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- Graff, M., et al.
(author)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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In: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Journal article (peer-reviewed)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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| 4. |
- Mahajan, Anubha, et al.
(author)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Journal article (peer-reviewed)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 6. |
- Wheeler, Eleanor, et al.
(author)
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Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis
- 2017
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In: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:9
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Journal article (peer-reviewed)abstract
- Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
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| 9. |
- Mahajan, Anubha, et al.
(author)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Journal article (peer-reviewed)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 11. |
- Sorokowska, Agnieszka, et al.
(author)
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Global study of social odor awareness
- 2018
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In: Chemical Senses. - : Oxford University Press (OUP). - 0379-864X .- 1464-3553. ; 43:7, s. 503-513
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Journal article (peer-reviewed)abstract
- Olfaction plays an important role in human social communication, including multiple domains in which people often rely on their sense of smell in the social context. The importance of the sense of smell and its role can however vary inter-individually and culturally. Despite the growing body of literature on differences in olfactory performance or hedonic preferences across the globe, the aspects of a given culture as well as culturally universal individual differences affecting odor awareness in human social life remain unknown. Here, we conducted a large-scale analysis of data collected from 10,794 participants from 52 study sites from 44 countries all over the world. The aim of our research was to explore the potential individual and country-level correlates of odor awareness in the social context. The results show that the individual characteristics were more strongly related than country-level factors to self-reported odor awareness in different social contexts. A model including individual-level predictors (gender, age, material situation, education and preferred social distance) provided a relatively good fit to the data, but adding country-level predictors (Human Development Index, population density and average temperature) did not improve model parameters. Although there were some cross-cultural differences in social odor awareness, the main differentiating role was played by the individual differences. This suggests that people living in different cultures and different climate conditions may still share some similar patterns of odor awareness if they share other individual-level characteristics.
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| 12. |
- Bertoni, Alessandro, et al.
(author)
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Virtual Modeling for Lifecycle Performance Assessment in Aerospace Design
- 2016
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In: Procedia CIRP. - Elsevier : Elsevier BV. - 2212-8271. ; 47, s. 335-340, s. 335-340
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Conference paper (peer-reviewed)abstract
- The aim of the paper is to present an approach for the multidisciplinary evaluation of alternative modular concepts in preliminary design with the intent of enhancing engineers’ capability to simulate alternative scenarios with different design configurations, so to derive decisions about the most valuable design concepts to further develop. The research contribution is novel in the way that it expands the Set-Based-Engineering approach by addressing the “servitization” challenge in two ways: firstly by the use of value models and sustainability models as decision making support, making possible a preliminary assessment of the value contribution and of the sustainability performances of a design concept; secondly, by the use of functional modelling modules and configurable systems elements for platform-based design, to manage the complex relationships within and between parts of the platform throughout the lifecycle. The paper presents the main features of the approach and introduces an industrial case concerning the development of a module component for an aircraft engine in which the approach is applied for demonstration. The paper finally elaborates on the benefits and implications of the approach in the design process.
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| 13. |
- Conroy-Beam, Daniel, et al.
(author)
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Assortative mating and the evolution of desirability covariation
- 2019
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In: Evolution and human behavior. - : Elsevier. - 1090-5138 .- 1879-0607. ; 40:5, s. 479-491
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Journal article (peer-reviewed)abstract
- Mate choice lies dose to differential reproduction, the engine of evolution. Patterns of mate choice consequently have power to direct the course of evolution. Here we provide evidence suggesting one pattern of human mate choice-the tendency for mates to be similar in overall desirability-caused the evolution of a structure of correlations that we call the d factor. We use agent-based models to demonstrate that assortative mating causes the evolution of a positive manifold of desirability, d, such that an individual who is desirable as a mate along any one dimension tends to be desirable across all other dimensions. Further, we use a large cross-cultural sample with n = 14,478 from 45 countries around the world to show that this d-factor emerges in human samples, is a cross-cultural universal, and is patterned in a way consistent with an evolutionary history of assortative mating. Our results suggest that assortative mating can explain the evolution of a broad structure of human trait covariation.
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| 14. |
- Isaksson, Ola, 1969, et al.
(author)
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Virtual Contextual Validation of technologies and methods for Product Development
- 2016
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In: 14th International Design Conference, DESIGN 2016, Cavtat, Dubrovnik, Croatia, 16-19 May 2016. - 1847-9073. ; DS 84, s. 669-678
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Conference paper (peer-reviewed)abstract
- In this paper the use of virtual demonstrators as means to contextually validate both design methods and novel Technologies in advance of industrial Product development. Since maturity requirements are high, and pure technology and methods development Projects typically result in promising, but not validated, methods and Technologies and full scale hardware demonstration initiatives are costly, there is a gap to fill.Functional Modeling and Value Driven design methods are used with Ceramic Metallic Composites technologies in a virtual demonstrator.
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| 16. |
- Merletti, F, et al.
(author)
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Occupational factors and risk of adult bone sarcomas: A multicentric case-control study in Europe
- 2006
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In: International Journal of Cancer. - : Wiley. - 0020-7136. ; 118:3, s. 721-727
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Journal article (peer-reviewed)abstract
- We investigated the association between occupational factors and risk of bone sarcoma, a rare tumor with a largely unknown aetiology. A multicentric case-control study was conducted in 7 European countries in 1995-97. Ninety-six cases aged 35-69 years with a centrally reviewed diagnosis of bone sarcoma (68 chondrosarcomas and 28 osteosarcomas) were compared to 2,632 population (68%) or colon cancer (32%) controls. Subjects were interviewed to obtain information on occupational, medical and reproductive history, smoking and alcohol consumption and selected exposures including use of pesticides. Response proportions were 90% among cases and 66% among controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for selected categories of job titles and branches of industry and for use of pesticides. We found an increased OR for bone sarcoma among blacksmiths, toolmakers, machine-tool operators (OR = 2.14, 95% CI 1.08-4.26), woodworkers (OR = 2.68, 95% CI 1.36-5.29) and construction workers (OR = 1.62, 95% CI 0.92-2.87). Ever users of pesticide had an OR of 2.33 (95% CI 1.31-4.13), with similar risks for exposure to insecticides and exposure to herbicides. Neither duration of employment in any of the analyzed occupational categories nor duration of use of pesticides showed an increasing trend in the risk of bone sarcoma. ORs of bone sarcoma were 1.03 (95% CI 0.23-4.57), 3.13 (95% CI 1.26-7.76) and 1.44 (95% CI 0.43-4.85) for the first, second and third fertile of days of use of pesticides. Our study suggests that novel and previously reported (woodworking) occupational factors play a role in the aetiology of bone sarcomas. (c) 2005 Wiley-Liss, Inc.
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