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bioRxiv2019

Genetic underpinnings of sociability in the UK Biobank

Difficulties with sociability include a tendency to avoid social contacts and activities, and to prefer being alone rather than being with others. While sociability is a continuously distributed trait in the population, decreased sociability represent a common early manifestation of multiple neuropsychiatric disorders such as Schizophrenia (SCZ), Bipolar Disorder (BP), Major Depressive Disorder (MDD), Autism Spectrum Disorders (ASDs), and Alzheimers disease (AD). We aimed to investigate the genetic underpinnings of sociability as a continuous trait in the general population. In this respect, we performed a genome-wide association study (GWAS) using a sociability score based on 4 social functioning-related self-report questions in the UK Biobank sample (n=342,461) to test the effect of individual genetic variants. This was followed by LD score analyses to investigate the genetic correlation with psychiatric disorders (SCZ, BP, MDD, ASDs) and a neurological disorder (AD) as well as related phenotypes (Loneliness and Social Anxiety). The phenotypic data indeed showed that the sociability score was decreased in individuals with ASD, (probable) MDD, BP and SCZ, but not in individuals with AD. Our GWAS showed 604 genome-wide significant SNPs, coming from 18 independent loci (SNP-based h2=0.06). Genetic correlation analyses showed significant correlations with SCZ (rg=0.15, p=9.8e-23), MDD (rg=0.68, p=6.6e-248) and ASDs (rg=0.27, p=4.5e-28), but no correlation with BP (rg=0.01, p=0.45) or AD (rg=0.04, p=0.55). Our sociability trait was also genetically correlated with Loneliness (rg=0.45, p=2.4e-8) and Social Anxiety (rg=0.48, p=0.002). Our study shows that there is a significant genetic component to variation in population levels of sociability, which is relevant to some psychiatric disorders (SCZ, MDD, ASDs), but not to BP and AD.

genetics↗

bioRxiv2019

Genome-wide association study identifies 49 common genetic variants associated with handedness.

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the worlds largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5x10-8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% - 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% - 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 - 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

genetics↗

bioRxiv2019

Estimating genetic inheritance in case-control studies

Case-control genetic association study is an efficient tool to search for the deleterious genetic variants predispose to human complex diseases, where the additive mode of inheritance is commonly assumed. However, how the genetic variants influence the occurrence of a certain disease is impossible to know beforehand. We show numerically that the existing procedures using the Hardy-Weinberg equilibrium test to choose the genetic model might be inconsistent. We propose a new method to choose the genetic model by adopting co-dominant code for risk allele and logistic regression model. Extensive computer simulation results demonstrate superiorities of the new method. Applications to six single nucleotide polymorphisms(SNPs) for breast cancer and eight SNPs for Type 2 Diabetes further show good performances of proposed method. In order to specify a genetic model for an allele, our method has some merits and is consistent as sample size is large. We propose to apply our method in related fields.

genetics↗

bioRxiv2019

Impute.me: an open source, non-profit tool for using data from DTC genetic testing to calculate and interpret polygenic risk scores.

To date, interpretation of genomic information has focused on single variants conferring disease risk, but most disorders of major public concern have a polygenic architecture. Polygenic risk scores (PRS) give a single measure of disease liability by summarising disease risk across hundreds of thousands of genetic variants. They can be calculated in any genome-wide genotype data-source, using a prediction model based on genome-wide summary statistics from external studies. As genome-wide association studies increase in power, the predictive ability for disease risk will also increase. While PRS are unlikely ever to be fully diagnostic, they may give valuable medical information for risk stratification, prognosis, or treatment response prediction. Public engagement is therefore becoming important on the potential use and acceptability of PRS. However, the current public perception of genetics is that it provides Yes/No answers about the presence/absence of a condition, or the potential for developing a condition, which in not the case for common, complex disorders with of polygenic architecture. Meanwhile, unregulated third-party applications are being developed to satisfy consumer demand for information on the impact of lower risk variants on common diseases that are highly polygenic. Often applications report results from single SNPs and disregard effect size, which is highly inappropriate for common, complex disorders where everybody carries risk variants. Tools are therefore needed to communicate our understanding of genetic predisposition as a continuous trait, where a genetic liability confers risk for disease. Impute.me is one such a tool, whose focus is on education and information on common, complex disorders with polygenetic architecture. Its research-focused open-source website allows users to upload consumer genetics data to obtain PRS, with results reported on a population-level normal distribution. Diseases can only be browsed by ICD10-chapter-location or alphabetically, thus prompting the user to consider genetic risk scores in a medical context of relevance to the individual. Here we present an overview of the implementation of the impute.me site, along with analysis of typical usage-patterns, which may advance public perception of genomic risk and precision medicine.

genetics↗

bioRxiv2019

The amplification of genetic factors for early vocabulary during children's language and literacy development

The heritability of language and literacy skills increases during development. The underlying mechanisms are little understood, and may involve (i) the amplification of early genetic influences and/or (ii) the emergence of novel genetic factors (innovation). Here, we use multivariate structural equation models to quantify these processes, as captured by genome-wide genetic markers. Studying expressive and receptive vocabulary at 38 months and subsequent language, literacy and cognitive skills (7-13 years) in unrelated children (ALSPAC: N[≤]6,092), we found little support for genetic innovation during mid-childhood and adolescence. Instead, genetic factors for early vocabulary, especially those unique to receptive skills, were amplified. Explaining as little as 3.9%(SE=1.8%) variation in early language, the same genetic influences accounted for 25.7%(SE=6.4%) to 45.1%(SE=7.6%) variation in verbal intelligence and literacy skills, but also performance intelligence, capturing the majority of SNP-heritability ([≤]99%). This suggests that complex verbal and non-verbal cognitive skills originate developmentaly in early receptive language.

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bioRxiv2025

Prevalence, distribution, and mechanisms of genetic dominance in the yeast mating pathway

The proportion of mutations that are dominant is a fundamental genetic parameter affecting the rate of adaptation, the efficacy of selection, and the maintenance of variation in populations. Yet, estimates for this parameter vary greatly. Here we directly quantify the rates and genetic targets of dominant and recessive mutations in the yeast mating pathway by performing parallel genetic screens in haploid (MATa) and diploid (MATa/a) yeast. We find that [~]1% of alpha-factor resistant mutations are dominant. We sequenced 95 alpha-factor resistant mutants to determine the genetic architecture of dominant and recessive mutations. We find recessive mutations throughout the mating pathway; however, dominant mutations are concentrated in three genes: STE4, GPA1, and CLN3. Finally, we investigate the mechanism of genetic dominance in each of these genes. This work sheds light on the prevalence and molecular basis of genetic dominance in a model eukaryotic signal transduction pathway.

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bioRxiv2025

Genetic Linkage Studies in F2 Cowpea (Vigna Unguiculata (L.) Walp) Mapping Populations Using Qualitative Morphological and SNP Markers

The research was conducted to study genetic linkage in 45 F2 cowpea mapping populations derived from a cross between two inbred lines Golinga (cultivated variety) and a Wild relative. The data used for the study were based on 13 polymorphic SNPs and 17 morphological markers. The segregation ratios were analyzed revealed that five traits (growth habit, growth pattern, leaf shape, plant hairiness and pod hairiness) segregated significantly according to 3:1 mendelian classical ratio for inheritance whilst the remaining 13 showed 9:7 ratios. Genetic linkage mapping was performed by using the software QTLiCIMapping version 4.2. All the markers used were polymorphic. Eleven linkage groups were detected which spanned a total map length of 93.8217 cM at a LOD score of 4. Variation in marker distribution on all the 11 linkage groups was observed. Fourteen markers were distributed on Chromosome 1. In all cases, segregation distortion was observed for all the markers in each of the linkage groups. Segregation distortion in Chromosome 1, Chromosome 5, Chromosome 8 and Chromosome 11 were highly skewed to the wild parental type. This work provides one of the few integrated morphological-SNP linkage maps for cowpea and highlights genomic regions associated with non-Mendelian inheritance. These findings supply foundational genetic information for QTL discovery, marker-assisted selection, and breeding strategies aimed at improving yield, nutrition, and climate resilience in cowpea. Author SummaryIn this study, we set out to understand how important physical traits in cowpea are passed from one generation to the next, and to build a simple genetic map that can guide future crop improvement. Cowpea is a major source of food and nutrition for millions of people, especially in Africa, yet progress in improving the crop has been slowed by limited genetic information. By crossing a cultivated cowpea variety with its wild relative, we examined how traits such as growth form, leaf shape, pod appearance, and seed characteristics segregate in their offspring. We also combined these observations with DNA markers to create a genetic map showing how these traits and markers are arranged along the chromosomes. Our results show that some traits follow the classic patterns of inheritance, while others are influenced by interactions between pairs of genes. We also discovered regions of the genome where inheritance was skewed toward one parent, offering clues about underlying biological processes. By providing one of the few combined morphological and DNA maps for cowpea, our work creates a foundation that breeders and researchers can use to develop improved, desired, and climate-resilient cowpea varieties.

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bioRxiv2026

Genetic influences on educational outcomes during and after the Soviet era: Revisiting evidence from Estonia

The origins of individual differences in socioeconomic outcomes, including educational attainment and occupational status, reflect a combination of genetic and environmental factors whose relative contributions may differ across historical contexts. Previous research suggested a doubling of the relative role of genetics in explaining variation in these traits in independent Estonia compared with the Soviet era. Using the Estonian Biobank, now tenfold larger than at the time of the original study, we aimed to replicate and extend these findings. We found converging evidence that the relative contribution of genetic factors to educational attainment, but not to occupational status, was higher in the post-Soviet era, although the differences were smaller than previously reported and varied across analytical approaches. However, analyses using narrower birth cohorts revealed a more complex pattern, with the relative genetic contribution to educational attainment decreasing gradually across successive cohorts. Thus, while the Soviet-to-post-Soviet transition was associated with an increase in the relative role of genetic factors in explaining individual differences in educational attainment, it represents only one component of the broader historical changes that have shaped genetic associations with educational attainment in Estonia over the last century.

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bioRxiv2026

Multilocus microsatellite typing (MLMT) reveals high genetic diversity of Leishmania infantum strains causing tegumentary leishmaniasis in northern Italy

BackgroundTegumentary leishmaniasis (TL) caused by Leishmania infantum has re-emerged in northern Italy, raising questions about the genetic diversity and population structure of circulating parasites and their potential role in shaping different clinical outcomes. Methodology/Principal findingsMultilocus microsatellite typing (MLMT) based on 15 polymorphic loci was applied to 44 L. infantum strains obtained from TL cases diagnosed between 2013 and 2024 in the Emilia-Romagna region. These strains were compared with sympatric isolates from VL cases, dogs and sand flies. MLMT revealed a considerable genetic variation among TL-associated strains, with 43 distinct multilocus genotypes identified. Population structure analyses using Bayesian clustering, multivariate approaches and phylogenetic reconstruction consistently identified three highly differentiated genetic populations (Fst >0.25). TL strains were divided into two main populations: one shared with VL-associated strains (PopB; 9/44) and a second population found exclusively among TL cases (PopC; 28/44). In contrast, the canine-associated population (PopA) showed no overlap with TL cases in this region. Populations also displayed divergent heterozygosity patterns, as indicated by positive and negative Fis values. Conclusions/SignificanceThese findings revealed previously unknown diversity within L. infantum in the study area and demonstrated that inclusion of tegumentary strains is essential to uncover hidden components of parasite population structure. The identification of a TL-associated population supports the existence of multiple evolutionary pathways and emphasises the importance of integrated One Health surveillance, which combines data from humans, animal hosts and vectors to improve understanding of the epidemiology of leishmaniasis in Italy. Author summaryLeishmania infantum is a parasite transmitted to humans through the bite of infected insect vectors. It can cause different forms of leishmaniasis, ranging from a systemic disease known as visceral leishmaniasis to a less common form that affects the skin and mucous membranes, called tegumentary leishmaniasis. Dogs are the main reservoir of the parasite and play a key role in maintaining its circulation in endemic areas. In recent years, cases of tegumentary leishmaniasis have re-emerged in northern Italy. This unexpected increase has raised questions about how the parasite is spreading and whether genetic differences among the parasites could explain these new patterns. To explore this, we examined parasitic DNA obtained from tegumentary leishmaniasis cases and compared it with DNA from patients with visceral leishmaniasis, from dogs and insect vectors from the same area. By examining multiple genetic markers, we found that parasites causing the tegumentary form of the disease are genetically diverse and belong to different groups. Notably, one parasite group was found only in cases of tegumentary leishmaniasis and not in visceral infections nor in infected dogs, suggesting that some parasite lineages may be more closely associated with skin and mucosal disease. Overall, our findings show that studying parasites from cutaneous and mucosal lesions provides important information that would otherwise remain hidden. By combining data from humans, animals and insect vectors, our study highlights the importance of integrated surveillance systems for improving our understanding of disease spread and supporting effective public health strategies.

genetics↗

bioRxiv2026

Distinct genetic architecture of gene and isoform level QTL in the Diversity Outbred (DO) mouse population

Genetic association studies of mRNA abundance phenotypes link regulatory gene loci to mRNA abundance (quantitative trait loci; QTL). Here, we used liver RNA-seq data from a large cohort of the Diversity Outbred (DO) mouse population to map QTL for gene abundance (eQTL), isoform abundance (isoQTL), isoform ratios (irQTL), and splicing (sQTL). QTL studies using this heterogeneous mouse population have been limited to gene-level abundance of mRNAs and have not focused on mRNA isoforms or splicing. We show for the first time that genetic effects on expression are distinct from splicing in the DO mouse population. Using allele-effect patterns from local QTL for protein-coding gene-isoform pairs, we show that genetic variation drives allele-specific isoform usage, generating isoforms whose genetic signals diverge from their aggregated gene-level effects. We conducted pathway enrichment on distal eQTL and isoQTL hotspots and uncovered pathways not detected with eQTL. We then applied a composite mediation approach at these distal hotspots that compares gene-gene, isoform-isoform, and isoform-gene mediator models. By contrasting these causal models of transcriptional regulation, we identified unique associations between mRNA isoforms. We identified candidate genes at irQTL and sQTL hotspots that regulate mRNAs primarily through isoform usage and splicing, including Alkbh1 and Dicer1. For these driver genes, we nominated novel candidate targets through mediation analysis and pathway associations with known RNA-binding targets. We integrated our QTL data with human genetic data, prioritizing effector genes in loci associated with metabolically relevant traits. Our data also suggest that sex and diet influence eQTL and isoQTL distinctly and primarily through distal-acting gene loci. Overall, our findings highlight distinctive genetic effects on transcriptional and post-transcriptional mechanisms of gene regulation.

genetics↗

bioRxiv2026

Phenome-wide genetic framework to identify mechanisms of social effects

Phenotypes are shaped not only by an individuals genotype (direct genetic effects, DGE) and environment but also by the genetic composition of social partners through indirect genetic effects (IGE). Although IGE have been detected across many traits and species, their mechanisms remain largely unknown, particularly for physiological traits. Here we introduce a phenome-wide genetic framework that identifies proxy phenotypes for the heritable traits of social partners mediating IGE by estimating genetic correlations between IGE on focal phenotypes and DGE on measured traits. Applying this approach to two large, outbred mouse datasets comprising hundreds of behavioural and physiological phenotypes, we find that behavioural traits are neither more affected by IGE nor better proxies for the traits mediating them, challenging the prevailing behavioural-centric view of social effects. Instead, immune, metabolic and growth phenotypes are both affected by IGE and informative proxies for their underlying mechanisms, potentially reflecting the social transmission of gut microbes. Our framework provides a novel strategy to better understand the genetic basis of complex traits and uncover mechanisms of social effects.

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bioRxiv2026

Evolution of the genetic architecture of uterine disorders

Uterine disorders and menstrual abnormalities are prevalent reproductive conditions with significant clinical consequences. Recent genome-wide association studies have identified hundreds of variants contributing to different uterine disorders, while epidemiological evidence suggests that these disorders co-occur more frequently than expected, implying shared genetic mechanisms. However, the specific genetic variants and biological pathways underlying this shared architecture remain poorly characterized. Here, we conducted a uterus-centric, multi-trait genome-wide association analysis across ten uterine disorders in a European cohort to elucidate this shared genetic architecture. Further, we embedded this architecture in a functional and population genomics framework to investigate its plausible biological mechanisms and its evolutionary history in humans. We confirm strong positive genetic correlations between major uterine disorders and identify 31 independent susceptibility loci jointly affecting the genetic risk of multiple uterine pathologies, substantiating an intertwined biological basis. Populational analyses demonstrated that several of these susceptibility variants exhibit pronounced allele frequency differentiation across global populations suggestive of recent polygenic selection, including variants with well-supported regulatory functions at the ESR1-CCDC170, WNT4, SFR1, FOXO1, ITPR1, DMRT1 and CDKN2B loci. Notably, we show that most derived alleles acquired during recent human evolution increase risk across multiple uterine disorders and may evolve under antagonistic selection. These findings provide functional annotation and population-level prioritization of genetic variants influencing multiple uterine disorders. They also highlight how past evolutionary histories may contribute to population differences in uterine disease prevalence and pathogenesis.

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bioRxiv2026

Laboratory yeast crosses reveal limited epistasis in the genetic basis of complex traits

Mapping the genetic basis of complex traits is complicated by the presence of epistatic interactions between loci. While work in molecular genetics identifies numerous specific genetic interactions, statistical analyses of quantitative traits frequently conclude that additive (nonepistatic) models explain most heritable variation. However, these conclusions are typically limited by the narrow range of genetic relatedness(e.g. in F1 offspring of a biparental or circular cross). Here, we use a barcoded panel of Saccharomyces cerevisiae genotypes with a broad range of relatedness to quantify the effects of epistasis on the genetic architecture of seven complex traits. We find limited contributions of epistasis to the genetic basis of these traits. These results indicate that epistasis beyond that detected in standard yeast crosses may exist, yet it contributes little to phenotypic variance in these systems.

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bioRxiv2026

The Value of Multi-Year Sampling for Detecting Fine-Scale Population Genetic Structure in Marine Fishes: A Case Study of Juvenile Southern Flounder

Understanding population structure is critical for effective fisheries management in species with complex life histories and variable recruitment. Southern flounder (Paralichthys lethostigma) is a valuable flatfish species with declining populations in the Southeast United States. Improved management may depend on a better understanding of fine-scale and temporal population genetic structure in this region; however, such structure remains poorly characterized. To address our lack of understanding of the spatial and temporal population structure of this important species, we used double digest reduced-representation genome sequencing (ddRADSeq) on juveniles from estuaries in North Carolina and Texas between 2014 and 2023. We found significant genetic differentiation between the Gulf of Mexico and Atlantic populations, supporting the management of these regions as distinct stocks. By contrast, we detected significant variance in genetic structure within Texas and North Carolina populations that was not consistent across sampling years between estuaries in close proximity. The population genetic structure of southern flounder suggests significant, temporally variable genetic differences within estuarine locations that may result from variation in larval dispersal and recruitment patterns. Our findings highlight the value of integrating fine-scale, multi-year genetic data to capture temporal dynamics and avoid misleading conclusions based on single-year or broad-scale sampling.

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bioRxiv2026

Molecular and genetic heterogeneity in iPSCs derived from an outbred laboratory mouse population

Genetically diverse panels of human pluripotent stem cells enable genetic dissection of cellular phenotypes, but comparable induced pluripotent stem cell (iPSC) resources in model organisms remain limited. We generated a panel of iPSCs from the Diversity Outbred (DO) mouse population and established 288 genetically unique lines that retain the allele frequency distribution, heterozygosity, and low population structure of the source population. The lines exhibit consistent growth, pluripotent gene expression profiles, and capacity to form embryoid bodies. Transcriptomic profiling of the lines revealed significant variation in gene expression driven in part by genetic background. We used expression quantitative trait locus (eQTL) mapping to identify over 10,000 regulatory loci that influence gene expression variation, including multiple distal eQTL hotspots that are key gene regulatory hubs and are shared with DO embryonic stem cells (ESCs). The largest hotspot, mediated by Lifr, showed a shift in founder allele effects relative to ESCs, consistent with differences in cellular state and culture conditions. These results establish the DO iPSC panel as a genetically diverse, publicly accessible platform derived from a laboratory mouse genetic reference population, enabling integration of in vitro cellular phenotypes with in vivo traits within a closed, outbred population.

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bioRxiv2026

Psychometric Validation of the Education and Assessment of Genetic Literacy (EAGL) Measure

Genetic literacy is an integral measure for examining societys interaction with genetics, but widely-used "genetic literacy" measures lack both knowledge comprehension measures and psychometric validation. To address these issues, we validated the Education and Assessment of Genetic Literacy measure (EAGL) in a sample of 2708 US participants, using both exploratory and confirmatory factor analysis. In addition to standard subjective and objective knowledge subscales, our measures distinct knowledge comprehension subscale focuses on autism as an example of a complex condition. Regression analyses showed a statistically significant interaction when looking at education and personal connection to autism in relation to knowledge comprehension (F=3.68, p=0.003). Separately, those in our sample with a connection to autism scored higher on the subjective knowledge section (F=19.52, p<0.001) only, concurring with previous demonstrations of a subjective-objective knowledge gap in science literacy. We explored geographic location as one potential factor in genetic literacy and found that metropolitan vs non-metropolitan status had no significant main effects on overall levels. After the validation process, we have two multi-domain measures which accurately capture the construct of genetic literacy and are available for wide use: the multi-faceted EAGL-long, which has previously been tested in thousands of participants, or the validated three-factor EAGL-short.

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bioRxiv2026

Bone response to intermittent parathyroid hormone (PTH) is both genetic and sex specific

Teriparatide (PTH 1-34) is an anabolic agent used to treat osteoporosis, yet clinical response varies widely among patients. To investigate genetic and sex-specific determinants of skeletal response, we administered intermittent PTH to male and female mice from eight genetically diverse inbred strains. Mice were treated for four weeks, and bone phenotypes were assessed via DXA, microCT, and mechanical testing. Response to PTH was highly strain- and sex-dependent, with some strains responding at the femur but not the spine, and vice versa. Heritability estimates for PTH-induced changes in areal bone mineral density (aBMD), cortical bone area at the femoral mid-diaphysis, femur strength, and trabecular bone volume fraction (BV/TV) ranged from moderate to high, with BV/TV showing the strongest genetic influence. Cortical bone response mechanisms differed by sex: males exhibited periosteal expansion, while females showed endosteal remodeling. These findings mirror clinical observations where non-response to PTH can be anatomic site specific. Further, our study suggests that genetic background and sex significantly influence bone response to PTH. Our data support the future use of genetically diverse mouse models to elucidate the genetic architecture of skeletal response to PTH.

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bioRxiv2026

A dish-to-biobank framework links β-cell nutrient-stress programs to genetic and dietary risk for Type 2 Diabetes

Type 2 diabetes (T2D) arises from genetic susceptibility and chronic metabolic stress, but whether these converge on shared molecular programs in human populations remains unclear. Here, we develop a dish-to-biobank framework linking controlled {beta}-cell perturbation to population-scale disease genetics through the circulating plasma proteome, and apply it to T2D. scRNA-seq of human stem cell-derived islets under factorial glucose and palmitate exposure identifies their combination (glucolipotoxicity) as the condition eliciting the strongest SC-{beta} cell transcriptional response, with glucolipotoxicity-upregulated genes uniquely enriched for T2D heritability, monogenic diabetes genes, and rare-variant burden signals. CRISPR knockout of {beta}-cell identity regulators PAX6 and PDX1 aligns with this program, establishing convergence of environmental and genetic perturbations on a shared disease-relevant state. We then used the plasma proteome as an accessible population-scale readout of these experimentally defined {beta}-cell stress programs, scoring 45,956 UK Biobank White British participants. We define heritable stress signatures that associate with refined carbohydrate and saturated fat intake, and undergo trans-tissue genetic regulation, with a subset of variants showing diet-dependent effects. Together, these findings establish glucolipotoxicity as a genetically anchored model of {beta}-cell dysfunction and provide a generalizable framework for linking controlled cellular perturbations to human disease genetics at population scale.

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