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The research program Spit For Science was launched at Virginia Commonwealth University (VCU) in 2011. Since then, more than 10,000 freshmen have been enrolled in the program, filling out extensive questionnaires about their drinking, general substance use, and related behaviors, and also contributing saliva for genotyping. The goals of the program, as initially stated by the investigators, were to find the genes underlying the heritability of alcohol use and related behaviors, and in addition to put genetic knowledge to work in ways that might aid university administrators and mental health professionals in the prevention and treatment of substance abuse. We review every empirical paper involving genetic data that has emerged from the program, and reach a surprising conclusion: the study has never identified a single genetic effect of more than trivial magnitude. Although the quantitative results of the studies were reported transparently, the theoretical ramifications of the negligible results have never been acknowledged. To the contrary, most of the papers ignore the tiny effects, reaching optimistic conclusions about the prospects for future genetic explanations of alcohol use. We explore the implications of these results for the broader prospects of applied psychiatric genetics. [ABSTRACT FROM AUTHOR]

Objective: Upper gastrointestinal (UGI) cancers, particularly esophageal cancer (EC) and gastric cancer (GC) represent a significant health burden with complex etiologies. Metabolic alterations are known to play a crucial role in cancer development and progression. Identifying key metabolic biomarkers may offer insights into the pathophysiology of UGI cancers and potential therapeutic targets. This study aimed to investigate the causal associations between 1,400 types of metabolites, specifically phosphate-to-alanine and bilirubin-to-androsterone glucuronide, and the risk of developing UGI cancers using Mendelian randomisation (MR) analysis. Method: We conducted a two-sample MR study utilising genetic instruments identified from large-scale genome-wide association studies (GWASs) for metabolic traits. The outcomes were derived from GWAS datasets of UGI cancer patients, including EC and GC. Several MR methods were employed to ensure the robustness of the findings, including inverse variance weighted (IVW), MR-Egger and weighted median approaches. Results: Our analysis found a total of 44 metabolites associated with EC and 15 metabolites associated with GC. The MR analyses revealed a significant causal relationship between the phosphate-to-alanine ratio (EC: OR = 1.002,95% CI = 1.00034-1.0037, p = 0.0037; GC: OR = 1.24,95% CI = 1.046-1.476, p = 0.01) and increased risk of UGI cancers. In contrast, the bilirubin-to-androsterone glucuronide ratio (EC: OR = 0.998,95% CI = 0.997-0.999, p = 0.03; GC: OR = 0.80,95% CI = 0.656-0.991, p = 0.04) was inversely associated with the risk, suggesting a potential protective effect. Conclusion: Our findings suggest that the phosphate-to-alanine ratio and bilirubin-to-androsterone glucuronide ratio are key hub metabolites in the etiology of UGI cancers. These metabolic ratios could serve as potential biomarkers for early detection or targets for therapeutic intervention. Further research is warranted to elucidate the underlying biological mechanisms and to validate the clinical utility of these associations. [ABSTRACT FROM AUTHOR]

Abstract Background Drought adaptation is critical to many tree species persisting under climate change, however our knowledge of the genetic basis for trees to adapt to drought is limited. This knowledge gap impedes our fundamental understanding of drought response and application to forest production and conservation. To improve our understanding of the genomic determinants, architecture, and trait constraints, we assembled a reference genome and detected ~ 6.5 M variants in 432 phenotyped individuals for the foundational tree Corymbia calophylla. Results We found 273 genomic variants determining traits with moderate heritability (h 2 SNP = 0.26–0.64). Significant variants were predominantly in gene regulatory elements distributed among several haplotype blocks across all chromosomes. Furthermore, traits were constrained by frequent epistatic and pleiotropic interactions. Conclusions Our results on the genetic basis for drought traits in Corymbia calophylla have several implications for the ability to adapt to climate change: (1) drought related traits are controlled by complex genomic architectures with large haplotypes, epistatic, and pleiotropic interactions; (2) the most significant variants determining drought related traits occurred in regulatory regions; and (3) models incorporating epistatic interactions increase trait predictions. Our findings indicate that despite moderate heritability drought traits are likely constrained by complex genomic architecture potentially limiting trees response to climate change.

Resistance traits are economically important in crops in terms of accessibility to promising resistant germplasm. This study was conducted to evaluate SNP marker-trait association for Cereal Cyst Nematode (CCN), Heterodera filipjevi, in a large number of natural bread wheat populations. Phenotypic data analyzed using GLM (Generalized Linear Model) indicated significant differences among the landrace accessions for resistance to H. filipjevi. The genotyping was performed by 152K SNP chip on 188 accessions. After filtering, 10,471 polymorphic SNPs were employed for Genome Wide Association Study (GWAS). Population structure among the wheat genotypes were investigated using 840 well distinct SNP markers. Two sub-populations were revealed by structure software, and eleven markers were found to be significantly (P-value< 0.001) associated with resistance to H. filipjevi on chromosomes 2A, 3B, 4A, 4B, 5A, 5B, 5D, and 6B. The linkage disequilibrium analysis for all significantly associated SNPs showed that markers on chromosomes 4A and 4B were in high intra-chromosomal linkage disequilibrium, and, consequently, eight markers were recommended as strongly associated with resistance to H. filipjevi. The present study demonstrated valuable sources of resistance in the studied wheat genotypes against a widespread and important species of CCNs. The associated markers could be used in molecular breeding programs of bread wheat. [ABSTRACT FROM AUTHOR]

Objective: Previous research suggests that peripheral immune cells may play a role in the development of Alzheimer's disease (AD). Our study aims to determine if the composition of peripheral immune cells directly contributes to the occurrence of AD. Methods: We utilized a two-sample Mendelian randomization (MR) approach to examine the association between peripheral immune cells and AD.The primary analysis method used was the inverse variance weighted (IVW) method, and we also conducted analyses using MR Egger, weighted median, simple mode, and weighted mode methods to ensure the accuracy of the results.Heterogeneity and horizontal pleiotropy were evaluated using Cochran's Q statistics and the MR Egger intercept, respectively. Results: The study found a significant correlation between increased IgD + CD24- AC cells (Odds Ratio [OR] = 1.03, 95% Confidence Interval [CI] = 1.01–1.06, P = 0.0172), increased CD4 + %leukocyte (OR = 1.08, 95% CI = 1.02–1.14, P = 0.0086), and increased CD4 + CD8dim AC cells (OR = 1.06, 95% CI = 1.01–1.11, P = 0.0218), with an increased susceptibility to AD. Conversely, an increase in EM DN (CD4-CD8-) %T cells (OR = 0.95, 95% CI = 0.92–0.99, P = 0.0164) and an increase in DN (CD4-CD8-) AC cells (OR = 0.93, 95% CI = 0.88–0.99, P = 0.0145) were associated with a protective effect against AD. Conclusion: Our findings establish a causal link between peripheral immune cells and AD. This study is the first to examine the relationship between peripheral immune cells and AD using MR, offering valuable insights for early diagnosis and treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Drought adaptation is critical to many tree species persisting under climate change, however our knowledge of the genetic basis for trees to adapt to drought is limited. This knowledge gap impedes our fundamental understanding of drought response and application to forest production and conservation. To improve our understanding of the genomic determinants, architecture, and trait constraints, we assembled a reference genome and detected ~ 6.5 M variants in 432 phenotyped individuals for the foundational tree Corymbia calophylla. Results: We found 273 genomic variants determining traits with moderate heritability (h2SNP = 0.26–0.64). Significant variants were predominantly in gene regulatory elements distributed among several haplotype blocks across all chromosomes. Furthermore, traits were constrained by frequent epistatic and pleiotropic interactions. Conclusions: Our results on the genetic basis for drought traits in Corymbia calophylla have several implications for the ability to adapt to climate change: (1) drought related traits are controlled by complex genomic architectures with large haplotypes, epistatic, and pleiotropic interactions; (2) the most significant variants determining drought related traits occurred in regulatory regions; and (3) models incorporating epistatic interactions increase trait predictions. Our findings indicate that despite moderate heritability drought traits are likely constrained by complex genomic architecture potentially limiting trees response to climate change. [ABSTRACT FROM AUTHOR]

Abstract Allelopathy has been considered as a natural method of weed control. Despite the nature of allelochemical compounds has been studied, little is known about the genetic basis underlying allelopathy. However, it is known that rice exhibits diverse allelopathic potentials across varieties, and breeding for rice plants exhibiting allelopathic potential conferring an advantage against weeds in paddy fields would be highly desirable. Knowledge of the gene factors and the identification of the genomic regions responsible for allelopathy would facilitate breeding programs. Taking advantage of the existing genetic diversity in rice, particularly in temperate japonica rice, we conducted a comprehensive investigation into the genetic determinants that contribute to rice allelopathy. Employing Genome-Wide Association Study, we identified four Quantitative Trait Loci, with the most promising loci situated on chromosome 2 and 5. Subsequent inspection of the genes located within these QTLs revealed genes associated with the biosynthesis of secondary metabolites such as Phenylalanine Ammonia Lyase (PAL), a key enzyme in the synthesis of phenolic compounds, and two genes coding for R2R3-type MYB transcription factors. The identification of these two QTLs associated to allelopathy in rice provides a useful tool for further exploration and targeted breeding strategies.

Cowpea is one of the most popular dry-land legumes cultivated for food and forage in arid and semi-arid areas. Genetic diversity for global germplasm can be organized into core collections providing optimum resources to serve breeding requirements. Here, we present diversity analysis and genome-wide association study (GWAS) results for part of the cowpea core collection of the United States Department of Agriculture (USDA) along with breeding line controls. Included in the analysis were a total of 373 accessions analyzed with 6880 Single Nucleotide Polymorphism (SNP) markers from Genotyping by Sequencing (GBS). Population structure differentiated accessions into two groups irrespective of geographical origin and formed three clusters based on taxa upon phylogenetic analysis. A total of 56 SNPs were significantly associated to nine traits including pod length (25 Quantitative Trait Nucleotides, QTNs), seed anti-oxidant content (7 QTNs), dry pod color (7 QTNs), plant maturity (5 QTNs), flower color (5 QTNs), seed weight (4 QTNs), tolerance to low phosphate (1 QTN), growth habit (1 QTN), and response to rock phosphate (1 QTN) using Bayesian-information, Linkage-disequilibrium Iteratively Nested Keyway (BLINK), and Fixed and random model Circulating Probability Unification (FarmCPU) association models. Key genes related to all significant SNPs were identified based on annotations of the cowpea reference genome, including a flavonoid gene controlling flower color (Vigun08g040200.1), a root nodulation regulator for tolerance to low phosphate (Vigun11g168000.1), and numerous genes involved in signaling, biosynthesis, metabolite transport, and abiotic stress. Our results highlight the importance of maintaining public phenotyping databases at USDA and strengthening collaborations for data collection in cowpea to maximize research impacts. [ABSTRACT FROM AUTHOR]

• Significant variation among the GWAS panel was recorded for all the traits • 143 MTAs associations were observed for all traits distributed on all chromosomes • Eleven stable QTLs were identified for number of seeds per plant and pods per plant • MLD was utilised to establish correlation between phenotypic traits to loci's Genome wide association study (GWAS) was performed to identify loci associated with three agronomic traits namely seeds per pod, pods per plant and number of seeds per plant of horsegram (Macrotyloma uniflorum). Total 87 accesions of horsegram from different geographical regions of India and one wild relative from Australia were utilised for the genome wide association studies. The genotyping was carried out using genotype-by-sequencing technology and after high quality filtering, minor allele frequency of 0.05, a total of 55,656 quality SNPs were utilised for determining Marker-Trait Association. The LD decay varied across the chromosomes form 8 kb to 300 kb. Further, the population structure analysis has clustered the accession into three subpopulations. All the 88 accessions of horsegram were evaluated at Palampur (32.1109° N, 76.5363° E) and Bajaura (31.8465°N, 77.1605°E) locations of North-Western Himalayan region, India from. In the current study, 143 MTAs associations were observed for seeds per pod distributed on all 8 chromosomes, 2 for pods per plant at chromosomes 2 and 3 and 1 for number of seeds per plant at chromosome 7. However, total 11 stable QTLs (9 for number of seeds per plant and 2 for pods per plant) were also identified. These QTLs can serve as a potential source for marker assisted selection. The genes identified within and in proximity to the stable QTLs will serve as a bridge between genetic information and its practical application for crop improvement. [ABSTRACT FROM AUTHOR]

Allelopathy has been considered as a natural method of weed control. Despite the nature of allelochemical compounds has been studied, little is known about the genetic basis underlying allelopathy. However, it is known that rice exhibits diverse allelopathic potentials across varieties, and breeding for rice plants exhibiting allelopathic potential conferring an advantage against weeds in paddy fields would be highly desirable. Knowledge of the gene factors and the identification of the genomic regions responsible for allelopathy would facilitate breeding programs. Taking advantage of the existing genetic diversity in rice, particularly in temperate japonica rice, we conducted a comprehensive investigation into the genetic determinants that contribute to rice allelopathy. Employing Genome-Wide Association Study, we identified four Quantitative Trait Loci, with the most promising loci situated on chromosome 2 and 5. Subsequent inspection of the genes located within these QTLs revealed genes associated with the biosynthesis of secondary metabolites such as Phenylalanine Ammonia Lyase (PAL), a key enzyme in the synthesis of phenolic compounds, and two genes coding for R2R3-type MYB transcription factors. The identification of these two QTLs associated to allelopathy in rice provides a useful tool for further exploration and targeted breeding strategies. [ABSTRACT FROM AUTHOR]

PurposeThe aim of this study was to investigate the causal relationships between circulating cell traits and risk of renal disorders.MethodsWe applied a comprehensive two-sample Mendelian randomization (MR) analysis. Single nucleotide polymorphisms (SNPs) from publicly available genome-wide association studies (GWAS) databases were utilized. Genetically predicted instrumental variables of human blood cell traits were extracted from Blood Cell Consortium (BCX) while data on renal diseases was obtained from Finngen consortium. The primary MR analysis was conducted using the inverse variance weighted (IVW) method, with the weighted median (WM) and MR-Egger models used as additional methods. Sensitivity analyses, including MR-PRESSO, radial regression and MR-Egger intercept were conducted to detect outliers and assess horizontal pleiotropy. We further utilized the leave-one-out analysis to assess the robustness of the results. Causal associations were considered significant based on false rate correction (FDR), specifically when the IVW method provided a pFDR

Background: Growing evidence links immunological responses to Multiple sclerosis (MS), but specific immune factors are still unclear. Methods: Mendelian randomization (MR) was performed to investigate the association between peripheral hematological traits, MS risk, and its severity. Then, further subgroup analysis of immune counts and circulating cytokines and growth factors were performed. Results: MR revealed higher white blood cell count (OR [95%CI] = 1.26 [1.10,1.44], P = 1.12E-03, P adjust = 3.35E-03) and lymphocyte count (OR [95%CI] = 1.31 [1.15,1.50], P = 5.37E-05, P adjust = 3.22E-04) increased the risk of MS. In further analysis, higher T cell absolute count (OR [95%CI] = 2.04 [1.36,3.08], P = 6.37E-04, P adjust = 2.19E-02) and CD4+ T cell absolute count (OR [95%CI] = 2.11 [1.37,3.24], P = 6.37E-04, P adjust = 2.19E-02), could increase MS risk. While increasing CD25+ +CD4+ T cell absolute count (OR [95%CI] = 0.75 [0.66,0.86], P = 2.12E-05, P adjust = 1.72E-03), CD25++CD4+ T cell in T cell (OR [95%CI] = 0.79[0.70,0.89], P = 8.54E-05, P adjust = 5.29E-03), CD25++CD4+ T cell in CD4+ T cell (OR [95%CI] = 0.80 [0.72,0.89], P = 1.85E-05, P adjust = 1.72E-03), and CD25++CD8+ T cell in T cell (OR [95%CI] = 0.68[0.57,0.81], P = 2.22E-05, P adjust = 1.72E-03), were proved to be causally defensive for MS. For the disease severity, the suggestive association between some traits related to CD4+ T cell, Tregs and MS severity were demonstrated. Moreover, elevated levels of IL-2Ra had a detrimental effect on the risk of MS (OR [95%CI] = 1.22 [1.12,1.32], P = 3.20E-06, P adjust = 1.34E-04). Conclusions: This study demonstrated a genetically predicted causal relationship between elevated peripheral immune cell counts and MS. Subgroup analysis revealed a specific contribution of peripheral immune cells, holding potential for further investigations into the underlying mechanisms of MS and its severity. [ABSTRACT FROM AUTHOR]

Soybean cyst nematode (SCN) is a destructive pathogen of soybeans responsible for annual yield loss exceeding $1.5 billion in the United States. Here, we conducted a series of genome-wide association studies (GWASs) to understand the genetic landscape of SCN resistance in the University of Missouri soybean breeding programs (Missouri panel), as well as germplasm and cultivars within the United States Department of Agriculture (USDA) Uniform Soybean Tests--Northern Region (NUST). For the Missouri panel, we evaluated the resistance of breeding lines to SCN populations HG 2.5.7 (Race 1), HG 1.2.5.7 (Race 2), HG 0 (Race 3), HG 2.5.7 (Race 5), and HG 1.3.6.7 (Race 14) and identified seven quantitative trait nucleotides (QTNs) associated with SCN resistance on chromosomes 2, 8, 11, 14, 17, and 18. Additionally, we evaluated breeding lines in the NUST panel for resistance to SCN populations HG 2.5.7 (Race 1) and HG 0 (Race 3), and we found three SCN resistance-associated QTNs on chromosomes 7 and 18. Through these analyses, we were able to decipher the impact of seven major genetic loci, including three novel loci, on resistance to several SCN populations and identified candidate genes within each locus. Further, we identified favorable allelic combinations for resistance to individual SCN HG types and provided a list of available germplasm for integration of these unique alleles into soybean breeding programs. Overall, this study offers valuable insight into the landscape of SCN resistance loci in U.S. public soybean breeding programs and provides a framework to develop new and improved soybean cultivars with diverse plant genetic modes of SCN resistance. [ABSTRACT FROM AUTHOR]

Soybean cyst nematode (SCN) is a destructive pathogen of soybeans responsible for annual yield loss exceeding $1.5 billion in the United States. Here, we conducted a series of genome-wide association studies (GWASs) to understand the genetic landscape of SCN resistance in the University of Missouri soybean breeding programs (Missouri panel), as well as germplasm and cultivars within the United States Department of Agriculture (USDA) Uniform Soybean Tests—Northern Region (NUST). For the Missouri panel, we evaluated the resistance of breeding lines to SCN populations HG 2.5.7 (Race 1), HG 1.2.5.7 (Race 2), HG 0 (Race 3), HG 2.5.7 (Race 5), and HG 1.3.6.7 (Race 14) and identified seven quantitative trait nucleotides (QTNs) associated with SCN resistance on chromosomes 2, 8, 11, 14, 17, and 18. Additionally, we evaluated breeding lines in the NUST panel for resistance to SCN populations HG 2.5.7 (Race 1) and HG 0 (Race 3), and we found three SCN resistance-associated QTNs on chromosomes 7 and 18. Through these analyses, we were able to decipher the impact of seven major genetic loci, including three novel loci, on resistance to several SCN populations and identified candidate genes within each locus. Further, we identified favorable allelic combinations for resistance to individual SCN HG types and provided a list of available germplasm for integration of these unique alleles into soybean breeding programs. Overall, this study offers valuable insight into the landscape of SCN resistance loci in U.S. public soybean breeding programs and provides a framework to develop new and improved soybean cultivars with diverse plant genetic modes of SCN resistance.

SUMMARY: In plants, variations in seed size and number are outcomes of different reproductive strategies. Both traits are often environmentally influenced, suggesting that a mechanism exists to coordinate these phenotypes in response to available maternal resources. Yet, how maternal resources are sensed and influence seed size and number is largely unknown. Here, we report a mechanism that senses maternal resources and coordinates grain size and number in the wild rice Oryza rufipogon, a wild progenitor of Asian cultivated rice. We showed that FT‐like 9 (FTL9) regulates both grain size and number and that maternal photosynthetic assimilates induce FTL9 expression in leaves to act as a long‐range signal that increases grain number and reduces size. Our findings highlight a strategy that benefits wild plants to survive in a fluctuating environment. In this strategy, when maternal resources are sufficient, wild plants increase their offspring number while preventing an increase in offspring size by the action of FTL9, which helps expand their habitats. In addition, we found that a loss‐of‐function allele (ftl9) is prevalent among wild and cultivated populations, offering a new scenario in the history of rice domestication. Significance Statement: Offspring number and size are the cornerstones of the life history of wild plants and are essential in crop yield. By using the phenotypic variation of grain traits among Oryza rufipogon, a wild progenitor of Asian cultivated rice, we found that FT‐like 9 (FTL9) mediates maternal‐offspring signaling that senses maternal resource availability and coordinates grain size and number. [ABSTRACT FROM AUTHOR]

Dry direct-seeded rice (dry-DSR) is typically sown deeply to circumvent the need for irrigation, and thus seedling emergence is a crucial trait affecting plant stand and yield. To breed elite cultivars that use less water and are climate-resilient, an understanding of the genomic regions and underlying genes that confer emergence in deeply sown dry-DSR would be highly advantageous. A combined diversity panel of 470 rice accessions (RDP1 plus aus subset of 3K RGP) was evaluated with 2.9 million single nucleotide polymorphisms (SNPs) to identify associations with dry-DSR traits in the field and component traits in a controlled-environment experiment. Using genome-wide association study (GWAS) analyses, we identified 18 unique QTLs on chromosomes 1, 2, 4, 5, 6, 7, 9, 10, and 11, explaining phenotypic variance ranging from 2.6% to 17.8%. Three QTLs, namely, qSOE-1.1, qEMERG-AUS-1.2, and qEMERG-AUS-7.1, were colocated with previously reported QTLs for mesocotyl length. Among the identified QTLs, half were associated with the emergence of aus, and six were unique to the aus genetic group. Based on functional annotation, we identified eleven compelling candidate genes that primarily regulate phytohormone pathways such as cytokinin, auxin, gibberellic acid, and jasmonic acid. Prior studies indicated that these phytohormones play a critical role in mesocotyl length under deep sowing. This study provides new insight into the importance of aus and indica as desirable genetic resources to mine favorable alleles for deep-sowing tolerance in rice. The candidate genes and marker-tagged desirable alleles identified in this study should benefit rice breeding programs directly. [ABSTRACT FROM AUTHOR]

Common bean (Phaseolus vulgaris L.) is an important legume crop worldwide and is a major nutrient source in the tropics. Common bean reproductive development is strongly affected by heat stress, particularly overnight temperatures above 20°C. The desert Tepary bean (Phaseolus acutifolius A. Gray) offers a promising source of adaptative genes due to its natural acclimation to arid conditions. Hybridization between both species is challenging, requiring in vitro embryo rescue and multiple backcrossing cycles to restore fertility. This labor-intensive process constrains developing mapping populations necessary for studying heat tolerance. Here we show the development of an interspecific mapping population using a novel technique based on a bridging genotype derived from P. vulgaris, P. Acutifolius and P. parvifolius named VAP1 and is compatible with both common and tepary bean. The population was based on two wild P. acutifolius accessions, repeatedly crossed with Mesoamerican elite common bush bean breeding lines. The population was genotyped through genotyping-by-sequencing and evaluated for heat tolerance by genome-wide association studies. We found that the population harbored 59.8% introgressions from wild tepary, but also genetic regions from Phaseolus parvifolius, a relative represented in some early bridging crosses. We found 27 significative quantitative trait loci, nine located inside tepary introgressed segments exhibiting allelic effects that reduced seed weight, and increased the number of empty pods, seeds per pod, stem production and yield under high temperature conditions. Our results demonstrate that the bridging genotype VAP1 can intercross common bean with tepary bean and positively influence the physiology of derived interspecific lines, which displayed useful variance for heat tolerance. [ABSTRACT FROM AUTHOR]

Objectives: Though type 2 diabetes (T2D) has been known as a metabolic disease caused by multiple factors, the etiology remains insufficiently understood. Here, we aimed to figure out whether circulating immune cell profiles causally impact T2D liability. Methods: We applied one genome-wide association study (GWAS) summary statistics of blood traits in 563,085 participants from the Blood Cell Consortium and another GWAS of flow cytometric profile of lymphocyte subsets comprising 3,757 Sardinians to identify genetically predicted blood immune cells. We also obtained GWAS summary statistics in 898,130 individuals from the DIAGRAM Consortium to evaluate genetically predicted T2D. We primarily used inverse variance weighted (IVW) and weighted median methods to perform Mendelian randomization analyses and sensitivity analyses to evaluate heterogeneity and pleiotropy. Results: For circulating blood leukocyte and its subpopulations, the increase of genetically predicted circulating monocyte count was causally correlated with a higher risk of T2D [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02-1.10, p = 0.0048]. For lymphocyte subsets, CD8+ T cell and CD4+ CD8dim T cell count were identified with causal effect on T2D susceptibility (CD8+ T cell: OR = 1.09, 95% CI = 1.03-1.17, p = 0.0053; CD4+ CD8dim T cell: OR = 1.04, 95% CI = 1.01-1.08, p = 0.0070). No pleiotropy was determined. Conclusions: These findings demonstrated that higher circulating monocyte and T-lymphocyte subpopulation predicted increased T2D susceptibility, which confirmed the immunity predisposition for T2D. Our results may have the potential to provide new therapeutic targets for the diagnosis and treatment of T2D. [ABSTRACT FROM AUTHOR]

[Display omitted] • Systematic evaluation of genetic diversity exists in wild and related tetraploid wheat wheat species T. turgidum and T. timopheevii. • Using genotypic datasets, we found duplicated accessions in T. timopheevii (∼65 %) and in T. turgidum (47 %). • We combined genotypic and phenotypic datasets to identify core set accessions to introduce novel genetic diversity in wheat breeding programs. The domestication bottleneck has reduced genetic diversity in wheat, necessitating the use of wild relatives in breeding programs. Wild tetraploid wheat are widely used in the breeding programs but with morphological characters, it is difficult to distinguish these, resulting in misclassification/mislabeling or duplication of accessions in the Gene bank. The study aims to explore Genotyping by sequencing (GBS) to characterize wild and domesticated tetraploid wheat accessions to generate a core set of accessions to be used in the breeding program. TASSEL-GBS pipeline was used for SNP discovery, fastStructure was used to determine the population structure and PowerCore was used to generate a core sets. Nucleotide diversity matrices of Nie's and F -statistics (F ST) index were used to determine the center of genetic diversity. We found 65 % and 47 % duplicated accessions in Triticum timopheevii and T. turgidum respectively. Genome-wide nucleotide diversity and F ST scan uncovered a lower intra and higher inter-species differentiation. Distinct F ST regions were identified in genomic regions belonging to domestication genes: non-brittle rachis (Btr1) and vernalization (VRN-1). Our results suggest that Israel, Jordan, Syria, and Lebanon as the hub of genetic diversity of wild emmer; Turkey, and Georgia for T. durum ; and Iraq, Azerbaijan, and Armenia for the T. timopheevii. Identified core set accessions preserved more than 93 % of the available genetic diversity. Genome wide association study (GWAS) indicated the potential chromosomal segment for resistance to leaf rust in T. timopheevii. The present study explored the potential of GBS technology in data reduction while maintaining the significant genetic diversity of the species. Wild germplasm showed more differentiation than domesticated accessions, indicating the availability of sufficient diversity for crop improvement. With reduced complexity, the core set preserves the genetic diversity of the gene bank collections and will aid in a more robust characterization of wild germplasm. [ABSTRACT FROM AUTHOR]

Dry direct-seeded rice (dry-DSR) is typically sown deeply to circumvent the need for irrigation, and thus seedling emergence is a crucial trait affecting plant stand and yield. To breed elite cultivars that use less water and are climate-resilient, an understanding of the genomic regions and underlying genes that confer emergence in deeply sown dry-DSR would be highly advantageous. A combined diversity panel of 470 rice accessions (RDP1 plus aus subset of 3K RGP) was evaluated with 2.9 million single nucleotide polymorphisms (SNPs) to identify associations with dry-DSR traits in the field and component traits in a controlled-environment experiment. Using genome-wide association study (GWAS) analyses, we identified 18 unique QTLs on chromosomes 1, 2, 4, 5, 6, 7, 9, 10, and 11, explaining phenotypic variance ranging from 2.6% to 17.8%. Three QTLs, namely, qSOE-1.1, qEMERG-AUS-1.2, and qEMERG-AUS-7.1, were co-located with previously reported QTLs for mesocotyl length. Among the identified QTLs, half were associated with the emergence of aus, and six were unique to the aus genetic group. Based on functional annotation, we identified eleven compelling candidate genes that primarily regulate phytohormone pathways such as cytokinin, auxin, gibberellic acid, and jasmonic acid. Prior studies indicated that these phytohormones play a critical role in mesocotyl length under deep sowing. This study provides new insight into the importance of aus and indica as desirable genetic resources to mine favorable alleles for deep-sowing tolerance in rice. The candidate genes and marker-tagged desirable alleles identified in this study should benefit rice breeding programs directly.

Common bean (Phaseolus vulgaris L.) is an important legume crop worldwide and is a major nutrient source in the tropics. Common bean reproductive development is strongly affected by heat stress, particularly overnight temperatures above 20°C. The desert Tepary bean (Phaseolus acutifolius A. Gray) offers a promising source of adaptative genes due to its natural acclimation to arid conditions. Hybridization between both species is challenging, requiring in vitro embryo rescue and multiple backcrossing cycles to restore fertility. This labor-intensive process constrains developing mapping populations necessary for studying heat tolerance. Here we show the development of an interspecific mapping population using a novel technique based on a bridging genotype derived from P. vulgaris, P. Acutifolius and P. parvifolius named VAP1 and is compatible with both common and tepary bean. The population was based on two wild P. acutifolius accessions, repeatedly crossed with Mesoamerican elite common bush bean breeding lines. The population was genotyped through genotyping-by-sequencing and evaluated for heat tolerance by genome-wide association studies. We found that the population harbored 59.8% introgressions from wild tepary, but also genetic regions from Phaseolus parvifolius, a relative represented in some early bridging crosses. We found 27 significative quantitative trait loci, nine located inside tepary introgressed segments exhibiting allelic effects that reduced seed weight, and increased the number of empty pods, seeds per pod, stem production and yield under high temperature conditions. Our results demonstrate that the bridging genotype VAP1 can intercross common bean with tepary bean and positively influence the physiology of derived interspecific lines, which displayed useful variance for heat tolerance.

Objective: Observational studies suggest CSF metabolites may be linked to Parkinson's disease (PD) onset, but causality is uncertain. This study uses a two-sample bidirectional Mendelian randomization approach to investigate the causal relationship between CSF metabolites and PD., Methods: Data on 338 CSF metabolites and PD-related traits were obtained from genome-wide association studies (GWAS). Causal relationships between CSF metabolites and PD were assessed using inverse variance-weighted (IVW), MR-Egger regression, weighted median method, simple mode, and weighted mode. Sensitivity analyses for heterogeneity and pleiotropy were conducted to explore the robustness of the results., Results: Our analysis identified an association between nine CSF metabolites and PD. Notably, significant increases in the risk of PD were observed for Ribitol (IVW, OR: 1.45; 95 % CI: 1.09-1.91; P = 9.04 ×E-03), Lysine (IVW, OR: 1.54; 95 % CI: 1.09-2.17; P = 1.24 ×E-02), and O-sulfo-l-tyrosine (IVW, OR: 1.38; 95 % CI: 1.06-1.79; P = 1.60 ×E-02). Additionally, we found that elevated levels of oxidized cysteinyl-glycine and 1,5-anhydroglucitol were associated with a decreased risk of PD. Furthermore, PD was associated with alterations in 12 CSF metabolites, including significant increases in Acetoacetate (IVW, OR: 1.15; 95 % CI: 1.02-1.30; P = 1.79 ×E-02), S-methylcysteine (IVW, OR: 1.14; 95 % CI: 1.02-1.29; P = 2.62 ×E-02), and N-acetyl-3-methylhistidine (IVW, OR: 1.12; 95 % CI: 1.01-1.23; P = 2.22 ×E-02)., Conclusion: The identified CSF metabolites may serve as potential CSF metabolic biomarkers for screening and preventing PD in clinical practice and could also be considered as candidate molecules for future mechanistic exploration and drug target selection., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in this work., (Copyright © 2025. Published by Elsevier B.V.)

Sugar beet (Beta vulgaris L.) is an important sugar-producing and energy crop worldwide. The sugar beet pure line IMA1 independently bred by Chinese scientists is a standard diploid parent material that is widely used in hybridbreeding programs. In this study, a high-quality, chromosome-level genome assembly for IMA1was conducted, and 99.1% of genome sequences were assigned to nine chromosomes. A total of 35,003 protein-coding genes were annotated, with 91.56% functionally annotated by public databases. Compared with previously released sugar beet assemblies, the new genome was larger with at least 1.6 times larger N50 size, thereby substantially improving the completeness and continuity of the sugar beet genome. A Genome-Wide Association Studies analysis identified 10 disease-resistance genes associated with three important beet diseases and five genes associated with sugar yield per hectare, which could be key targets to improve sugar productivity. Nine highly expressed genes associated with pollen fertility of sugar beet were also identified. The results of this study provide valuable information to identify and dissect functional genes affecting sugar beet agronomic traits, which can increase sugar beet production and help screen for excellent sugar beet breeding materials. In addition, information is provided that can precisely incorporate biotechnology tools into breeding efforts. [ABSTRACT FROM AUTHOR]

Drought is a detrimental factor to gaining higher yields in rice (Oryza sativa L.), especially amid the rising occurrence of drought across the globe. To combat this situation, it is essential to develop novel drought-resilient varieties. Therefore, screening of drought-adaptive genotypes is required with high precision and high throughput. In contemporary emerging science, high throughput plant phenotyping (HTPP) is a crucial technology that attempts to break the bottleneck of traditional phenotyping. In traditional phenotyping, screening significant genotypes is a tedious task and prone to human error while measuring various plant traits. In contrast, owing to the potential advantage of HTPP over traditional phenotyping, image-based traits, also known as i-traits, were used in our study to discriminate 110 genotypes grown for genome-wide association study experiments under controlled (well-watered), and drought-stress (limited water) conditions, under a phenomics experiment in a controlled environment with RGB images. Our proposed framework non-destructively estimated drought-adaptive plant traits from the images, such as the number of leaves, convex hull, plant–aspect ratio (plant spread), and similarly associated geometrical and morphological traits for analyzing and discriminating genotypes. The results showed that a single trait, the number of leaves, can also be used for discriminating genotypes. This critical drought-adaptive trait was associated with plant size, architecture, and biomass. In this work, the number of leaves and other characteristics were estimated non-destructively from top view images of the rice plant for each genotype. The estimation of the number of leaves for each rice plant was conducted with the deep learning model, YOLO (You Only Look Once). The leaves were counted by detecting corresponding visible leaf tips in the rice plant. The detection accuracy was 86–92% for dense to moderate spread large plants, and 98% for sparse spread small plants. With this framework, the susceptible genotypes (MTU1010, PUSA-1121 and similar genotypes) and drought-resistant genotypes (Heera, Anjali, Dular and similar genotypes) were grouped in the core set with a respective group of drought-susceptible and drought-tolerant genotypes based on the number of leaves, and the leaves' emergence during the peak drought-stress period. Moreover, it was found that the number of leaves was significantly associated with other pertinent morphological, physiological and geometrical traits. Other geometrical traits were measured from the RGB images with the help of computer vision. [ABSTRACT FROM AUTHOR]

Objectives: Multiple sclerosis (MS) is a complex central nervous system (CNS) demyelinating disease, the etiology of which involves the interplay between genetic and environmental factors. We aimed to determine whether genetically predicted peripheral immune cell counts may have a causal effect on MS. Methods: We used genetic variants strongly associated with cell counts of circulating leukocyte, lymphocyte, monocyte, neutrophil, eosinophil, and basophil, in addition to some subpopulations of T and B lymphocyte, as instrumental variables (IVs) to perform Mendelian randomization (MR) analyses. The effect of immune cell counts on MS risk was measured using the summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) genome-wide association studies (GWAS). Results: Our findings indicated that higher leucocyte count [odds ratio (OR), 1.24; 95% confidence interval (CI), 1.07 - 1.43; p = 0.0039] and lymphocyte count (OR, 1.17; 95% CI, 1.01 – 1.35; p = 0.0317) were causally associated with MS susceptibility. In addition, we also found that increase of genetically predicted natural killer T (NKT) cell count is also associated with an increase MS risk (OR, 1.24; 95% CI, 1.06 - 1.45; p = 0.0082). Conclusions: These findings show that the genetic predisposition to higher peripheral immune cell counts can exert a causal effect on MS risk, which confirms the crucial role played by peripheral immunity in MS. Particularly, the causal association between NKT cell count and MS underscores the relevance of exploring the functional roles of NKT cells in disease pathogenesis in future. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is caused by the T cell-driven autoimmune destruction of insulin-producing cells in the pancreas. T1D served as the prototypical autoimmune disease for genome wide association studies (GWAS) after having already been the subject of many linkage and association studies prior to the development of GWAS technology. Of the many T1D-associated gene variants, a minority appear disease-specific, while most are shared with one or more other autoimmune condition. Shared disease variants suggest defects in fundamental aspects of immune tolerance. The first layer of protective tolerance induction is known as central tolerance and takes place during the thymic selection of T cells. In this article, we will review candidate genes for type 1 diabetes whose function implicates them in central tolerance. We will describe examples of gene variants that modify the function of T cells intrinsically and others that indirectly affect thymic selection. Overall, these insights will show that a significant component of the genetic risk for T1D – and autoimmunity in general – pertains to the earliest stages of tolerance induction, at a time when protective intervention may not be feasible. [ABSTRACT FROM AUTHOR]

Multi-parent advanced generation inter-cross (MAGIC) populations facilitate the genetic dissection of complex quantitative traits in plants and are valuable breeding materials. We report the development of the first eggplant MAGIC population (S3 Magic EGGplant InCanum, S3MEGGIC; 8-way), constituted by the 420 S3 individuals developed from the intercrossing of seven cultivated eggplant (Solanum melongena) and one wild relative (S. incanum) parents. The S3MEGGIC recombinant population was genotyped with the eggplant 5k probes SPET platform and phenotyped for anthocyanin presence in vegetative plant tissues (PA) and fruit epidermis (FA), and for the light-insensitive anthocyanic pigmentation under the calyx (PUC). The 7,724 filtered high-confidence single-nucleotide polymorphisms (SNPs) confirmed a low residual heterozygosity (6.87%), a lack of genetic structure in the S3MEGGIC population, and no differentiation among subpopulations carrying a cultivated or wild cytoplasm. Inference of haplotype blocks of the nuclear genome revealed an unbalanced representation of the founder genomes, suggesting a cryptic selection in favour or against specific parental genomes. Genome-wide association study (GWAS) analysis for PA, FA, and PUC detected strong associations with two myeloblastosis (MYB) genes similar to MYB113 involved in the anthocyanin biosynthesis pathway, and with a COP1 gene which encodes for a photo-regulatory protein and may be responsible for the PUC trait. Evidence was found of a duplication of an ancestral MYB113 gene with a translocation from chromosome 10 to chromosome 1 compared with the tomato genome. Parental genotypes for the three genes were in agreement with the identification of the candidate genes performed in the S3MEGGIC population. Our new eggplant MAGIC population is the largest recombinant population in eggplant and is a powerful tool for eggplant genetics and breeding studies. [ABSTRACT FROM AUTHOR]

ObjectivesMultiple sclerosis (MS) is a complex central nervous system (CNS) demyelinating disease, the etiology of which involves the interplay between genetic and environmental factors. We aimed to determine whether genetically predicted peripheral immune cell counts may have a causal effect on MS.MethodsWe used genetic variants strongly associated with cell counts of circulating leukocyte, lymphocyte, monocyte, neutrophil, eosinophil, and basophil, in addition to some subpopulations of T and B lymphocyte, as instrumental variables (IVs) to perform Mendelian randomization (MR) analyses. The effect of immune cell counts on MS risk was measured using the summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) genome-wide association studies (GWAS).ResultsOur findings indicated that higher leucocyte count [odds ratio (OR), 1.24; 95% confidence interval (CI), 1.07 - 1.43; p = 0.0039] and lymphocyte count (OR, 1.17; 95% CI, 1.01 – 1.35; p = 0.0317) were causally associated with MS susceptibility. In addition, we also found that increase of genetically predicted natural killer T (NKT) cell count is also associated with an increase MS risk (OR, 1.24; 95% CI, 1.06 - 1.45; p = 0.0082).ConclusionsThese findings show that the genetic predisposition to higher peripheral immune cell counts can exert a causal effect on MS risk, which confirms the crucial role played by peripheral immunity in MS. Particularly, the causal association between NKT cell count and MS underscores the relevance of exploring the functional roles of NKT cells in disease pathogenesis in future.

Type 1 diabetes (T1D) is caused by the T cell-driven autoimmune destruction of insulin-producing cells in the pancreas. T1D served as the prototypical autoimmune disease for genome wide association studies (GWAS) after having already been the subject of many linkage and association studies prior to the development of GWAS technology. Of the many T1D-associated gene variants, a minority appear disease-specific, while most are shared with one or more other autoimmune condition. Shared disease variants suggest defects in fundamental aspects of immune tolerance. The first layer of protective tolerance induction is known as central tolerance and takes place during the thymic selection of T cells. In this article, we will review candidate genes for type 1 diabetes whose function implicates them in central tolerance. We will describe examples of gene variants that modify the function of T cells intrinsically and others that indirectly affect thymic selection. Overall, these insights will show that a significant component of the genetic risk for T1D – and autoimmunity in general – pertains to the earliest stages of tolerance induction, at a time when protective intervention may not be feasible.

Multi-parent advanced generation inter-cross (MAGIC) populations facilitate the genetic dissection of complex quantitative traits in plants and are valuable breeding materials. We report the development of the first eggplant MAGIC population (S3 Magic EGGplant InCanum, S3MEGGIC; 8-way), constituted by the 420 S3 individuals developed from the intercrossing of seven cultivated eggplant (Solanum melongena) and one wild relative (S. incanum) parents. The S3MEGGIC recombinant population was genotyped with the eggplant 5k probes SPET platform and phenotyped for anthocyanin presence in vegetative plant tissues (PA) and fruit epidermis (FA), and for the light-insensitive anthocyanic pigmentation under the calyx (PUC). The 7,724 filtered high-confidence single-nucleotide polymorphisms (SNPs) confirmed a low residual heterozygosity (6.87%), a lack of genetic structure in the S3MEGGIC population, and no differentiation among subpopulations carrying a cultivated or wild cytoplasm. Inference of haplotype blocks of the nuclear genome revealed an unbalanced representation of the founder genomes, suggesting a cryptic selection in favour or against specific parental genomes. Genome-wide association study (GWAS) analysis for PA, FA, and PUC detected strong associations with two myeloblastosis (MYB) genes similar to MYB113 involved in the anthocyanin biosynthesis pathway, and with a COP1 gene which encodes for a photo-regulatory protein and may be responsible for the PUC trait. Evidence was found of a duplication of an ancestral MYB113 gene with a translocation from chromosome 10 to chromosome 1 compared with the tomato genome. Parental genotypes for the three genes were in agreement with the identification of the candidate genes performed in the S3MEGGIC population. Our new eggplant MAGIC population is the largest recombinant population in eggplant and is a powerful tool for eggplant genetics and breeding studies.

Objective: Upper gastrointestinal (UGI) cancers, including esophageal (EC) and gastric (GC) cancers, pose a significant global health challenge. Previous studies have indicated a fundamental correlation between basophil count and the risk of UGI cancer. However, confirming a causal relationship demands further investigation. Mendelian randomization (MR) provides a critical method for evaluating the possible causal connections between peripheral circulating blood cells (PCBCs) and UGI cancer., Method: Our study comprehensively employed a two-sample MR analysis. We used publicly available genetic data to survey the causal association between PCBC and UGI cancer. We used inverse variance weighting and weighted median for MR analyses and sensitivity analyses to assess heterogeneity and pleiotropy., Results: In terms of the association between PCBCs and UGI cancer, we found that basophils count (EC: OR = 1.416, 95% CI = 1.125-1.783, p = 0.003; GC: OR = 1.623, 95% CI = 1.052-2.505, p = 0.029) were all strongly correlated with both EC and GC. Interestingly, Basophil count was a risk factor for both EC and GC. However, no significant correlations were seen between eosinophil, monocyte, lymphocyte or white blood cell count and UGI cancer., Conclusion: The findings of this research corroborate the idea that basophils might serve as a fundamental risk factor for UGI cancer. Further exploration of the underlying mechanisms driving this relationship could provide crucial understanding helpful in creating prospective preventive and treatment methods for UGI cancer., Competing Interests: No competing interests., (© the authors; licensee ecancermedicalscience.)

This is the first UK genome wide association study investigating potential links between Video Image Analysis (VIA) carcass traits and molecular polymorphisms in crossbred sheep. Phenotypic and genotypic data were collected from two crossbred lamb populations: Texel x Scotch Mule (TxSM, n = 2330) and Texel x Lleyn (TxL, n = 3816). Traits measured included live weights at birth, eight weeks and weaning (∼15 weeks). VIA-predicted traits included total weights and weights of fat, muscle and bone in the whole carcass and primal (hind leg, saddle, shoulder) regions. Within-breed heritabilities estimated for the VIA traits ranged from 0.01 to 0.70, indicating potential for inclusion of some traits in breeding programmes. The two crossbred populations differed in SNPs associated with different traits. Two SNPs on chromosomes two (s74618.1) and eight (s68536.1), respectively, reached genome-wise significance for TxSM, explaining <1% of trait variance, for whole carcass fat and muscle weights, hind leg and saddle fat weights and shoulder bone weights. For TxL, four SNPs reached genome-wise significance, on chromosome two for hind leg muscle weight (OAR2_117,959,202 and OAR2_11804335), on chromosome 10 for whole carcass bone weight (OAR19_8,995,957.1), and on chromosome 19 for weaning weight (s40847.1), each explaining <1% of trait genetic variation. Differences in apparent genetic control of carcass traits may be influenced by the lambs' cross-breed, but also by management decisions affecting environmental variance and trait definitions, which should be understood in order to define protocols for incorporation of carcass traits into (cross)breeding programmes. Combining VIA-measured carcass traits with conventional production traits in a breeding programme could potentially improve the production and product quality of meat sheep. Phenotypes for VIA traits could be collected relatively easily if VIA machines were present at all abattoir sites. The current study and future Genome Wide Association Studies may help to identify potentially informative molecular markers, that explain large proportions of the genetic variance observed in VIA-measured carcass traits. Including this information in the estimation of breeding values could increase the accuracy of prediction, increasing the potential rate of genetic improvement for product quality. This study confirms the polygenic architecture of the investigated carcass traits, with a small number of molecular markers that each explain a small amount of genetic variation. Further studies across breed types are recommended to further test and validate molecular markers for traits related to lamb carcass quality, as measured by video image analysis. [ABSTRACT FROM AUTHOR]

Drought is a detrimental factor to gaining higher yields in rice (Oryza sativa L.), especially amid the rising occurrence of drought across the globe. To combat this situation, it is essential to develop novel drought-resilient varieties. Therefore, screening of drought-adaptive genotypes is required with high precision and high throughput. In contemporary emerging science, high throughput plant phenotyping (HTPP) is a crucial technology that attempts to break the bottleneck of traditional phenotyping. In traditional phenotyping, screening significant genotypes is a tedious task and prone to human error while measuring various plant traits. In contrast, owing to the potential advantage of HTPP over traditional phenotyping, image-based traits, also known as i-traits, were used in our study to discriminate 110 genotypes grown for genome-wide association study experiments under controlled (well-watered), and drought-stress (limited water) conditions, under a phenomics experiment in a controlled environment with RGB images. Our proposed framework non-destructively estimated drought-adaptive plant traits from the images, such as the number of leaves, convex hull, plant–aspect ratio (plant spread), and similarly associated geometrical and morphological traits for analyzing and discriminating genotypes. The results showed that a single trait, the number of leaves, can also be used for discriminating genotypes. This critical drought-adaptive trait was associated with plant size, architecture, and biomass. In this work, the number of leaves and other characteristics were estimated non-destructively from top view images of the rice plant for each genotype. The estimation of the number of leaves for each rice plant was conducted with the deep learning model, YOLO (You Only Look Once). The leaves were counted by detecting corresponding visible leaf tips in the rice plant. The detection accuracy was 86–92% for dense to moderate spread large plants, and 98% for sparse spread small plants. With this framework, the susceptible genotypes (MTU1010, PUSA-1121 and similar genotypes) and drought-resistant genotypes (Heera, Anjali, Dular and similar genotypes) were grouped in the core set with a respective group of drought-susceptible and drought-tolerant genotypes based on the number of leaves, and the leaves’ emergence during the peak drought-stress period. Moreover, it was found that the number of leaves was significantly associated with other pertinent morphological, physiological and geometrical traits. Other geometrical traits were measured from the RGB images with the help of computer vision.

The Research Domain Criteria (RDoC) initiative was established by the US National Institute of Mental Health as a multilevel, disorder-agnostic framework for analysis of human psychopathology through designated domains and constructs, including the "Positive Valence Systems" domain focused on reward-related behavior. This study investigates the reward valuation subconstruct of "effort" and its association with genetic markers, functional neurobiological pathways, and polygenic risk scores for psychopathology in 1215 children aged 6-12 and their parents (n = 1044). All participants completed the effort expenditure for rewards task (EEfRT), which assesses "effort" according to two quantitative measures: hard-task choice and reward sensitivity. Genetic association analyses were undertaken in MAGMA, utilizing EEfRT outcome variables as genome-wide association studies phenotypes to compute SNP and gene-level associations. Genome-wide association analyses found two distinct genetic loci that were significantly associated with measures of reward sensitivity and a separate genetic locus associated with hard task choice. Gene-set enrichment analysis yielded significant associations between "effort" and multiple gene sets involved in reward processing-related pathways, including dopamine receptor signaling, limbic system and forebrain development, and biological response to cocaine. These results serve to establish "effort" as a relevant construct for understanding reward-related behavior at the genetic level and support the RDoC framework for assessing disorder-agnostic psychopathology., (© 2023 Wiley Periodicals LLC.)

Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from functional, cytoarchitectural, or other cortical parcellation schemes. We investigated genetic pleiotropy by applying genomic structural equation modeling (SEM) to map the genetic architecture of cortical surface area (SA) and cortical thickness (CT) for the 34 brain regions recently reported in the ENIGMA cortical GWAS. Genomic SEM uses the empirical genetic covariance estimated from GWAS summary statistics with LD score regression (LDSC) to discover factors underlying genetic covariance, which we are denoting genetically informed brain networks (GIBNs). Genomic SEM can fit a multivariate GWAS from summary statistics for each of the GIBNs, which can subsequently be used for LD score regression (LDSC). We found the best-fitting model of cortical SA identified 6 GIBNs and CT identified 4 GIBNs. The multivariate GWASs of these GIBNs identified 74 genome-wide significant (GWS) loci (p<5×10 -8 ), including many previously implicated in neuroimaging phenotypes, behavioral traits, and psychiatric conditions. LDSC of GIBN GWASs found that SA-derived GIBNs had a positive genetic correlation with bipolar disorder (BPD), and cannabis use disorder, indicating genetic predisposition to a larger SA in the specific GIBN is associated with greater genetic risk of these disorders. A negative genetic correlation was observed with attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), and insomnia, indicating genetic predisposition to a larger SA in the specific GIBN is associated with lower genetic risk of these disorders. CT GIBNs displayed a negative genetic correlation with alcohol dependence. Jointly modeling the genetic architecture of complex traits and investigating multivariate genetic links across phenotypes offers a new vantage point for mapping the cortex into genetically informed networks., Competing Interests: Dr. Thompson received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the topic of this manuscript. No other authors have competing financial interests in relation to the research presented herein. The material presented is original research that has not been previously published and has not been submitted for publication elsewhere.