| 1. |
- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 2. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 4. |
- Santangelo, James S., et al.
(författare)
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Global urban environmental change drives adaptation in white clover
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 7. |
- de las Fuentes, Lisa, et al.
(författare)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 8. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 13. |
- Ai Lucas, R., et al.
(författare)
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Targeting workload to ameliorate risk of heat stress in industrial sugarcane workers
- 2023
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Ingår i: Scandinavian Journal of Work Environment & Health. - : Scandinavian Journal of Work, Environment and Health. - 0355-3140 .- 1795-990X. ; 49:1, s. 43-52
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this study was to quantify the physiological workload of manual laborers in industrial sugarcane and assess the effect of receiving a rest, shade, and hydration intervention to reduce heat stress exposure risk.Methods In an observational study, physiological workload was evaluated for burned cane cutters (BCC), seed cutters (SC) and drip irrigation repair workers (DIRW) using heart rate (HR) recorded continuously (Polar (R)) across a work shift. Workers' percentage of maximal HR (%HRmax), time spent in different HR zones, and estimated core temperature (ECTemp) were calculated. The effect of increasing rest across two harvests was evaluated for BCC and SC.Results A total of 162 workers participated in this study [52 BCC (all male), 71 SC (13 female) and 39 DIRW (16 female)]. Average %HRmax across a work shift was similar between BCC and SC (BCC: 58%, SC: 59%), but lower in DIRW (51%). BCC and SC spent similar proportions of work shifts at hard/very hard intensities (BCC: 13%, SC: 15%), versus DIRW who worked mostly at light (46%) or light-moderate (39%) intensities. SC maximum ECTemp reached 38.2 degrees C, BCC 38.1 degrees C; while DIRW only reached 37.7 degrees C. Females performed at a higher %HRmax than males across work shifts (SC 64% versus 58%; DIRW 55% versus 49%). An additional rest period was associated with a lower average %HRmax across a work shift in BCC.Conclusion In this setting, BCC and SC both undertake very physiologically demanding work. Females maintained a higher workload than male co-workers. Regulated rest periods each hour, with water and shade access, appears to reduce physiological workload/strain.
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| 14. |
- Alexandridis, Nikolaos, et al.
(författare)
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Archetype models upscale understanding of natural pest control response to land-use change
- 2022
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Ingår i: Ecological Applications. - : Wiley. - 1051-0761 .- 1939-5582. ; 32:8
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Tidskriftsartikel (refereegranskat)abstract
- Control of crop pests by shifting host plant availability and natural enemy activity at landscape scales has great potential to enhance the sustainability of agriculture. However, mainstreaming natural pest control requires improved understanding of how its benefits can be realized across a variety of agroecological contexts. Empirical studies suggest significant but highly variable responses of natural pest control to land-use change. Current ecological models are either too specific to provide insight across agroecosystems, or too generic to guide management with actionable predictions. We suggest getting the full benefit of available empirical, theoretical and methodological knowledge, by combining trait-mediated understanding from correlative studies with the explicit representation of causal relationships achieved by mechanistic modeling. To link these frameworks, we adapt the concept of archetypes, or context-specific generalizations, from sustainability science. Similar responses of natural pest control to land-use gradients across cases that share key attributes, such as functional traits of focal organisms, indicate general processes that drive system behavior in a context-sensitive manner. Based on such observations of natural pest control, a systematic definition of archetypes can provide the basis for mechanistic models of intermediate generality that cover all major agroecosystems worldwide. Example applications demonstrate the potential for upscaling understanding and improving prediction of natural pest control, based on knowledge transfer and scientific synthesis. A broader application of this mechanistic archetype approach promises to enhance ecology's contribution to natural resource management across diverse regions and social-ecological contexts.
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| 15. |
- Alexandridis, Nikolaos, et al.
(författare)
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Models of natural pest control : Towards predictions across agricultural landscapes
- 2021
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Ingår i: Biological Control. - : Elsevier BV. - 1049-9644. ; 163
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Forskningsöversikt (refereegranskat)abstract
- Natural control of invertebrate crop pests has the potential to complement or replace conventional insecticide-based practices, but its mainstream application is hampered by predictive unreliability across agroecosystems. Inconsistent responses of natural pest control to changes in landscape characteristics have been attributed to ecological complexity and system-specific conditions. Here, we review agroecological models and their potential to provide predictions of natural pest control across agricultural landscapes. Existing models have used a multitude of techniques to represent specific crop-pest-enemy systems at various spatiotemporal scales, but less wealthy regions of the world are underrepresented. A realistic representation of natural pest control across systems appears to be hindered by a practical trade-off between generality and realism. Nonetheless, observations of context-sensitive, trait-mediated responses of natural pest control to land-use gradients indicate the potential of ecological models that explicitly represent the underlying mechanisms. We conclude that modelling natural pest control across agroecosystems should exploit existing mechanistic techniques towards a framework of contextually bound generalizations. Observed similarities in causal relationships can inform the functional grouping of diverse agroecosystems worldwide and the development of the respective models based on general, but context-sensitive, ecological mechanisms. The combined use of qualitative and quantitative techniques should allow the flexible integration of empirical evidence and ecological theory for robust predictions of natural pest control across a wide range of agroecological contexts and levels of knowledge availability. We highlight challenges and promising directions towards developing such a general modelling framework.
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| 16. |
- Coral, Daniel E, et al.
(författare)
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A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes
- 2023
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 5:2, s. 237-247
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Tidskriftsartikel (refereegranskat)abstract
- Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.
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| 17. |
- Poveda, A., et al.
(författare)
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Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation : OPINION primary analysis
- 2022
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258. ; 164:3, s. 498-504
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. Methods: In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. Results: Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2 months (95% confidence interval [CI], 7.6–10.9) in the overall population. At 12 and 18 months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. Conclusion: Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.
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| 18. |
- Riggi, Laura, et al.
(författare)
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Early-season mass-flowering crop cover dilutes wild bee abundance and species richness in temperate regions : A quantitative synthesis
- 2024
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Ingår i: Journal of Applied Ecology. - 0021-8901 .- 1365-2664. ; 61:3, s. 452-464
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Tidskriftsartikel (refereegranskat)abstract
- Pollinators benefit from increasing floral resources in agricultural landscapes, which could be an underexplored co-benefit of mass-flowering crop cultivation. However, the impacts of mass-flowering crops on pollinator communities are complex and appear to be context-dependent, mediated by factors such as crop flowering time and the availability of other flower resources in the landscape. A synthesis of research is needed to develop management recommendations for effective pollinator conservation in agroecosystems. By combining 22 datasets from 13 publications conducted in nine temperate countries (20 European, 2 North American), we investigated if mass-flowering crop flowering time (early or late season), bloom state (during or after crop flowering) and extent of non-crop habitat cover in the landscape moderated the effect of mass-flowering crop cover on wild pollinator abundance and species richness in mass-flowering crop and non-crop habitats. During bloom, wild bee abundance and richness are negatively related to mass-flowering crop cover. Dilution effects were predominant in crop habitats and early in the season, except for bumblebees, which declined with mass-flowering crop cover irrespective of habitat or season. Late in the season and in non-crop habitats, several of these negative relationships were either absent or reversed. Late-season mass-flowering crop cover is positively related to honeybee abundance in crop habitats and to other bee abundance in non-crop habitats. These results indicate that crop-adapted species, like honeybees, move to forage and concentrate on late-season mass-flowering crops at a time when flower availability in the landscape is limited, potentially alleviating competition for flower resources in non-crop habitats. We found no evidence of pollinators moving from mass-flowering crop to non-crop habitats after crop bloom. Synthesis and applications: Our results confirm that increasing early-season mass-flowering crop cover dilutes wild pollinators in crop habitats during bloom. We find that dilution effects were absent late in the season. While mass-flowering crop cultivation alone is unlikely to be sufficient for maintaining pollinators, as part of carefully designed diverse crop rotations or mixtures combined with the preservation of permanent non-crop habitats, it might provide valuable supplementary food resources for pollinators in temperate agroecosystems, particularly later in the season when alternative flower resources are scarce.
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