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2. |
- de Vries, Paul S., et al.
(author)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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In: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Journal article (peer-reviewed)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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3. |
- Feitosa, Mary F., et al.
(author)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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In: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Journal article (peer-reviewed)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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4. |
- Sung, Yun Ju, et al.
(author)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Journal article (peer-reviewed)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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5. |
- Lai, Heidi T. M., et al.
(author)
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Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes : Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE)
- 2022
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 45:4, s. 854-863
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.RESEARCH DESIGN AND METHODS: We included data from an international consortium of 12 prospective cohorts and nested case-control studies from six nations. TFA biomarkers were measured in blood collected between 1990 and 2008 from 25,126 participants aged >= 18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.RESULTS: During a mean follow-up of 13.5 years, 2,843 cases of incident T2D were identified. In multivariable-adjusted pooled analyses, no significant associations with T2D were identified for trans/trans-18:2, relative risk (RR) 1.09 (95% CI 0.94-1.25); cis/trans-18:2, 0.89 (0.73-1.07); and trans/cis-18:2, 0.87 (0.73-1.03). Trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated with T2D (RR 0.81 [95% CI 0.67-0.99], 0.86 [0.75-0.99], and 0.84 [0.74-0.96], respectively). Findings were not significantly different according to prespecified sources of potential heterogeneity (each P >= 0.1).CONCLUSIONS: Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.
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6. |
- Middleton, Anna, et al.
(author)
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Global Public Perceptions of Genomic Data Sharing : What Shapes the Willingness to Donate DNA and Health Data?
- 2020
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 107:4, s. 743-752
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Journal article (peer-reviewed)abstract
- Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison. This paper presents results from a very large public survey on attitudes toward genomic data sharing. Data from 36,268 individuals across 22 countries (gathered in 15 languages) are presented. In general, publics across the world do not appear to be aware of, nor familiar with, the concepts of DNA, genetics, and genomics. Willingness to donate one's DNA and health data for research is relatively low, and trust in the process of data's being shared with multiple users (e.g., doctors, researchers, governments) is also low. Participants were most willing to donate DNA or health information for research when the recipient was specified as a medical doctor and least willing to donate when the recipient was a for-profit researcher. Those who were familiar with genetics and who were trusting of the users asking for data were more likely to be willing to donate. However, less than half of participants trusted more than one potential user of data, although this varied across countries. Genetic information was not uniformly seen as different from other forms of health information, but there was an association between seeing genetic information as special in some way compared to other health data and increased willingness to donate. The global perspective provided by our "Your DNA, Your Say" study is valuable for informing the development of international policy and practice for sharing genomic data. It highlights that the research community not only needs to be worthy of trust by the public, but also urgent steps need to be taken to authentically communicate why genomic research is necessary and how data donation, and subsequent sharing, is integral to this.
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7. |
- Pennells, Lisa, et al.
(author)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Journal article (peer-reviewed)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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8. |
- Di Angelantonio, Emanuele, et al.
(author)
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Association of Cardiometabolic Multimorbidity With Mortality : The Emerging Risk Factors Collaboration
- 2015
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In: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 314:1, s. 52-60
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Journal article (peer-reviewed)abstract
- IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing.OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.DESIGN, SETTING, AND PARTICIPANTS Age-and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy.RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
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9. |
- Lee, Crystal Man Ying, et al.
(author)
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Comparison of relationships between four common anthropometric measures and incident diabetes
- 2017
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In: Diabetes Research and Clinical Practice. - : Elsevier. - 0168-8227 .- 1872-8227. ; 132, s. 36-44
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Journal article (peer-reviewed)abstract
- Aims: First, to conduct a detailed exploration of the prospective relations between four commonly used anthropometric measures with incident diabetes and to examine their consistency across different population subgroups. Second, to compare the ability of each of the measures to predict five-year risk of diabetes. Methods: We conducted a meta- analysis of individual participant data on body mass index (BMI), waist circumference (WC), waist- hip and waist- height ratio (WHtR) from the Obesity, Diabetes and Cardiovascular Disease Collaboration. Cox proportional hazard models were used to estimate the association between a one standard deviation increment in each anthropometric measure and incident diabetes. Harrell's concordance statistic was used to test the predictive accuracy of each measure for diabetes risk at five years. Results: Twenty- one studies with 154,998 participants and 9342 cases of incident diabetes were available. Each of the measures had a positive association with incident diabetes. A one standard deviation increment in each of the measures was associated with 64- 80% higher diabetes risk. WC and WHtR more strongly associated with risk than BMI (ratio of hazard ratios: 0.95 [0.92,0.99] - 0.97 [0.95,0.98]) but there was no appreciable difference between the four measures in the predictive accuracy for diabetes at five years. Conclusions: Despite suggestions that abdominal measures of obesity have stronger associations with incident diabetes and better predictive accuracy than BMI, we found no overall advantage in any one measure at discriminating the risk of developing diabetes. Any of these measures would suffice to assist in primary diabetes prevention efforts.
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10. |
- 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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11. |
- Middleton, Anna, et al.
(author)
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'Your DNA, Your Say': global survey gathering attitudes toward genomics : design, delivery and methods
- 2018
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In: Personalized Medicine. - : Future Medicine Ltd. - 1741-0541 .- 1744-828X. ; 15:4, s. 311-318
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Journal article (peer-reviewed)abstract
- Our international study, 'Your DNA, Your Say', uses film and an online cross-sectional survey to gather public attitudes toward the donation, access and sharing of DNA information. We describe the methodological approach used to create an engaging and bespoke survey, suitable for translation into many different languages. We address some of the particular challenges in designing a survey on the subject of genomics. In order to understand the significance of a genomic result, researchers and clinicians alike use external databases containing DNA and medical information from thousands of people. We ask how publics would like their 'anonymous' data to be used (or not to be used) and whether they are concerned by the potential risks of reidentification; the results will be used to inform policy.
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12. |
- Milne, Richard, et al.
(author)
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Demonstrating trustworthiness when collecting and sharing genomic data : public views across 22 countries
- 2021
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In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 13:1
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Journal article (peer-reviewed)abstract
- BackgroundPublic trust is central to the collection of genomic and health data and the sustainability of genomic research. To merit trust, those involved in collecting and sharing data need to demonstrate they are trustworthy. However, it is unclear what measures are most likely to demonstrate this.MethodsWe analyse the ‘Your DNA, Your Say’ online survey of public perspectives on genomic data sharing including responses from 36,268 individuals across 22 low-, middle- and high-income countries, gathered in 15 languages. We examine how participants perceived the relative value of measures to demonstrate the trustworthiness of those using donated DNA and/or medical information. We examine between-country variation and present a consolidated ranking of measures.ResultsProviding transparent information about who will benefit from data access was the most important measure to increase trust, endorsed by more than 50% of participants across 20 of 22 countries. It was followed by the option to withdraw data and transparency about who is using data and why. Variation was found for the importance of measures, notably information about sanctions for misuse of data—endorsed by 5% in India but almost 60% in Japan. A clustering analysis suggests alignment between some countries in the assessment of specific measures, such as the UK and Canada, Spain and Mexico and Portugal and Brazil. China and Russia are less closely aligned with other countries in terms of the value of the measures presented.ConclusionsOur findings highlight the importance of transparency about data use and about the goals and potential benefits associated with data sharing, including to whom such benefits accrue. They show that members of the public value knowing what benefits accrue from the use of data. The study highlights the importance of locally sensitive measures to increase trust as genomic data sharing continues globally.
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13. |
- Nakamura, Rumi, et al.
(author)
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Multiscale Currents Observed by MMS in the Flow Braking Region
- 2018
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In: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 123:2, s. 1260-1278
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Journal article (peer-reviewed)abstract
- We present characteristics of current layers in the off-equatorial near-Earth plasma sheet boundary observed with high time-resolution measurements from the Magnetospheric Multiscale mission during an intense substorm associated with multiple dipolarizations. The four Magnetospheric Multiscale spacecraft, separated by distances of about 50 km, were located in the southern hemisphere in the dusk portion of a substorm current wedge. They observed fast flow disturbances (up to about 500 km/s), most intense in the dawn-dusk direction. Field-aligned currents were observed initially within the expanding plasma sheet, where the flow and field disturbances showed the distinct pattern expected in the braking region of localized flows. Subsequently, intense thin field-aligned current layers were detected at the inner boundary of equatorward moving flux tubes together with Earthward streaming hot ions. Intense Hall current layers were found adjacent to the field-aligned currents. In particular, we found a Hall current structure in the vicinity of the Earthward streaming ion jet that consisted of mixed ion components, that is, hot unmagnetized ions, cold ExB drifting ions, and magnetized electrons. Our observations show that both the near-Earth plasma jet diversion and the thin Hall current layers formed around the reconnection jet boundary are the sites where diversion of the perpendicular currents take place that contribute to the observed field-aligned current pattern as predicted by simulations of reconnection jets. Hence, multiscale structure of flow braking is preserved in the field-aligned currents in the off-equatorial plasma sheet and is also translated to ionosphere to become a part of the substorm field-aligned current system.
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14. |
- Nakamura, Rumi, et al.
(author)
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Near-Earth plasma sheet boundary dynamics during substorm dipolarization
- 2017
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In: Earth Planets and Space. - : Springer Berlin/Heidelberg. - 1343-8832 .- 1880-5981. ; 69
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Journal article (peer-reviewed)abstract
- We report on the large-scale evolution of dipolarization in the near-Earth plasma sheet during an intense (AL similar to -1000 nT) substorm on August 10, 2016, when multiple spacecraft at radial distances between 4 and 15 RE were present in the night-side magnetosphere. This global dipolarization consisted of multiple short-timescale (a couple of minutes) Bz disturbances detected by spacecraft distributed over 9 MLT, consistent with the large-scale substorm current wedge observed by ground-based magnetometers. The four spacecraft of the Magnetospheric Multiscale were located in the southern hemisphere plasma sheet and observed fast flow disturbances associated with this dipolarization. The high-time-resolution measurements from MMS enable us to detect the rapid motion of the field structures and flow disturbances separately. A distinct pattern of the flow and field disturbance near the plasma boundaries was found. We suggest that a vortex motion created around the localized flows resulted in another fieldaligned current system at the off-equatorial side of the BBF-associated R1/R2 systems, as was predicted by the MHD simulation of a localized reconnection jet. The observations by GOES and Geotail, which were located in the opposite hemisphere and local time, support this view. We demonstrate that the processes of both Earthward flow braking and of accumulated magnetic flux evolving tailward also control the dynamics in the boundary region of the near-Earth plasma sheet.
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15. |
- Petersen, Gloria M, et al.
(author)
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A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 224-228
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Journal article (peer-reviewed)abstract
- We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.
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