161 olive germplas. 33 samples were selected as core olive germplasm and Fingerprints were constructed. After GWAS analysis of olive leaf shape, 14 candidate genes were localized. Olive (Olea europaea L.) has been introduced to China since the 1960s. After a prolonged period of variation and domestication, there is a lack of comprehensive research on its genetics. The olive oil directly extracted from Olea europaea L. is recognized as 'liquid gold', nevertheless, people constantly overlook the valuable wealth of olive leaves. High-throughput next-generation sequencing was performed on 161 olive germplasm to analyze the kinship, genetic structure and diversity of olives, and the core germplasm of olives were selected and fingerprints were constructed. Meanwhile, Genome-wide association analysis (GWAS) was performed to locate the gene for regulating olive leaf shape. Herein, the results parsed that most of the Chinese olive germplasm was more closely related to the Italian germplasm. A wealth of hybridized germplasm possessed high genetic diversity and had the potential to be used as superior parental material for olive germplasm. A total of 33 samples were selected and characterized as core germplasm of olive and Fingerprints were also constructed. A total of 14 candidate genes were localized after GWAS analysis of four olive leaf shape phenotypes, including leaf shape, leaf curvature shape, leaf tip and leaf base shape. Collectively, this study revealed the genetic basis of olives in China and also succeeded in constructing the core germplasm that stands for the genetic diversity of olives, which can contributeto the scientific and effective collection and preservation of olive germplasm resources, and provide a scientific basis for the in-depth excavation and utilization of genes regulating olive leaf shape.

Structural and transcriptional signatures of arithmetic abilities in children

Arithmetic ability is critical for daily life, academic achievement, career development, and future economic success. Individual differences in arithmetic skills among children and adolescents are related to variations in brain structures. Most existing studies have used hypothesis-driven region of interest analysis. To identify distributed brain regions related to arithmetic ability, we used data-driven cross-validated predictive models to analyze cross-sectional behavioral and structural MRI data in children and adolescents. The gray matter volume (GMV) of widespread brain regions reliably predicted arithmetic abilities measured by the Comprehensive Mathematical Abilities Test. Furthermore, we applied neuroimaging-transcriptome association analysis to explore transcriptional signatures associated with structural patterns of arithmetic ability. Structural patterns of arithmetic ability primarily correlated with transcriptional profiles enriched for genes involved in transmembrane transport and synaptic signaling. Our findings enhance our understanding of the neural and genetic mechanisms underlying children’s arithmetic ability and offer a practical predictor for arithmetic skills during development.

Powerful Rare-Variant Association Analysis of Secondary Phenotypes.

Most genome-wide association studies are based on case-control designs, which provide abundant resources for secondary phenotype analyses. However, such studies suffer from biased sampling of primary phenotypes, and the traditional statistical methods can lead to seriously distorted analysis results when they are applied to secondary phenotypes without accounting for the biased sampling mechanism. To our knowledge, there are no statistical methods specifically tailored for rare variant association analysis with secondary phenotypes. In this article, we proposed two novel joint test statistics for identifying secondary-phenotype-associated rare variants based on prospective likelihood and retrospective likelihood, respectively. We also exploit the assumption of gene-environment independence in retrospective likelihood to improve the statistical power and adopt a two-step strategy to balance statistical power and robustness. Simulations and a real-data application are conducted to demonstrate the superior performance of our proposed methods.

Exploring the Relationship between Vitamin D Levels and Obsessive-Compulsive Disorder: A Comprehensive Meta-analysis and Systematic Review

Background: A growing body of research has implicated lower levels of vitamin D in the pathogenesis of neurological and psychiatric disorders including obsessive-compulsive disorder (OCD). The main of this study was to investigate the relationship between vitamin D levels and OCD. Methodology: This meta-analysis follows the PRISMA guidelines and utilizes PubMed, Scopus, Web of Science, and Lens databases without temporal constraints. Six pertinent studies were selected to ensure methodological consistency and robustness in our analysis. Data were pooled using a Random-Effects Model to estimate the standard mean difference (SMD) for evaluation of the strength of association analyses. Result: Our analysis revealed a noteworthy reduction in vitamin D levels among individuals with OCD compared to controls (SMD = -0.603, 95% CI = -0.8001 to -0.4053, p < 0.001, I2 = 50.86%; Q statistic p = 0.093). Conclusion: These findings underscore the significant impact of vitamin D in the pathogenesis of OCD, suggesting its potential role in both the prevention and treatment of this psychiatric disorder. However, despite the compelling evidence presented, further studies are warranted to refine our understanding and draw more precise conclusions regarding the intricate interplay between vitamin D levels and OCD. Bangladesh J Medicine 2024; 35: 156-166

Effect of mixed probiotics on pulmonary flora in patients with mechanical ventilation: an exploratory randomized intervention study

ObjectiveThe study objective was to investigate the effect of mixed probiotics on the diversity of the pulmonary flora in critically ill patients requiring mechanical ventilation by analysing the changes in lung microbes.Methods24 adult critically ill patients who needed mechanical ventilation in our hospital were randomly divided into a probiotic group and a control group. Then, the probiotic group was given Live Combined Bifidobacterium, Lactobacillus and Enterococcus Capsules, Oral (Bifico) by nasal feeding within 24 h after mechanical ventilation. Bronchoalveolar lavage fluid (BALF) and venous blood were collected within 24 h after mechanical ventilation and on the 5th day after mechanical ventilation, and the treatment status of patients (mechanical ventilation time, 28-day survival), measured cytokine levels (IL-1 β, IL-6, IL-8, IL-17A) and changes in pulmonary microorganisms were observed.ResultsThe microbial diversity of BALF samples decreased in the control group, and there was no significant difference in the probiotic group. Species difference analysis showed that among the three probiotics (Bifidobacterium, Lactobacillus, Enterococcus) used for intervention, Lactobacillus caused significant differences in BALF in the control group. Clinical factor association analysis displayed significant associations with IL-17A levels in both blood and BALF.ConclusionMechanical ventilation can cause a decline in pulmonary microbial diversity, which can be improved by administering mixed probiotics.

Genetic diversity, population structure and marker-trait association analysis for yield-related traits in chickpea (Cicer arietinum L.)

Genetic diversity, population structure and marker-trait association analysis for yield-related traits in chickpea (Cicer arietinum L.)

Imaging genetics of language network functional connectivity reveals links with language-related abilities, dyslexia and handedness

Language is supported by a distributed network of brain regions with a particular contribution from the left hemisphere. A multi-level understanding of this network requires studying its genetic architecture. We used resting-state imaging data from 29,681 participants (UK Biobank) to measure connectivity between 18 left-hemisphere regions involved in multimodal sentence-level processing, as well as their right-hemisphere homotopes, and interhemispheric connections. Multivariate genome-wide association analysis of this total network, based on genetic variants with population frequencies >1%, identified 14 genomic loci, of which three were also associated with asymmetry of intrahemispheric connectivity. Polygenic dispositions to lower language-related abilities, dyslexia and left-handedness were associated with generally reduced leftward asymmetry of functional connectivity. Exome-wide association analysis based on rare, protein-altering variants (frequencies <1%) suggested 7 additional genes. These findings shed new light on genetic contributions to language network organization and related behavioural traits.

Tracing post-domestication historical events and screening pre-breeding germplasm from large gene pools in wheat in the absence of phenotype data.

Wheat, particularly common wheat (Triticum aestivum L.), is a major crop accounting for 25% of the world cereal production and thriving indiverse ecogeographic regions. Its adaptation to diverse environments arises from its three distinct genomes adapted to different environments and post-domestication anthropogenic interventions. In search of key genomic regions revealing historic events and breeding significance to common wheat, we performed genome scan and genome-environment association (GEA) analyses using high-marker density genotype datasets. Whole-genome scans revealed highly differentiated regions on chromosomes 2A, 3B, and 4A. In-depth analyses corroborated our previous prediction of the 4A differentiated region signifying the separation between Spelt/Macha and other wheat types. Individual chromosome scans captured key introgressions, includingone from T. timopheevii and one fromThinopyrum ponticum on 2B and 3D, respectively, as well as known genes such as Vrn-A1 on 5A. GEA highlighted loci linked to latitude-induced environmental variations, influencing traits such as photoperiodism and responses to abiotic stress. Variation at theVrn-A1 locus on 5A assigned accessions to two haplotypes (6% and 94%). Further analysis on Vrn-A1 coding gene revealed four subgroups of the major haplotype, while the minor haplotype remained undifferentiated. Analyses at differentiated loci mostly dichotomized the population, illustrating the possibility of isolating pre-breeding materials with desirable traits from large gene pools in the absence of phenotype data. Given the current availability of broad genetic data, the genome-scan-GEA hybrid can be anefficient and cost-effective approach for pinpointing environmentally resilient pre-breeding germplasm from vast gene pools, including gene banks regardless of trait characterization.

Genome-wide association analysis of flowering date in a collection of cultivated olive tree

Genome-wide association analysis of flowering date in a collection of cultivated olive tree

Integrated Analysis Reveals Genetic Basis of Growth Curve Parameters in an F2 Designed Pig Population Based on Genome and Transcriptome Data

Appropriate growth curves can reflect more sophisticated growth patterns of animals than body weight, and thus, the identification of genes and variants related to the growth curve parameter traits contributes to revealing the fine growth and development characteristics of livestock. However, the ability of single genome-wide association analysis (GWAS) and transcriptome analyses to identify valuable genes and variants is limited. In this study, based on genome and transcriptome data, the growth curve parameter traits of hybrid pigs were analyzed, and a set of genes and variants were identified. The Gompertz–Laird growth curve model was optimized to reveal the growth pattern of F2 individuals of Duroc × Erhualian pigs over four time points. Five growth parameters were estimated, including initial body weight (W0), instantaneous growth rate per day (L), coefficient of relative growth or maturing index (k), body weight at inflection point (Wi), and average growth rate (GR). These five parameters were subjected to a genome-wide association study, differential gene expression analysis, and weighted gene co-expression network analysis (WGCNA). In the study, 336 pigs were genotyped, and 39,494 SNP markers were used for each pig in the analysis. Thirty of these pigs were also included in the transcriptomics analysis. Based on genome and transcriptome data, the integrated analyses identified five putative SNPs (including INRA0056460 on chromosome X, DRGA0004151 on chromosome 3, INRA0056460 on chromosome X, H3GA0049324 on chromosome 17, and H3GA0037747 on chromosome 13) and 15 candidate genes (PDGFA, VEGFD, CSPP1, EFHC1, PIK3C3, ZZZ3, GCC2, MAPK14, ZPR1, ISG15, ANG, CEBPD, ZHX3, CTBP2, and MYNN). The functional analysis indicated that these candidate genes played important roles in cell division and differentiation, development and aging, and skeletal muscle and fat formation. Our results provide insight into the genetic mechanisms underlying the growth and development of hybrid pigs and offer a theoretical basis for genomic breeding.

Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment

BackgroundTreatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively.ResultsWe identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10−7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10−6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively.ConclusionsWe report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

Association Analysis Provides Insights into Molecular Evolution in Salt Tolerance during Tomato Domestication.

Salt stress impairs plant growth and development, generally resulting in crop failure. Tomato domestication gave rise to a dramatic decrease in salt tolerance caused by the genetic variability of the wild ancestors. However, the nature of artificial selection in reducing tomato salt tolerance remains unclear. Here, we generated and analyzed datasets on the survival rates and sodium (Na+) and potassium (K+) concentrations of hundreds of tomato varieties from wild ancestors to contemporary breeding accessions under high salinity. Genome-wide association studies (GWAS) revealed that natural variation in the promoter region of the putative K+ channel regulatory subunit-encoding gene KSB1 (potassium channel beta subunit in Solanum lycopersicum) is associated with survival rates and root Na+/K+ ratios in tomato under salt stress. This variation is deposited in tomato domestication sweeps and contributes to modified expression of KSB1 by salt-induced transcription factor SlHY5 in response to high salinity. We further found that KSB1 interacts with the K+ channel protein KSL1 to maintain cellular Na+ and K+ homeostasis, thus enhancing salt tolerance in tomato. Our findings reveal the crucial role of the SlHY5-KSB1-KSL1 module in regulating ion homeostasis and salt tolerance during tomato domestication, elucidating that selective pressure imposed by humans on the evolutionary process provides insights into further crop improvement.