Egg weight is a primary economic trait in poultry breeding. Putian Black duck, an excellent local laying duck breed in Fujian Province, includes two different strains, black feather strain and white feather strain. The white feather strain of Putian Black duck is also known as Putian White duck. Except for the different feather colors, these two strains differ in egg weight. In this study, whole-genome resequencing was conducted on Putian Black duck and Putian White duck to explore the differences in the genetic mechanism of egg weight. LRP8, VLDLR, and LPL were identified as key candidate genes affecting egg weight. Mass spectrometry was used to detect the SNPs of LRP8, VLDLR, and LPL. Result indicates that the SNPs of LRP8, VLDLR, and LPL in both populations exhibited moderate polymorphism, and Putian Black duck possessed higher genetic variation and potential selectivity. Association analysis indicated that in Putian Black duck, four SNPs in the LRP8 gene were significantly associated with egg weight. These loci can be used as molecular markers for improving egg weight in Putian Black duck.

It is estimated that 40-50% of severe asthma has an atopic basis, representing a clinical challenge and a significant economic burden for healthcare systems. The most effective treatment has emerged with the use of biologic therapies such as omalizumab; however, the rate of therapy switching due to loss of efficacy is high, which has a negative impact on the healthcare system. The aim was to evaluate the influence of genetic polymorphisms as predictors of omalizumab survival. We conducted a retrospective observational cohort study of 110 patients with uncontrolled severe allergic asthma treated with omalizumab in a tertiary hospital. We analyzed FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622) and GATA2 (rs4857855) by real-time PCR using Taqman probes. Drug survival was defined as the time from initiation to discontinuation of omalizumab. Cox regression analysis adjusted for the presence of respiratory disease, GERD, SAHS and years with asthma showed that the SNPs FCER1B rs573790 - CT (p < .001; HR = 3.38; CI95% = 1.66-6.87), FCGR3A rs10127939-AC (p = .018; HR = 3.85; CI95% = 1.25-11.81) and FCGR3A rs396991-CC (p = .020; HR = 2.23; CI95% = 1.14-4.38) were the independent variables associated with worse survival in patients diagnosed with asthma. A trend toward statistical significance was also found between and FCGR3A rs10127939-CC (p = .080; HR = 0.13; CI95% = 0.01-1.28) and longer drug survival. The results of this study demonstrate the potential influence of the polymorphisms studied on omalizumab survival and the clinical benefit that could be achieved by defining predictive biomarkers of drug survival.

Major depressive disorder (MDD) is a polygenic condition with substantial heritability, with genome-wide association studies (GWAS) identifying several risk loci in European populations, including the VRK2 gene. However, the association between VRK2 and MDD in non-European populations, particularly in Han Chinese, remains underexplored.

We genotyped four VRK2 SNPs (rs2678907, rs11682175, rs1568452, rs1518395) in a cohort of 1878 MDD cases and 1800 controls of Han Chinese descent. Genotyping was performed using SNaPShot, and linkage disequilibrium (LD) was assessed with SHEsis. Associations between the SNPs and MDD were evaluated via logistic regression in PLINK. VRK2 mRNA expression in the amygdala and peripheral blood was quantified by RT-qPCR, with statistical significance determined by ANCOVA and t-tests. A meta-analysis incorporating an independent East Asian GWAS cohort was also conducted.

In our Han Chinese cohort, rs2678907 was significantly associated with MDD (P = 4.17 × 10-5, OR = 1.217). Meta-analysis with independent East Asian GWAS further confirmed the associations of rs2678907 with MDD. Haplotype analysis of VRK2 SNPs in Han Chinese revealed the haplotypes (T-G for rs11682175-rs2678907 and C-G for rs1568452-rs2678907) associated with an increased MDD risk and elevated VRK2 mRNA expression. Additionally, MDD patients showed significantly higher VRK2 mRNA levels in peripheral blood than controls (P = 1.85 × 10-7).

These findings provide strong evidence for the role of VRK2 in MDD risk in Han Chinese individuals. Our results underscore the potential of VRK2 as a genetic and expression-based biomarker for MDD, highlighting the importance of accounting for population-specific genetic variations in psychiatric research. Further research is essential to explore the functional implications of VRK2 in MDD pathogenesis.

Indian-origin Gir and Ongole cattle are international transboundary breeds that are reared in Brazil, The United States, Mexico, Malaysia, Panama, and other nations to provide meat and dairy products. These breeds have shown substantial genetic diversity in recent years and well suited to the ecological niche in Brazil. 90 cattle samples of Indian Gir (n = 15), Ongole (n = 17), Brazilian Gyr (n = 27), and Nellore (n = 31) breeds were genotyped using Illumina BovineHD BeadChip. Samples were analyzed to identify selection signatures using two complementing approaches: Integrated Haplotype Score (iHS) and Fixation Index (FST). Gir versus Gyr and Ongole versus Nellore revealed Pairwise FST differences of 2.85 % and 2.35 %, respectively. Using integrated haplotype score (iHS) method, 4004, 3322, 3437, and 3485 genes were found in Gir, Gyr, Ongole, and Nellore, respectively, underlying top 1 % of selected regions. Under top 1 % of selected regions, FST based method identified1897 genes for the Ongole-Nellore pair and 1966 genes for the Gir-Gyr pair. Runs of homozygosity (ROH) analysis revealed that both recent as well as ancient inbreeding in these breeds were in range of 2.6-4.5 % indicating populations to be less inbred. Numerous candidate genes, including IER5, MILR1 (immunity related traits) in Gir; and FGF12, SV2C, JMY (average daily gain, body size, reproduction related traits) in Ongole, were found under the top-selected regions. Nellore breed had carcass/growth traits (PARP2, and KCNJ11) and genes linked to mammary gland development, udder size, and carcass (MYO16, MYO1B) were found in Gyr. Present findings reveals that Brazilian cattle population (Gyr and Nellore) is more selected for carcass and growth traits along with milk production traits, whereas in Indian cattle population (Gir and Ongole) selection signature related to immunity and adaptation were more prominent. Further, sufficient genetic diversity exist within these cattle breeds for their genetic improvement.

Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event; globally, it is the most common cause of emergency presentations with angioedema. Several genome-wide association studies (GWASs) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWASs from Africa.

The aim of this study was to conduct a GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population.

The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from the Vanderbilt-Marshfield cohort, which consisted of 174 case patients and 489 controls).

No single-nucleotide polymorphisms (SNPs) attained genome-wide significance; however, 26 SNPs in the postimputation standard GWAS of the South African cohort and 73 SNPs in the meta-analysis attained suggestive thresholds (P < 5.0 × 10-06). Some of these SNPs were found to be located close to the genes PRKCQ (protein kinase C theta), RAD51B (RAD51 Paralog B), and RIMS1 (regulating synaptic membrane exocytosis 1), which were previously linked with drug-induced angioedema, and also close to the CSMD1 (CUB and sushi multiple domains 1) gene, which has been linked to ACEI cough, providing replication at the gene level but with novel lead SNPs. The study also replicated SNP rs500766 on chromosome 10, which was previously found to be associated with AE-ACEI.

Our results highlight the importance of African populations for detection of novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.

The development of posttraumatic stress disorder (PTSD) is attributable to the interplay between exposure to severe traumatic events, environmental factors, and biological characteristics. Blood and brain imaging markers have been associated with PTSD. However, to our knowledge, no study has systematically investigated the genetic relationship between PTSD, metabolic biomarkers, and brainwide imaging.

We integrated genome-wide data informative of PTSD, 233 metabolic biomarkers, and 3935 brain imaging-derived phenotypes (IDPs). Pleiotropy was assessed by applying global and local genetic correlation, colocalization, and genetically inferred causality.

We observed significant genetic overlap between PTSD and glycoprotein acetyls (GlycA) (a stable inflammatory biomarker) in 2 independent cohorts (discovery r g = 0.26, p = 1.00 × 10-4; replication r g = 0.23, p = 5.99 × 10-19). Interestingly, there was no genetic correlation between anxiety and GlycA (p = .33). PTSD and GlycA were both genetically correlated with median T2∗ in the left pallidum (IDP-1444: r g = 0.14, p = 1.39 × 10-5; r g = -0.38, p = 2.50 × 10-3, respectively). Local genetic correlation between PTSD and GlycA was observed in 7 genetic regions (p < 2.0 × 10-5), mapping genes related to immune and stress response, inflammation, and metabolic processes. Furthermore, we identified 1 variant, rs12048743, with evidence of horizontal pleiotropy linking GlycA and IDP-1444 (z IDP-1444 = 17.14, z GlycA = -6.07, theta p = 2.06 × 10-8). Regional colocalization was observed among GlycA, IDP-1444, and tissue-specific transcriptomic regulation for brain frontal cortex and testis (rs12048743-chr1q32.1; posterior probability > 0.8). While we also tested causality between PTSD, metabolomic biomarkers, and brain IDPs, these were not consistent across different genetically informed causal inference methods.

Our findings highlight a new putative pleiotropic mechanism that links systemic inflammation and pallidum structure to PTSD.

Hyperglycemia and diabetes may influence GBM progression by altering tumor metabolism and the tumor microenvironment. However, the causal relationship between blood glucose levels and GBM remains unclear.

Mendelian randomization (MR) analysis was performed using GWAS data from the UK Biobank and FinnGen databases, with fasting blood glucose, plasma glucose, cerebrospinal fluid (CSF) glucose, and diabetes as exposures. Single-cell RNA sequencing of GBM mouse models on high-glucose and control diets was conducted to explore the cellular landscape of the tumor microenvironment under hyperglycemic conditions. Additionally, gene set enrichment analysis (GSEA) was performed on transcriptomic data from brain tissues of diabetic patients to assess the activity of GBM-related pathways.

MR analysis demonstrated a significant genetic relationship between elevated fasting blood glucose and GBM risk, with an odds ratio (OR) of 40.991 (95 % CI: 2.066-813.447, p = 0.015). Type 2 diabetes (T2D) also showed a potential causal link with GBM, with the Weighted Median and Inverse Variance Weighted methods yielding ORs of 2.740 (95 % CI: 1.033-7.273, p = 0.043) and 2.100 (95 % CI: 1.029-4.287, p = 0.042), respectively. Single-cell transcriptomic analysis of GBM mouse models revealed an increased proportion of GBM tumor stem cells and pro-tumorigenic M2 macrophages in the high-glucose diet (HGD) group. GSEA of diabetic patient brain tissue revealed heightened activity of GBM-related pathways, particularly in astrocytes, endothelial cells, and neurons.

These findings suggest that hyperglycemia may actively contribute to GBM progression by promoting cellular changes within the tumor microenvironment and activating GBM-related pathways in brain tissues.

The comorbidity between bipolar disorder (BD) and high body mass index (BMI) is well-documented, but their shared genetic architecture remains unclear. Our study aimed to explore this genetic correlation and potential causality.

Utilizing large-scale genome-wide association study (GWAS) summary statistics, we quantified global and local genetic correlations between BD and BMI using linkage disequilibrium score regression (LDSC) and Heritability Estimation from Summary Statistics. Stratified LDSC characterized genetic overlap across functional categories. Cross-trait meta-analyses identified shared risk single nucleotide polymorphisms (SNPs), followed by colocalization analysis using Coloc. Bi-directional Mendelian randomization (MR) assessed causality, while tissue-level SNP heritability enrichment for BD and BMI was evaluated using LDSC-specific expressed genes and Multi-marker Analysis of Genomic Annotation.

We found a genetic correlation between BD and BMI, especially in localized genomic regions. Cross-trait meta-analysis identified 46 significant SNPs shared between BD and BMI, including three novel shared risk SNPs. Colocalization analysis verified two novel SNPs with shared causal variants linked to ITIH1 and TM6SF2 genes. MR analysis demonstrated a causal effect of BD on BMI, but not the reverse. Gene expression data revealed genetic correlation enrichment in five specific brain regions.

This study comprehensively analyzes the genetic correlation between BD and BMI, uncovering shared genetic architecture and identifying novel risk loci. These findings provide new insights into the interplay between BD and BMI, informing the development of diagnostic tools and therapeutic strategies.

The rising prevalence of youth depression underscores the need to identify modifiable factors for prevention and intervention. This study aims to investigate the protective role of Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet on depressive symptoms in adolescents.

Participants were identified from the Adolescent Brain Cognitive Development study. Adherence to the MIND diet was measured by the Child Nutrition Assessment or the Block Kids Food Screener. Depressive symptoms were measured annually using the Child Behavior Checklist's depression subscale. We utilized regression analyses and cross-lagged panel modeling (CLPM) to examine longitudinal associations. Additional analyses adjusted for polygenic risk scores for depression, and changes in Body Mass Index (BMI) and waist-to-height ratio.

Of the 8459 children (52.3 % male; mean age 10.9 [SD, 0.6] years), 2338 (27.6 %) demonstrated high MIND diet adherence, while 2120 (25.1 %) showed low adherence. High adherence was prospectively associated with reduced depressive symptoms (adjusted β, -0.64, 95 % CI, -0.73 to -0.55; p < 0.001) and 46 % lower odds of clinically relevant depression (adjusted odds ratio, 0.54, 95 % CI, 0.39 to 0.75; p < 0.001) at two-year follow-up. CLPM analyses showed significant cross-lag paths from MIND diet scores to less depressive symptoms across three time points. These associations persisted independently of changes in BMI and waist-to-height ratios, and were not significantly moderated by genetic predisposition to depression.

Higher adherence to the MIND dietary pattern was longitudinally associated with decreased risk of depressive symptoms in adolescents. Promoting MIND diet may represent a promising strategy for depression prevention in adolescent populations.

Recent studies have linked branched-chain amino acids (BCAAs) metabolism with the risk of major depressive disorder (MDD). However, it is unclear whether associations of plasma BCAA levels with MDD are causal or driven by reverse causality.

Mendelian randomization (MR) was used to investigate the causal association of genetically determined BCAA levels with the risk of MDD. The large genome-wide association study (GWAS) datasets on plasma BCAA levels (n = 115,051) were obtained from the UK Biobank. The summary GWAS dataset for MDD was obtained from the Psychiatric Genomics Consortium (n = 1,035,760). We applied the inverse variance-weighted (IVW) method to explore the causal relationships between BCAA levels and MDD, followed by multiple pleiotropy and heterogeneity tests.

Our results demonstrated that genetically determined circulating total BCAAs (odds ratio (OR): 1.05, 95 % confidence interval (CI): 1.01-1.10, P = 0.016), leucine (OR: 1.06, 95 % CI: 1.02-1.11, P = 7.22 × 10-3), and isoleucine (OR: 1.08, 95 % CI: 1.01-1.16, P = 0.032) levels were associated with an increased risk of MDD. There was suggestive evidence supporting the causal effect of valine levels on MDD (OR: 1.04, 95 % CI: 1.00-1.08, P = 0.075). Bidirectional MR analysis did not provide evidence of reverse causality.

We report evidence supporting the causal role of BCAAs in the development of MDD. This study offers new insights into the mechanisms and treatment of MDD.

Extracellular lipoprotein aggregation is a critical event in age-related macular degeneration (AMD) pathogenesis. In this study, we sought to analyze associations between clinical and genetic-based factors related to lipoprotein metabolism and risk for AMD in the All of Us research program.

Cross-sectional retrospective data analysis.

A total of 5028 healthy participants and 2328 patients with AMD from All of Us.

Participants with and without AMD were age, race, and sex matched in a 1:2 ratio, respectively. Smoking status, history of hyperlipidemia, and statin use were extracted in a binary manner. Statin use was further subcategorized into hepatically versus nonhepatically metabolized statins. Laboratory values for low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TGs) were also extracted, and outliers were excluded from analysis. The PLINK toolkit was used to extract single nucleotide polymorphisms (SNPs) associated with LDL and HDL dysregulation, as published in prior work. Odds ratio curves were computed to assess the risk between LDL, TG, and HDL versus AMD. All clinical and genetic variables were input into a multivariable logistic regression model, and odds ratios and P values were generated.

Statistical significance of risk factors for AMD, thresholded at P ≤ 0.05.

On multivariable regression analysis, statin use and low and high HDL were significantly associated with increased AMD risk (P < 0.001 for all variables). Additionally, the multivariable regression implicated HDL-associated SNP's increased risk for AMD. Last, LPA was identified (P = 0.007) as a novel SNP associated with increased AMD risk.

There exists a U-shaped relationship between HDL and AMD risk, such that high and low HDL are significantly associated with increased AMD risk. Additionally, SNPs associated with HDL metabolism are associated with AMD risk. This analysis further establishes the role of HDL in AMD pathogenesis.

Proprietary or commercial disclosure may be found after the references.

The fall armyworm (Spodoptera frugiperda, FAW) is one of the most devastating invasive pests in the world, owing to its extraordinary migration performance. Research has clarified the migratory pathways and external environmental factors affecting FAW migration. However, the internal genes and loci regulating migration or reside in FAW remain largely unknown.

In this study, we used a tethered flight mill system to distinguish migratory and resident individuals, which exhibit significant differences in flight-related traits such as flight distance, duration, and maximum speed. Selective sweep analysis of 51 resequencing FAW (23 migratory and 28 resident individuals) identified 652 candidate genes, and genome-wide association analysis (GWAS) identified 79 functional annotated genes associated with the most significant trait, flight distance. These candidate genes were mainly concentrated in amino acid metabolism, signal transduction, and environmental adaptation. The neuroendocrine convertase 2 gene was crossed between the two analyses, with 65 selective mutation loci in the intron region. Casein kinase I, which reported regulating circadian rhythm by phosphorylating the period, was simultaneously involved in several enriched signaling pathways, and had 11 selective loci in the regulatory region. These selective mutation loci may affect the expression of target genes and regulate the migration behavior of FAW.

Key loci and genes may determine the migration behavior of FAW by regulating the circadian rhythm and other signaling pathways. These findings provide a new perspective for elucidating the internal driving mechanism of migratory insects, and provide a new possibility for developing eco-friendly control strategies for migratory pests. © 2025 Society of Chemical Industry.

Plant interactions with abiotic and biotic environments are mediated by diverse metabolites, which are crucial for stress response and defense. These metabolites can not only support diversity by shaping species niche differences but also display heritable and plastic intraspecific variation, which few studies have quantified in terms of their relative contributions. To address this shortcoming, we used untargeted metabolomics to annotate and quantify foliar metabolites and restriction-site associated DNA (RAD) sequencing to assess genetic distances among 300 individuals of 10 locally abundant species from a diverse tropical community in Southwest China. We quantified the relative contributions of relatedness and the abiotic and biotic environment to intraspecific metabolite variation, considering different biosynthetic pathways. Intraspecific variation contributed most to community-level metabolite diversity, followed by species-level variation. Biotic factors had the largest effect on total and secondary metabolites, while abiotic factors strongly influenced primary metabolites, particularly carbohydrates. The relative importance of these factors varied widely across different biosynthetic pathways and different species. Our findings highlight that intraspecific variation is an essential component of community-level metabolite diversity. Furthermore, species rely on distinct classes of metabolites to adapt to environmental pressures, with genetic, abiotic, and biotic factors playing pathway-specific roles in driving intraspecific variation.

The repeated evolution of herbicide resistance in agriculture provides an unprecedented opportunity to understand how organisms rapidly respond to strong anthropogenic-driven selection pressure. We recently identified agricultural populations of the grass species Bromus tectorum L. with resistance to multiple herbicides. To understand the evolutionary origins and spread of resistance, we investigated the resistance mechanisms to acetolactate synthase (ALS) inhibitors and photosystem II inhibitors, two widely used herbicide modes of action, in 49 B. tectorum populations. We assessed the genetic diversity, structure and relatedness in a subset of 21 populations. Resistance to ALS inhibitors was associated with multiple nonsynonymous mutations in ALS, the target site gene, despite the relatively small geographic region where populations originated, suggesting ALS inhibitor resistance evolution occurred multiple times in the region. We also found evidence that mechanisms not related to the target site evolved and were common in the populations studied. Resistance to photosystem II inhibitors was confirmed in two populations and was conferred by nonsynonymous mutations in the plastid gene psbA. Population genomics analyses suggested that ALS resistance in most populations, at the nucleotide level, spread via gene flow, except for one population where we found evidence that Pro-197-His mutations may have evolved in three separate events. Our results suggest that both gene flow via pollen and/or seed dispersal and multiple local evolutionary events were involved in the spread of herbicide-resistant B. tectorum. Our results provide an empirical example of the rapid repeated evolution of a trait under strong anthropogenic selection and elucidate the evolutionary origins of herbicide resistance in a plant species of agricultural importance.

NAT2 polymorphisms affect isoniazid metabolism, but their effect on mortality among individuals with tuberculosis (TB) remains unclear.

This study used data from two TB cohorts (2005-2011, 2014-2020) and death certificate records in Thailand. Newly diagnosed Thai individuals treated with isoniazid-containing regimens were included. NAT2 genotypes-rapid, intermediate, and slow acetylator (RA, IA, SA)-were classified via haplotype inference. The primary outcome was 1-year all-cause mortality, while secondary outcomes included TB-related mortality, TB+respiratory disease-related mortality recorded in the vital registration system, and death as a TB treatment outcome. Adjusted hazard ratios (aHRs) relative to the IA type were estimated using stratified Cox proportional hazards models. Subgroup analyses targeted individuals with isoniazid-resistant TB and HIV infection.

A total of 1,065 individuals (766 males; mean age=51 years) were analyzed. Individuals with RA had a 1.70-fold greater all-cause mortality risk (95 % CI: 1.03-2.80) than IA. The aHRs for RA were 1.14 (0.43-3.03) for TB-related mortality, 1.59 (0.80-3.18) for TB+respiratory disease-related mortality, and 1.26 (0.67-2.37) for TB treatment outcome death. Among individuals with isoniazid-resistant TB, those with RA had a 4.68-fold (1.14-19.12) greater aHR for all-cause mortality.

The RA type is associated with increased 1-year all-cause mortality.

The Fuzhou cattle breed, native to northeast China, is widely recognized for its adaptability, disease resistance, and docility. Despite being known for these qualities, its population has declined recently, and there is a significant lack of genomic studies on this species. We sequenced 21 samples from a primary breeding farm to determine the genetic structure, diversity, and selection signature to address this. Additionally, we combined 100 published genomic datasets from diverse geographical regions to characterize the genomic variation of Fuzhou cattle. There were 53 752 978 bi-allelic SNPs retained for downstream analysis. In population structure analysis, Fuzhou cattle show a predominantly East Asian taurine ancestry, with strong genetic affinities to Hanwoo and Yanbian cattle. Despite high nucleotide diversity within the Bos taurine lineage, genetic diversity analysis also revealed significant levels of inbreeding in Fuzhou cattle populations, indicating the need for conservation. Utilizing various methods such as θπ, iHS, FST, π-ratio, and XP-EHH, we identified genes associated with traits like growth, meat quality, energy metabolism, and immunity. Several genes related to cold adaptation were identified, including PLIN5, PLB1, and CPT2. These findings provide a basis for conservation strategies to safeguard the genetic resources of Fuzhou cattle.

We describe FoundHaplo, an identity-by-descent algorithm that can be used to screen untyped disease-causing variants using single nucleotide polymorphism (SNP) array data. FoundHaplo leverages knowledge of shared disease haplotypes for inherited variants to identify those who share the disease haplotype and are, therefore, likely to carry the rare [minor allele frequency (MAF) ≤ 0.01%] variant. We performed a simulation study to evaluate the performance of FoundHaplo across 33 disease-harbouring loci. FoundHaplo was used to infer the presence of two rare (MAF ≤ 0.01%) pathogenic variants, SCN1B c.363C>G (p.Cys121Trp) and WWOX c.49G>A (p.E17K), which can cause mild dominant and severe recessive epilepsy, respectively, in the Epi25 cohort and the UK Biobank. FoundHaplo demonstrated substantially better sensitivity at inferring the presence of these rare variants than existing genome-wide imputation. FoundHaplo is a valuable screening tool for searching disease-causing variants with known founder effects using only SNP genotyping data. It is also applicable to nonhuman applications and nondisease-causing traits, including rare-variant drivers of quantitative traits. The FoundHaplo algorithm is available at https://github.com/bahlolab/FoundHaplo (DOI:10.5281/zenodo.8058286).

In response to global climate change, numerous taxa are expanding their living ranges. In highly migratory species such as sea turtles, this expansion may be driven by individuals from nearby or distant areas. Recent nests outside the species' typical nesting range and reports of adult-sized individuals in the western Mediterranean suggest a green turtle (Chelonia mydas) range expansion into the central and western Mediterranean. To assess the green turtles' origin in these novel habitats, we built a genomic baseline using 2bRAD sequencing on five individuals from each of three Regional Management Units (RMUs): North Atlantic, South Atlantic and Mediterranean. We then compared this baseline with genotyped hatchlings from three nests laid in new central and eastern Mediterranean sites and four mature-sized green turtles tagged with satellite telemetry in the western Mediterranean. Our analyses revealed that the Tunisia nest originated from the South Atlantic RMU, while the Crete nests were produced by turtles from the Mediterranean RMU. Additionally, the three adult-sized turtles sampled in the southwestern Mediterranean were assigned to the South Atlantic RMU, while the mature-sized individual sampled in the northwestern Mediterranean belonged to the Mediterranean RMU. These results suggest a simultaneous incipient colonisation by two geographically distant RMUs. We propose that the range expansion of green turtles into the central and western Mediterranean is likely climate driven and these populations may become globally important as temperatures rise. Finally, our results highlight the essential role of the cost-effective RAD-Seq genomic assessment combined with tagging data to understand potential new colonisations.

Improving calf health on dairy farms contributes to animal welfare and business productivity gains. In recent years, traditional genetic evaluations have broadened to include cow health traits that have economic importance. Calf health is a new frontier to explore, but new traits require sufficient data to be effectively evaluated. Researchers who work in countries without obligatory recordkeeping systems, commonly promote the need to significantly improve recordkeeping practices to enable research, benchmarking, and genetic evaluation, as is the case in Australia. The aim of this study was to estimate variance components for novel calf traits using a dataset that was co-designed with farmers and included calf identity, calving ease, health records, and genotypes. Almost 20,000 calf records from more than 50 farms located throughout Australia were collected between 2020 and 2023. In Holstein calves, the mean ± SE prevalence of preweaning mortality (PWM) and scours, were 0.020 ± 0.001 and 0.059 ± 0.002, respectively. A newly defined and subjectively scored trait called calf vitality was co-developed with farmers, where 21% of calves were classed in the top category of vigorous or "ripper," 54% were good or average, 6% were "duds," and 19% of scored calves died. Univariate linear models that included a genomic relationship matrix were used to estimate variance components for diseases and vitality, where h2 values were between 1% and 11% in Holsteins, depending on the trait. The models included herd-year-season, sex, parity group, and calving ease (Holstein only) as fixed effects and these were found to be significant for most breed and trait combinations. The estimated reliability of EBVs ranged between 0.2 and 0.3. In Australia, Holsteins are more numerous than the Jersey breed, and so despite efforts to compile an appropriate dataset, the disease prevalence and record numbers were too low to report genetic variance for calf health traits in the Jersey breed. Approximate genetic correlations with other calf health traits such as stillbirth and PWM were modest but favorable. There were few significant correlations with lactating cow traits (such as survival, SCC, and likeability) and national selection indexes that are routinely evaluated in Australia and those that were significant were in a favorable direction.

Cannabis (Cannabis sativa L.), once sidelined by decades of prohibition, has now gained recognition as a multifaceted and promising plant in both medical research and commercial applications following its recent legalization. This study leverages a genome-wide association study (GWAS) on 174 drug-type Cannabis accessions from the legal Canadian market, focusing on identifying quantitative trait loci (QTL) and candidate genes associated with eleven cannabinoid traits using 282K common single-nucleotide polymorphisms. This approach aims to transform our understanding of Cannabis genetics. We have pinpointed 33 significant markers that significantly influence cannabinoid production, promising to drive the development of Cannabis varieties with specific cannabinoid profiles. Among the notable findings is a massive haplotype of ∼60 Mb on chromosome 7 in Type I (i.e., tetrahydrocannabinol [THC]-dominant) accessions, highlighting a major genetic influence on cannabinoid profiles. These insights offer valuable guidance for Cannabis breeding programs, enabling the use of precise genetic markers to select and refine promising Cannabis varieties. This approach promises to speed up the breeding process, reduce costs significantly compared to traditional methods, and ensure that the resulting Cannabis varieties are optimized for specific medical and recreational needs. This study marks a significant stride toward fully integrating Cannabis into modern agricultural practices and genetic research, paving the way for future innovations.

This study offers insight into the genetic complexity of the interaction between production and reproduction in German dairy cows. The phenotypes and genotypes of 32,352 primiparous German Holstein cows were available for investigation, and datasets (DS) of similar size were generated according to their milk yield. Five distinct DS, each including more than 6,400 animals, from lowest to highest milk yield (DSLowest, DSLow, DSMean, DSHigh, DSHighest) were included for subsequent analysis. Heritabilities and genetic correlations (rG) between traits were estimated, followed by GWAS. The overall heritability estimates were relatively low, with a maximum of h2 = 0.127 for ovary cycle disturbances in DSHighest and a minimum of h2 = 0.026 for retained placenta (NGV) in the complete DS. The rG between milk yield and reproduction traits exhibited a range from rG = -0.436 between milk yield and metritis (MET) in DSHigh to rG = 0.435 between milk yield and NGV in DSHigh. Genetic correlations between the various reproduction traits were moderate, as evidenced by the correlation between calving ease maternal (CEm) and MET in DSHigh (rG = 0.329). In contrast, a striking divergence within the specific traits was evident contingent on the performance subset. The range of rG between CEm and NGV was covered from rG = -0.146 in DSLowest up to rG = 0.318 in DSHighest. The heritabilities and rG estimates did not demonstrate a straightforward linear relationship between milk yield and the analyzed reproduction parameters. Moreover, GWAS identified several significant SNPs across the various DS, with a total of 86 genome-wide and chromosome-wide signals. These findings led to the identification of previously described genes in the context of reproduction, as well as the postulation of additional potential candidate genes, including a high number of zinc finger proteins. Overall, this study provides important insights into the genetic background and interrelations of reproduction traits with special regards to the nonlinear relationship between milk yield and reproduction, and the findings may help to further improve selection decisions.

Rare variants in the MYOC gene are associated with glaucoma risk, with p.Gln368Ter the most common pathogenic variant in Europeans. Genetics-based risk stratification may aid with early diagnosis for glaucoma but it is unclear how best to combine the p.Gln368Ter status with polygenic risk scores (PRS). Our study aimed to examine approaches for identifying p. Gln368Ter carriers using genotyping array data and the utility of integrating p.Gln368Ter status into glaucoma PRS.

Retrospective cohort study.

We identified p.Gln368Ter carriers using directly genotyped and imputed data. Results were confirmed in a subset with sequencing data. We evaluated the combined effects of p.Gln368Ter status and PRS in stratified analyses by considering them as two separate factors and as an aggregate score.

A total of 58,452 participants from the Genetics of Glaucoma, the QSkin Sun and Health Study (QSKIN), and CARTaGENE projects, including 6015 with sequencing data.

The concordance of direct genotyping, compared with imputation and sequencing for p.Gln368Ter identification.

Without appropriate quality control, substantial mis-calling may occur. Nevertheless, the p.Gln368Ter variant could be accurately genotyped in most cases by filtering individuals for call rate and heterozygosity. In 6015 individuals with sequencing data, direct genotyping exhibited perfect concordance with sequencing results. Filtered direct genotyping results showed high agreement with imputed results, with only 16 discrepancies among 57,468 individuals. When quality control is not possible (eg, heterozygosity filtering for an individual), we recommend comparing genotyped and imputed results to ensure accuracy. Incorporating p.Gln368Ter into PRS had additional effects on stratifying high-risk individuals, but did not improve risk prediction for the general population given the variant's rarity. The MYOC-enhanced PRS increased the proportion of p.Gln368Ter carriers classified as high risk from 32.31% to 75.38% in QSKIN and from 38.24% to 79.41% in CARTaGENE.

The p.Gln368Ter variant can be genotyped with high accuracy using array data, provided careful quality control measures are implemented. Incorporating p.Gln368Ter into glaucoma PRS improved risk stratification for carriers.

Schizophrenia (SCZ) is a severe mental disorder affecting around 1% of individuals worldwide. The variability in response to antipsychotic drugs (APDs) among SCZ patients presents a significant challenge for clinicians in determining the most effective medication. In this study, we investigated the biological markers and established a predictive model for APD response based on a large-scale genome-wide association study using 3269 Chinese schizophrenia patients. Each participant underwent an 8-week treatment regimen with one of five mono-APDs: olanzapine, risperidone, aripiprazole, quetiapine, or amisulpride. By dividing the response into ordinal groups of "high", "medium", and "low", we mitigated the bias of unclear treatment outcome and identified three novel significantly associated genetic loci in or near CDH12, WDR11, and ELAVL2. Additionally, we developed predictive models of response to each specific APDs, with accuracies ranging from 79.5% to 98.0%. In sum, we established an effective method to predict schizophrenia patients' response to APDs across three categories, integrating novel biomarkers to guide personalized medicine strategies.

As an important noncereal food crop grown worldwide, the genetic improvement of potato in tuber yield and quality is largely constrained due to the lacking of a high-quality reference genome and understanding of the regulatory mechanism underlying the formation of superior alleles. Here, a chromosome-scale haplotype-resolved genome assembled from an anther-cultured progeny of 'Ningshu 15', a tetraploid variety featured by its high starch content and drought resistance was presented. The assembled genome size was 1.653 Gb, with a contig N50 of approximately 1.4 Mb and a scaffold N50 of 61 Mb. The long terminal repeat assembly index score of the two identified haplotypes of 'Ningshu 15' was 11.62 and 11.94, respectively. Comparative genomic analysis revealed that positive selection occurred in gene families related to starch, sucrose, fructose and mannose metabolism, and carotenoid biosynthesis. Further genome-wide association study in 141 accessions identified a total number of 53 quantitative trait loci related to fructose, glucose, and sucrose content. Among them, a tonoplast sugar transporter encoding gene, StTST2, closely associated with glucose content was identified. Constitutive expression of StTST2 in potato and Arabidopsis increased the photosynthetic rate, chlorophyll and sugar content, biomass tuber and seed production in transgenic plants. In addition, co-immunoprecipitation assays demonstrated that StTST2 directly interacted with SUT2. Our study provides a high-quality genome assembly and new genetic locus of potato for molecular breeding.

One of the most intractable problems in bamboo systematics concerns the three-branched bamboos of tribe Arundinarieae (Poaceae: Bambusoideae), which are collectively characterized by having three branches per mid-culm node. Previous phylogenetic studies based on double-digest restriction-site associated DNA sequencing (ddRAD-seq) data confirmed that Oligostachyum, a member of this group, is non-monophyletic, and in particular that Oligostachyum oedogonatum is a problematic species deserving further attention, as it appears to be morphologically and phylogenetically distinct from the other three-branched bamboos. Here we aim to define and confirm the phylogenetic position of O. oedogonatum, by including representatives from across its geographic range. We also provide new insights into the overall phylogeny of the three-branched bamboos and closely related genera, using multiple phylogenomic datasets. While a plastid genome-based tree is very poorly supported, phylogenies inferred using two sets of conserved nuclear genes and single nucleotide polymorphism (SNP) data yield generally well-supported and congruent topologies using coalescent-based approaches. The tree inferred from the largest concatenated gene set is the most dissimilar to other inferences. The nuclear-based data sets all recover a major clade that includes all of the three-branched bamboos and four other genera, which can be distinguished from related taxa due to their possession of three stigmas per floret and leptomorph rhizomes. Notably, eight O. oedogonatum samples form a clade that is distantly related to other members of Oligostachyum, including the type species of the genus (Oligostachyum sulcatum). Population genetic approaches and multi-species coalescent-based analysis of the nuclear data sets imply that seven of these populations can be treated as a single species, O. oedogonatum, but that one population from Jinggangshan is likely an intergeneric hybrid between O. oedogonatum and Pleioblastus. Morphologically, O. oedogonatum differs from all other three-branched bamboos, in having strongly asymmetrically swollen supra-nodal ridges, a laterally compressed spikelet, and rachilla segments that disarticulate readily below fertile florets. Because of its morphological distinctiveness and molecular phylogenetic position, we propose that this taxon should be reinstated as Clavinodum oedogonatum. We provide a new description for this monotypic genus here.

A healthy uterine environment is essential for establishing and maintaining pregnancy and normal embryo development after insemination. In this context, the primary objectives of this study were to assess the genetic background of vaginal discharge score (VDS) traits during the voluntary waiting period in Holstein cows and to identify genomic regions and candidate genes influencing postpartum uterine health based on the integration of phenotypic, genomic, and transcriptomic datasets. Genetic parameters of 5 VDS traits defined according to lactation stage (VDS1, VDS2, VDS3, VDS4, and VDS5) were estimated based on VDS records from 64,241 Holstein cows that calved between 2019 and 2023 and genomic information from 2,489 cows. The GWAS were performed aiming to identify genomic regions associated with VDS traits. Differentially expressed genes and modular genes were obtained through RNA sequencing (RNA-seq) data of uterine secretion from 6 healthy and 6 diseased cows. The VDS traits had low-h2 estimates ranging from 0.006 ± 0.002 to 0.081 ± 0.011. Among the VDS traits, there were relatively strong genetic correlations between VDS1 (0-14 DIM) and metritis (0.678-0.763), as well as VDS3 (29-55 DIM) and endometritis (0.579-0.628). A total of 190 genes harboring 32 significant SNPs were identified as candidate genes regulating VDS in primiparous cows. The candidate genes identified were significantly enriched for pathways involved in cytokine-cytokine receptor interaction, mitogen-activated protein kinase signaling, and oxytocin signaling. Based on RNA-seq data of uterine secretions, 2,803 differentially expressed genes and 3,570 modular genes were identified. Furthermore, 7 genes were identified based on GWAS, differential gene expression, and weighted gene coexpression network analysis. The VSTM1, IL10RA, FXYD5, C2CD5, CETN4, ALS2CL, and PBX1 genes were considered to be the most promising candidate genes influencing postpartum uterine health in Holstein cows. This study provides novel insights on the genetic background of postpartum uterine health in Holstein cows. The results obtained can contribute to further refinements of selection indexes for improving uterine health and fertility in dairy cattle.

Dermacentor silvarum (D. silvarum) is an arthropod that feeds on blood. It is a primary tick species found in northern China that poses a significant security risk to the health and life of the host, as it has the potential to transmit a variety of pathogens to humans and animals. Through ongoing research on tick genome sequences, researchers have successfully assembled and reported reference genomes for numerous tick species. These significant advances have greatly accelerated the study of tick biology and population genomics. D. silvarum samples were obtained from the body surface of free-range goats in Yulin, Shaanxi Province, China. The whole genomes of the samples were resequenced and merged with preexisting data from the National Genomics Data Center database (project ID: PRJCA002242) to analyze the genetic structure, genetic diversity, mitochondrial genetic structure, and selection signatures of D. silvarum in the Shaanxi Province. Based on the available data, the D.silvarum species in China could be classified into two main branches. These populations exhibited low nucleotide diversity. A slight discrepancy was noted between the mitochondrial phylogenetic tree and the autosomal whole-genome phylogenetic tree of D. silvarum, consistent with a previous study. In the selected analysis of D. silvarum in the Shaanxi Province, China, genes linked to immunity, iron storage, fatty acid biosynthesis, pesticide defense, and blood digestion were identified. Leutriene A4 hydrolase (LOC119466376) was also identified, although its function remains unknown. This information is crucial for understanding the biology of D. silvarum and developing management measures.

L-asparaginase is essential in treating pediatric acute lymphoblastic leukemia (ALL) but is limited by hypersensitivity reactions in up to 70% of patients, leading to severe, dose-limiting complications and compromised event-free survival.

This study conducted a genome-wide association study (GWAS) in a discovery cohort of 221 pediatric cancer patients who experienced l-asparaginase-induced hypersensitivity reactions (≥CTCAE grade 2) and 705 controls without hypersensitivity despite equivalent exposure. Results were replicated in an independent cohort of 41 cases and 139 controls.

Significant associations were identified between hypersensitivity and four genes crucial for amino acid stress response: CYP1B1 (rs59569490; odds ratio [OR]  =  8.5; 95% confidence interval [CI], 3.9-18.5; p  =  1.5 × 10-10), SEC16B (rs115461320; OR  =  4.2; 95% CI, 2.5-7.9; p  =  1.2 × 10-6), OPLAH (rs11993268; OR  =  4.8; 95% CI, 2.4-9.9; p  =  2.0 × 10-6), and SORCS2 (rs11940340; OR  =  6.7; 95% CI, 2.8-15.7; p  =  5.7 × 10-7). Variants in SEC16B, OPLAH, and SORCS2 remained significant in the analysis of the replication cohort (p < 0.05). Patients who carried risk alleles in two or more of these genes experienced an 86.4% increased incidence of hypersensitivity reactions in the discovery cohort (OR  =  25.2; 95% CI, 7.4-86.2; p  =  1.0 × 10-10), which was replicated in the independent cohort with a 100% incidence in carriers (p  =  0.04).

The cumulative incidence of these large effect variants highlights their significance for the identification of patients at high risk of l-asparaginase-induced hypersensitivity. Successfully identifying patients at increased risk of hypersensitivity reactions can inform personalized treatment strategies and limit these harmful dose-limiting reactions in pediatric ALL.

This study explores the genetic and epidemiologic correlates of long-term photoplethysmography-derived pulse rate variability (PRV) measurements with anxiety disorders. Individuals with whole-genome sequencing, Fitbit, and electronic health record data (N = 920; 61,333 data points) were selected from the All of Us Research Program. Anxiety polygenic risk scores (PRS) were derived with PRS-CS after meta-analyzing anxiety genome-wide association studies from three major cohorts- UK Biobank, FinnGen, and the Million Veterans Program (NTotal =364,550). PRV was estimated as the standard deviation of average five-minute pulse wave intervals over full 24-hour pulse rate measurements (SDANN). Antidepressant exposure was defined as an active antidepressant prescription at the time of the PRV measurement in the EHR. Anxiety PRS and antidepressant use were tested for association with daily SDANN. The potential causal effect of anxiety on PRV was assessed with one-sample Mendelian randomization (MR). Anxiety PRS was independently associated with reduced SDANN (beta = -0.08; p = 0.003). Of the eight antidepressant medications and four classes tested, venlafaxine (beta = -0.12, p = 0.002) and bupropion (beta = -0.071, p = 0.01), tricyclic antidepressants (beta = -0.177, p = 0.0008), selective serotonin reuptake inhibitors (beta = -0.069; p = 0.0008) and serotonin and norepinephrine reuptake inhibitors (beta = -0.16; p = 2×10-6) were associated with decreased SDANN. One-sample MR indicated an inverse effect of anxiety on SDANN (beta = -2.22, p = 0.03). Anxiety and antidepressants are independently associated with decreased PRV, and anxiety appears to exert a causal effect on reduced PRV. Those observational findings provide insights into the impact of anxiety on PRV.

ADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity in adgrl3.1-/- zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.

Adipocytokines, including leptin, adiponectin, and resistin, are key mediators linking adiposity, insulin resistance, and inflammation. We present the first genome-wide association study (GWAS; N = 5258) and exome-wide association study (ExWAS; N = 4578) on leptin, adiponectin, and resistin in South Asian population. We identified novel associations in genes ZNF467, and LEPREL2 for leptin; ZNF467, LEPREL2, CRLF3, ZNF732, SOX30, XIRP1, ATP8B3, SPATA2L, TMCO4, TLN2, ABCA12, and SHB for adiponectin; and D2HGDH for resistin. Additionally, we confirmed known associations of FTO, MC4R, and HOXB3 with leptin and ADIPOQ with adiponectin. Notably, ADIPOQ variants were consistently significant across GWAS, ExWAS, and gene-based analyses, reinforcing their central role in regulating adiponectin levels. Most of these novel associations identified were population-specific, highlighting the importance of studying diverse populations to uncover unique genetic signals. After adjusting for BMI, the associations with adiponectin and resistin remained significant, whereas most associations for leptin weakened in both effect size and significance. Functional annotation revealed that the identified variants were enriched for expression in adipose tissue, the brain (cerebellar hemisphere and cerebral cortex), and the pituitary gland. These variants act as eQTLs and splice-QTLs in adipose, brain, and pancreas, suggesting cross-tissue regulatory mechanisms. ExWAS further implicated rare variant burden in genes such as LONP1, ZNF335, and TTC16 for adiponectin and resistin. These findings enhance our understanding of adipocytokine biology, emphasises the need for population-specific genetic research, and lays foundation for future functional studies.

Genome-wide association has identified regions of the genome that mediate risk for psychosis. It is possible that variants in these regions confer risk by altering gene expression. This work has predominantly been conducted in individuals of European descent and has focused narrowly on schizophrenia rather than psychosis as a syndrome. In the present study we investigated alterations in gene expression in African American individuals with a range of psychotic diagnoses to increase understanding of the etiology in an underserved population. We performed RNA-seq in whole bloody to survey the transcriptome in 126 patients with a psychosis-spectrum disorder and 217 healthy controls and applied differential gene expression analyses across the genome while controlling for age, sex, population stratification and batch. We found 18 differentially expressed genes (DEGs), some of the locations of the corresponding genes overlap with previously implicated regions for psychosis, but many of which were novel associations. Enrichment analysis of nominally significant genes (p < 0.05) revealed overrepresentation of biological processes relating to platelet, immune and cellular function, and sensory perception. Weighted gene co-expression network analysis, applied to identify modules of co-expressed genes associated with psychosis, revealed 10 modules, one of which was significantly associated with psychosis. This module was significantly enriched for DEGs, and for platelet function. These results support the potential role of immune function in the etiology of psychosis, identify novel candidate gene expression phenotypes that correspond to both established and new genomic regions, in individuals of African American ancestry.

The production of VLDL is one of the primary mechanisms through which liver cells regulate intracellular lipid homeostasis. We hypothesize that the disease characteristics of metabolic dysfunction-associated steatotic liver disease (MASLD) differentially impact VLDL lipid composition. This study comprehensively examines the relationship between VLDL-lipidome and MASLD histology and disease-associated genetics, aiming to define MASLD-related VLDL changes.

We performed untargeted lipidomics on serum VLDL particles in a cohort of biopsy-proven MASLD patients to examine the relationship between VLDL-lipidome and MASLD disease features as well as MASLD-related genetic variants.

Among 1514 detected lipid species in VLDL, triglyceride (TG), phosphatidylcholine (PC), and ceramide (Cer) were the top classes. Moderate to severe hepatic steatosis was associated an increase in VLDL-TG, especially those with palmitic acid (C16:0). A unified acyl chain distribution analysis revealed that steatosis was associated with increases in TGs with saturated and monounsaturated fatty acyl chains, but decreases in polyunsaturated fatty acyl chains, a pattern that was not mirrored in acyl chains from VLDL-PC or VLDL-Cer. Lobular inflammation was associated with reductions in lipids with polyunsaturated acyl chains, particularly docosahexaenoic acid (C22:6). Meanwhile, patients with advanced liver fibrosis (stages 3-4) had reductions in VLDL-TGs with both saturated and polyunsaturated acyl chains and overall enrichment in Cer species. Furthermore, MASLD-associated genetic variants in PNPLA3, TM6SF2, GPAM, HSD17B13, and MTARC1 demonstrated distinct VLDL-lipidomic signatures in keeping with their biology in lipoprotein metabolism.

Hepatic steatosis and liver fibrosis in MASLD are associated with distinct VLDL-lipidomic signatures, respectively. This relationship is further modified by MASLD-genetics, suggesting a differential impact of pathogenic features on hepatocellular lipid homeostasis.