Mendelian randomization analysis reveals causal effects of blood lipidome on gestational diabetes mellitus.

BACKGROUND: Observational studies have revealed associations between maternal lipid metabolites and gestational diabetes mellitus (GDM). However, whether these associations are causal remain uncertain. OBJECTIVE: To evaluate the causal relationship between lipid metabolites and GDM. METHODS: A two-sample Mendelian randomization (MR) analysis was performed based on summary statistics. Sensitivity analyses, validation analyses and reverse MR analyses were conducted to assess the robustness of the MR results. Additionally, a phenome-wide MR (Phe-MR) analysis was performed to evaluate potential side effects of the targeted lipid metabolites. RESULTS: A total of 295 lipid metabolites were included in this study, 29 of them had three or more instrumental variables (IVs) suitable for sensitivity analyses. The ratio of triglycerides to phosphoglycerides (TG_by_PG) was identified as a potential causal biomarker for GDM (inverse variance weighted (IVW) estimate: odds ratio (OR) = 2.147, 95% confidential interval (95% CI) 1.415-3.257, P = 3.26e-4), which was confirmed by validation and reverse MR results. Two other lipid metabolites, palmitoyl sphingomyelin (d18:1/16:0) (PSM(d18:1/16:0)) (IVW estimate: OR = 0.747, 95% CI 0.583-0.956, P = 0.021) and triglycerides in very small very low-density lipoprotein (XS_VLDL_TG) (IVW estimate: OR = 2.948, 95% CI 1.197-5.215, P = 0.015), were identified as suggestive potential biomarkers for GDM using a conventional cut-off P-value of 0.05. Phe-MR results indicated that lowering TG_by_PG had detrimental effects on two diseases but advantageous effects on the other 13 diseases. CONCLUSION: Genetically predicted elevated TG_by_PG are causally associated with an increased risk of GDM. Side-effect profiles indicate that TG_by_PG might be a target for GDM prevention, though caution is advised due to potential adverse effects on other conditions.

A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes.

Uric acid has been linked to various disease outcomes. However, it remains unclear whether uric acid-lowering therapy could be repurposed as a treatment for conditions other than gout. We first performed both observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to identify associations of uric acid levels with a wide range of disease outcomes. Then, trajectory analysis was conducted to explore temporal progression patterns of the observed disease outcomes. Finally, we investigated whether uric acid-lowering drugs could be repurposed using a factorial Mendelian randomization (MR) study design. A total of 41 overlapping phenotypes associated with uric acid levels were identified by both Obs- and PRS- PheWASs, primarily cardiometabolic diseases. The trajectory analysis illustrated how elevated uric acid levels contribute to cardiometabolic diseases, and finally death. Meanwhile, we found that uric acid-lowering drugs exerted a protective role in reducing the risk of coronary atherosclerosis (OR = 0.96, 95%CI: 0.93, 1.00, P = 0.049), congestive heart failure (OR = 0.64, 95%CI: 0.42, 0.99, P = 0.043), occlusion of cerebral arteries (OR = 0.93, 95%CI: 0.87, 1.00, P = 0.044) and peripheral vascular disease (OR = 0.60, 95%CI: 0.38, 0.94, P = 0.025). Furthermore, the combination of uric acid-lowering therapy (e.g. xanthine oxidase inhibitors) with antihypertensive treatment (e.g. calcium channel blockers) exerted additive effects and was associated with a 6%, 8%, 8%, 10% reduction in risk of coronary atherosclerosis, heart failure, occlusion of cerebral arteries and peripheral vascular disease, respectively. Our findings support a role of elevated uric acid levels in advancing cardiovascular dysfunction and identify potential repurposing opportunities for uric acid-lowering drugs in cardiovascular treatment.

Phenomics in Livestock Research: Bottlenecks and Promises of Digital Phenotyping and Other Quantification Techniques on a Global Scale.

Bottlenecks in moving genomics to real-life applications also include phenomics. This is true not only for genomics medicine and public health genomics but also in ecology and livestock phenomics. This expert narrative review explores the intricate relationship between genetic makeup and observable phenotypic traits across various biological levels in the context of livestock research. We unpack and emphasize the significance of precise phenotypic data in selective breeding outcomes and examine the multifaceted applications of phenomics, ranging from improvement to assessing welfare, reproductive traits, and environmental adaptation in livestock. As phenotypic traits exhibit strong correlations, their measurement alongside specific biological outcomes provides insights into performance, overall health, and clinical endpoints like morbidity and disease. In addition, automated assessment of livestock holds potential for monitoring the dynamic phenotypic traits across various species, facilitating a deeper comprehension of how they adapt to their environment and attendant stressors. A key challenge in genetic improvement in livestock is predicting individuals with optimal fitness without direct measurement. Temporal predictions from unmanned aerial systems can surpass genomic predictions, offering in-depth data on livestock. In the near future, digital phenotyping and digital biomarkers may further unravel the genetic intricacies of stress tolerance, adaptation and welfare aspects of animals enabling the selection of climate-resilient and productive livestock. This expert review thus delves into challenges associated with phenotyping and discusses technological advancements shaping the future of biological research concerning livestock.

Toward Next-Generation Phenomics: Precision Medicine, Spaceflight, Astronaut Omics, and Beyond.

Large investments over many decades in genomics in diverse fields such as precision medicine, plant biology, and recently, in space life science research and astronaut omics were not accompanied by a commensurate focus on high-throughput and granular characterization of phenotypes, thus resulting in a "phenomics lag" in systems science. There are also limits to what can be achieved through increases in sample sizes in genotype-phenotype association studies without commensurate advances in phenomics. These challenges beg a question. What might next-generation phenomics look like, given that the Internet of Things and artificial intelligence offer prospects and challenges for high-throughput digital phenotyping as a key component of next-generation phenomics? While attempting to answer this question, I also reflect on governance of digital technology and next-generation phenomics. I argue that it is timely to broaden the technical discourses through a lens of political theory. In this context, this analysis briefly engages with the recent book "The Earthly Community: Reflections on the Last Utopia," written by the historian and political theorist Achille Mbembe. The question posed by the book, "Will we be able to invent different modes of measuring that might open up the possibility of a different aesthetics, a different politics of inhabiting the Earth, of repairing and sharing the planet?" is directly relevant to healing of human diseases in ways that are cognizant of the interdependency of human and nonhuman animal health, and critical and historically informed governance of digital technologies that promise to benefit next-generation phenomics.

Phenome-wide association study identifies new clinical phenotypes associated with Staphylococcus aureus infections.

BACKGROUND: Phenome-Wide Association study (PheWAS) is a powerful tool designed to systematically screen clinical observations derived from medical records (phenotypes) for association with a variable of interest. Despite their usefulness, no systematic screening of phenotypes associated with Staphylococcus aureus infections (SAIs) has been done leaving potential novel risk factors or complications undiscovered. METHOD AND COHORTS: We tailored the PheWAS approach into a two-stage screening procedure to identify novel phenotypes correlating with SAIs. The first stage screened for co-occurrence of SAIs with other phenotypes within medical records. In the second stage, significant findings were examined for the correlations between their age of onset with that of SAIs. The PheWAS was implemented using the medical records of 754,401 patients from the Marshfield Clinic Health System. Any novel associations discovered were subsequently validated using datasets from TriNetX and All of Us, encompassing 109,884,571 and 118,538 patients respectively. RESULTS: Forty-one phenotypes met the significance criteria of a p-value < 3.64e-5 and odds ratios of > 5. Out of these, we classified 23 associations either as risk factors or as complications of SAIs. Three novel associations were discovered and classified either as a risk (long-term use of aspirin) or complications (iron deficiency anemia and anemia of chronic disease). All novel associations were replicated in the TriNetX cohort. In the All of Us cohort, anemia of chronic disease was replicated according to our significance criteria. CONCLUSIONS: The PheWAS of SAIs expands our understanding of SAIs interacting phenotypes. Additionally, the novel two-stage PheWAS approach developed in this study can be applied to examine other disease-disease interactions of interest. Due to the possibility of bias inherent in observational data, the findings of this study require further investigation.

CoPheScan: phenome-wide association studies accounting for linkage disequilibrium.

Phenome-wide association studies (PheWAS) facilitate the discovery of associations between a single genetic variant with multiple phenotypes. For variants which impact a specific protein, this can help identify additional therapeutic indications or on-target side effects of intervening on that protein. However, PheWAS is restricted by an inability to distinguish confounding due to linkage disequilibrium (LD) from true pleiotropy. Here we describe CoPheScan (Coloc adapted Phenome-wide Scan), a Bayesian approach that enables an intuitive and systematic exploration of causal associations while simultaneously addressing LD confounding. We demonstrate its performance through simulation, showing considerably better control of false positive rates than a conventional approach not accounting for LD. We used CoPheScan to perform PheWAS of protein-truncating variants and fine-mapped variants from disease and pQTL studies, in 2275 disease phenotypes from the UK Biobank. Our results identify the complexity of known pleiotropic genes such as APOE, and suggest a new causal role for TGM3 in skin cancer.

GILEA: In silico phenome profiling and editing using GAN Inversion.

BACKGROUND: Modeling heterogeneous disease states by data-driven methods has great potential to advance biomedical research. However, a comprehensive analysis of phenotypic heterogeneity is often challenged by the complex nature of biomedical datasets and emerging imaging methodologies. METHODS: Here, we propose a novel GAN Inversion-enabled Latent Eigenvalue Analysis (GILEA) framework and apply it to in silico phenome profiling and editing. RESULTS: We show the performance of GILEA using cellular imaging datasets stained with the multiplexed fluorescence Cell Painting protocol. The quantitative results of GILEA can be biologically supported by editing of the latent representations and simulation of dynamic phenotype transitions between physiological and pathological states. CONCLUSION: In conclusion, GILEA represents a new and broadly applicable approach to the quantitative and interpretable analysis of biomedical image data. The GILEA code and video demos are available at https://github.com/CTPLab/GILEA.

Feature engineering and parameter tuning: improving phenomic prediction ability in multi-environmental durum wheat breeding trials.

KEY MESSAGE: Optimized phenomic selection in durum wheat uses near-infrared spectra, feature engineering and parameter tuning. Our study reports improvements in predictive ability and emphasizes customized preprocessing for different traits and models. The success of plant breeding programs depends on efficient selection decisions. Phenomic selection has been proposed as a tool to predict phenotype performance based on near-infrared spectra (NIRS) to support selection decisions. In this study, we test the performance of phenomic selection in multi-environmental trials from our durum wheat breeding program for three breeding scenarios and use feature engineering as well as parameter tuning to improve the phenomic prediction ability. In addition, we investigate the influence of genotype and environment on the phenomic prediction ability for agronomic and quality traits. Preprocessing, based on a grid search over the Savitzky-Golay filter parameters based on 756,000 genotype best linear unbiased estimate (BLUE) computations, improved the phenomic prediction ability by up to 1500% (0.02-0.3). Furthermore, we show that preprocessing should be optimized depending on the dataset, trait, and model used for prediction. The phenomic prediction scenarios in our durum breeding program resulted in low-to-moderate prediction abilities with the highest and most stable prediction results when predicting new genotypes in the same environment as used for model training. This is consistent with the finding that NIRS capture both the genotype and genotype-by-environment ( G × E ) interaction variance.

A Mendelian randomization study of the entire phenome to explore the causal links between epilepsy.

OBJECTIVE: The causes and triggering factors of epilepsy are still unknown. The results of genome-wide association studies can be utilized for a phenome-wide association study using Mendelian randomization (MR) to identify potential risk factors for epilepsy. METHODS: This study utilizes two-sample MR analysis to investigate whether 316 phenotypes, including lifestyle, environmental factors, blood biomarker, and more, are causally associated with the occurrence of epilepsy. The primary analysis employed the inverse variance weighted (IVW) model, while complementary MR analysis methods (MR Egger, Wald ratio) were also employed. Sensitivity analyses were also conducted to evaluate heterogeneity and pleiotropy. RESULTS: There was no evidence of a statistically significant causal association between the examined phenotypes and epilepsy following Bonferroni correction (p < 1.58 × 10-4) or false discovery rate correction. The results of the MR analysis indicate that the frequency of tiredness or lethargy in the last 2 weeks (p = 0.042), blood uridine (p = 0.003), blood propionylcarnitine (p = 0.041), and free cholesterol (p = 0.044) are suggestive causal risks for epilepsy. Lifestyle choices, such as sleep duration and alcohol consumption, as well as biomarkers including steroid hormone levels, hippocampal volume, and amygdala volume were not identified as causal factors for developing epilepsy (p > 0.05). CONCLUSIONS: Our study provides additional insights into the underlying causes of epilepsy, which will serve as evidence for the prevention and control of epilepsy. The associations observed in epidemiological studies may be partially attributed to shared biological factors or lifestyle confounders.

Genomic and phenomic predictions help capture low-effect alleles promoting seed germination in oilseed rape in addition to QTL analyses.

KEY MESSAGE: Phenomic prediction implemented on a large diversity set can efficiently predict seed germination, capture low-effect favorable alleles that are not revealed by GWAS and identify promising genetic resources. Oilseed rape faces many challenges, especially at the beginning of its developmental cycle. Achieving rapid and uniform seed germination could help to ensure a successful establishment and therefore enabling the crop to compete with weeds and tolerate stresses during the earliest developmental stages. The polygenic nature of seed germination was highlighted in several studies, and more knowledge is needed about low- to moderate-effect underlying loci in order to enhance seed germination effectively by improving the genetic background and incorporating favorable alleles. A total of 17 QTL were detected for seed germination-related traits, for which the favorable alleles often corresponded to the most frequent alleles in the panel. Genomic and phenomic predictions methods provided moderate-to-high predictive abilities, demonstrating the ability to capture small additive and non-additive effects for seed germination. This study also showed that phenomic prediction estimated phenotypic values closer to phenotypic values than GEBV. Finally, as the predictive ability of phenomic prediction was less influenced by the genetic structure of the panel, it is worth using this prediction method to characterize genetic resources, particularly with a view to design prebreeding populations.

Near-infrared reflectance spectroscopy phenomic prediction can perform similarly to genomic prediction of maize agronomic traits across environments.

For nearly two decades, genomic prediction and selection have supported efforts to increase genetic gains in plant and animal improvement programs. However, novel phenomic strategies for predicting complex traits in maize have recently proven beneficial when integrated into across-environment sparse genomic prediction models. One phenomic data modality is whole grain near-infrared spectroscopy (NIRS), which records reflectance values of biological samples (e.g., maize kernels) based on chemical composition. Predictions of hybrid maize grain yield (GY) and 500-kernel weight (KW) across 2 years (2011-2012) and two management conditions (water-stressed and well-watered) were conducted using combinations of reflectance data obtained from high-throughput, F2 whole-kernel scans and genomic data obtained from genotyping-by-sequencing within four different cross-validation (CV) schemes (CV2, CV1, CV0, and CV00). When predicting the performance of untested genotypes in characterized (CV1) environments, genomic data were better than phenomic data for GY (0.689 ± 0.024-genomic vs. 0.612 ± 0.045-phenomic), but phenomic data were better than genomic data for KW (0.535 ± 0.034-genomic vs. 0.617 ± 0.145-phenomic). Multi-kernel models (combinations of phenomic and genomic relationship matrices) did not surpass single-kernel models for GY prediction in CV1 or CV00 (prediction of untested genotypes in uncharacterized environments); however, these models did outperform the single-kernel models for prediction of KW in these same CVs. Lasso regression applied to the NIRS data set selected a subset of 216 NIRS bands that achieved comparable prediction abilities to the full phenomic data set of 3112 bands predicting GY and KW under CV1 and CV00.

Prevalence of comorbidities in individuals with neurodevelopmental disorders from the aggregated phenomics data of 51,227 pediatric individuals.

The prevalence of comorbidities in individuals with neurodevelopmental disorders (NDDs) is not well understood, yet these are important for accurate diagnosis and prognosis in routine care and for characterizing the clinical spectrum of NDD syndromes. We thus developed PhenomAD-NDD, an aggregated database containing the comorbid phenotypic data of 51,227 individuals with NDD, all harmonized into Human Phenotype Ontology (HPO), with in total 3,054 unique HPO terms. We demonstrate that almost all congenital anomalies are more prevalent in the NDD population than in the general population, and the NDD baseline prevalence allows for an approximation of the enrichment of symptoms. For example, such analyses of 33 genetic NDDs show that 32% of enriched phenotypes are currently not reported in the clinical synopsis in the Online Mendelian Inheritance in Man (OMIM). PhenomAD-NDD is open to all via a visualization online tool and allows us to determine the enrichment of symptoms in NDD.

Identification of bacterial determinants of tuberculosis infection and treatment outcomes: a phenogenomic analysis of clinical strains.

BACKGROUND: Bacterial diversity could contribute to the diversity of tuberculosis infection and treatment outcomes observed clinically, but the biological basis of this association is poorly understood. The aim of this study was to identify associations between phenogenomic variation in Mycobacterium tuberculosis and tuberculosis clinical features. METHODS: We developed a high-throughput platform to define phenotype-genotype relationships in M tuberculosis clinical isolates, which we tested on a set of 158 drug-sensitive M tuberculosis strains sampled from a large tuberculosis clinical study in Ho Chi Minh City, Viet Nam. We tagged the strains with unique genetic barcodes in multiplicate, allowing us to pool the strains for in-vitro competitive fitness assays across 16 host-relevant antibiotic and metabolic conditions. Relative fitness was quantified by deep sequencing, enumerating output barcode read counts relative to input normalised values. We performed a genome-wide association study to identify phylogenetically linked and monogenic mutations associated with the in-vitro fitness phenotypes. These genetic determinants were further associated with relevant clinical outcomes (cavitary disease and treatment failure) by calculating odds ratios (ORs) with binomial logistic regressions. We also assessed the population-level transmission of strains associated with cavitary disease and treatment failure using terminal branch length analysis of the phylogenetic data. FINDINGS: M tuberculosis clinical strains had diverse growth characteristics in host-like metabolic and drug conditions. These fitness phenotypes were highly heritable, and we identified monogenic and phylogenetically linked variants associated with the fitness phenotypes. These data enabled us to define two genetic features that were associated with clinical outcomes. First, mutations in Rv1339, a phosphodiesterase, which were associated with slow growth in glycerol, were further associated with treatment failure (OR 5·34, 95% CI 1·21-23·58, p=0·027). Second, we identified a phenotypically distinct slow-growing subclade of lineage 1 strains (L1.1.1.1) that was associated with cavitary disease (OR 2·49, 1·11-5·59, p=0·027) and treatment failure (OR 4·76, 1·53-14·78, p=0·0069), and which had shorter terminal branch lengths on the phylogenetic tree, suggesting increased transmission. INTERPRETATION: Slow growth under various antibiotic and metabolic conditions served as in-vitro intermediate phenotypes underlying the association between M tuberculosis monogenic and phylogenetically linked mutations and outcomes such as cavitary disease, treatment failure, and transmission potential. These data suggest that M tuberculosis growth regulation is an adaptive advantage for bacterial success in human populations, at least in some circumstances. These data further suggest markers for the underlying bacterial processes that contribute to these clinical outcomes. FUNDING: National Health and Medical Research Council/A∗STAR, National Institutes of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the Wellcome Trust Fellowship in Public Health and Tropical Medicine.

Field-based high-throughput phenotyping enhances phenomic and genomic predictions for grain yield and plant height across years in maize.

Field-based phenomic prediction employs novel features, like vegetation indices (VIs) from drone images, to predict key agronomic traits in maize, despite challenges in matching biomarker measurement time points across years or environments. This study utilized functional principal component analysis (FPCA) to summarize the variation of temporal VIs, uniquely allowing the integration of this data into phenomic prediction models tested across multiple years (2018-2021) and environments. The models, which included 1 genomic, 2 phenomic, 2 multikernel, and 1 multitrait type, were evaluated in 4 prediction scenarios (CV2, CV1, CV0, and CV00), relevant for plant breeding programs, assessing both tested and untested genotypes in observed and unobserved environments. Two hybrid populations (415 and 220 hybrids) demonstrated the visible atmospherically resistant index's strong temporal correlation with grain yield (up to 0.59) and plant height. The first 2 FPCAs explained 59.3 ± 13.9% and 74.2 ± 9.0% of the temporal variation of temporal data of VIs, respectively, facilitating predictions where flight times varied. Phenomic data, particularly when combined with genomic data, often were comparable to or numerically exceeded the base genomic model in prediction accuracy, particularly for grain yield in untested hybrids, although no significant differences in these models' performance were consistently observed. Overall, this approach underscores the effectiveness of FPCA and combined models in enhancing the prediction of grain yield and plant height across environments and diverse agricultural settings.

Modern phenomics to empower holistic crop science, agronomy, and breeding research.

Crop phenomics enables the collection of diverse plant traits for a large number of samples along different time scales, representing a greater data collection throughput compared with traditional measurements. Most modern crop phenomics use different sensors to collect reflective, emitted, and fluorescence signals, etc., from plant organs at different spatial and temporal resolutions. Such multi-modal, high-dimensional data not only accelerates basic research on crop physiology, genetics, and whole plant systems modeling, but also supports the optimization of field agronomic practices, internal environments of plant factories, and ultimately crop breeding. Major challenges and opportunities facing the current crop phenomics research community include developing community consensus or standards for data collection, management, sharing, and processing, developing capabilities to measure physiological parameters, and enabling farmers and breeders to effectively use phenomics in the field to directly support agricultural production.

Phenome-wide identification of therapeutic genetic targets, leveraging knowledge graphs, graph neural networks, and UK Biobank data.

The ongoing expansion of human genomic datasets propels therapeutic target identification; however, extracting gene-disease associations from gene annotations remains challenging. Here, we introduce Mantis-ML 2.0, a framework integrating AstraZeneca's Biological Insights Knowledge Graph and numerous tabular datasets, to assess gene-disease probabilities throughout the phenome. We use graph neural networks, capturing the graph's holistic structure, and train them on hundreds of balanced datasets via a robust semi-supervised learning framework to provide gene-disease probabilities across the human exome. Mantis-ML 2.0 incorporates natural language processing to automate disease-relevant feature selection for thousands of diseases. The enhanced models demonstrate a 6.9% average classification power boost, achieving a median receiver operating characteristic (ROC) area under curve (AUC) score of 0.90 across 5220 diseases from Human Phenotype Ontology, OpenTargets, and Genomics England. Notably, Mantis-ML 2.0 prioritizes associations from an independent UK Biobank phenome-wide association study (PheWAS), providing a stronger form of triaging and mitigating against underpowered PheWAS associations. Results are exposed through an interactive web resource.

Enhancing winter wheat prediction with genomics, phenomics and environmental data.

In the realm of multi-environment prediction, when the goal is to predict a complete environment using the others as a training set, the efficiency of genomic selection (GS) falls short of expectations. Genotype by environment interaction poses a challenge in achieving high prediction accuracies. Consequently, current efforts are focused on enhancing efficiency by integrating various types of inputs, such as phenomics data, environmental information, and other omics data. In this study, we sought to evaluate the impact of incorporating environmental information into the modeling process, in addition to genomic and phenomics information. Our evaluation encompassed five data sets of soft white winter wheat, and the results revealed a significant improvement in prediction accuracy, as measured by the normalized root mean square error (NRMSE), through the integration of environmental information. Notably, there was an average gain in prediction accuracy of 49.19% in terms of NRMSE across the data sets. Moreover, the observed prediction accuracy ranged from 5.68% (data set 3) to 60.36% (data set 4), underscoring the substantial effect of integrating environmental information. By including genomic, phenomic, and environmental data in prediction models, plant breeding programs can improve selection efficiency across locations.

High night temperature stress on rice (Oryza sativa) - insights from phenomics to physiology. A review.

Rice (Oryza sativa ) faces challenges to yield and quality due to urbanisation, deforestation and climate change, which has exacerbated high night temperature (HNT). This review explores the impacts of HNT on the physiological, molecular and agronomic aspects of rice growth. Rise in minimum temperature threatens a potential 41% reduction in rice yield by 2100. HNT disrupts rice growth stages, causing reduced seed germination, biomass, spikelet sterility and poor grain development. Recent findings indicate a 4.4% yield decline for every 1°C increase beyond 27°C, with japonica ecotypes exhibiting higher sensitivity than indica. We examine the relationships between elevated CO2 , nitrogen regimes and HNT, showing that the complexity of balancing positive CO2 effects on biomass with HNT challenges. Nitrogen enrichment proves crucial during the vegetative stage but causes disruption to reproductive stages, affecting grain yield and starch synthesis. Additionally, we elucidate the impact of HNT on plant respiration, emphasising mitochondrial respiration, photorespiration and antioxidant responses. Genomic techniques, including CRISPR-Cas9, offer potential for manipulating genes for HNT tolerance. Plant hormones and carbohydrate enzymatic activities are explored, revealing their intricate roles in spikelet fertility, grain size and starch metabolism under HNT. Gaps in understanding genetic factors influencing heat tolerance and potential trade-offs associated with hormone applications remain. The importance of interdisciplinary collaboration is needed to provide a holistic approach. Research priorities include the study of regulatory mechanisms, post-anthesis effects, cumulative HNT exposure and the interaction between climate variability and HNT impact to provide a research direction to enhance rice resilience in a changing climate.

The role of phenomics and genomics in delineating the genetic basis of complex traits in millets.

Millets, comprising a diverse group of small-seeded grains, have emerged as vital crops with immense nutritional, environmental, and economic significance. The comprehension of complex traits in millets, influenced by multifaceted genetic determinants, presents a compelling challenge and opportunity in agricultural research. This review delves into the transformative roles of phenomics and genomics in deciphering these intricate genetic architectures. On the phenomics front, high-throughput platforms generate rich datasets on plant morphology, physiology, and performance in diverse environments. This data, coupled with field trials and controlled conditions, helps to interpret how the environment interacts with genetics. Genomics provides the underlying blueprint for these complex traits. Genome sequencing and genotyping technologies have illuminated the millet genome landscape, revealing diverse gene pools and evolutionary relationships. Additionally, different omics approaches unveil the intricate information of gene expression, protein function, and metabolite accumulation driving phenotypic expression. This multi-omics approach is crucial for identifying candidate genes and unfolding the intricate pathways governing complex traits. The review highlights the synergy between phenomics and genomics. Genomically informed phenotyping targets specific traits, reducing the breeding size and cost. Conversely, phenomics identifies promising germplasm for genomic analysis, prioritizing variants with superior performance. This dynamic interplay accelerates breeding programs and facilitates the development of climate-smart, nutrient-rich millet varieties and hybrids. In conclusion, this review emphasizes the crucial roles of phenomics and genomics in unlocking the genetic enigma of millets.

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).