| 1. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 2. |
- Lunetta, Kathryn L., et al.
(författare)
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Rare coding variants and X-linked loci associated with age at menarche
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
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| 3. |
- Abecasis, David, et al.
(författare)
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A review of acoustic telemetry in Europe and the need for a regional aquatic telemetry network
- 2018
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Ingår i: Animal Biotelemetry. - : Springer. - 2050-3385. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Globally, there are a large and growing number of researchers using biotelemetry as a tool to studyaquatic animals. In Europe, this community lacks a formal network structure. The aim of this study is to review the useof acoustic telemetry in Europe and document the contribution of cross-boundary studies and inter-research groupcollaborations. Based on this, we explore the potential benefits and challenges of a network approach to identifyfuture priorities and best practices for aquatic biotelemetry research in Europe.Results: Over the past decade, there was an approximately sevenfold increase in the number of acoustic telemetrystudies published on marine and diadromous species in Europe compared to a sixfold increase globally. Over 90%of these studies were conducted on fishes and undertaken in coastal areas, estuaries, or rivers. 75% of these studieswere conducted by researchers based in one of five nations (Norway, UK, France, Portugal, and Spain) and, eventhough 34% were based on collaborations between scientists from several countries, there was only one study withan acoustic receiver array that extended beyond the borders of a single country. In recent years, acoustic telemetryin European waters has evolved from studying behavioural aspects of animals (82.2%), into more holistic approachesaddressing management-related issues (10%), tagging methods and effects (5%), and technology and data analysisdevelopment (2.8%).Conclusions: Despite the increasing number of publications and species tracked, there is a prominent lack ofplanned and structured acoustic telemetry collaborations in Europe. A formal pan-European network structure wouldpromote the development of (1) a research platform that could benefit the acoustic telemetry community throughcapacity building, (2) a centralized database, and (3) key deployment sites and studies on priority species requiringresearch in Europe. A network may increase efficiency, expand the scope of research that can be undertaken, promoteEuropean science integration, enhance the opportunities and success of acquiring research funding and, ultimately,foster regional and transatlantic collaborations. It may also help address research priorities such as the large-scalesocietal challenges arising from climate change impacts and assist the EU’s Marine Strategy Framework Directive viaidentification of good environmental status of endangered or commercially important species.
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| 4. |
- de Vries, Paul S., et al.
(författare)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Feitosa, Mary F., et al.
(författare)
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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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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Jakobsdottir, Johanna, et al.
(författare)
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Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
- 2016
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade.
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| 7. |
- Jencson, Jacob E., et al.
(författare)
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Discovery of an Intermediate-luminosity Red Transient in M51 and Its Likely Dust-obscured, Infrared-variable Progenitor
- 2019
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 880:2
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Tidskriftsartikel (refereegranskat)abstract
- We present the discovery of an optical transient (OT) in Messier. 51, designated M51 OT2019-1 (also ZTF 19aadyppr, AT 2019abn, ATLAS19bz1), by the Zwicky Transient Facility (ZTF). The OT rose over 15. days to an observed luminosity of M-r = -13 (nu L-nu = 9 x 10(6) L-circle dot), in the luminosity gap between novae and typical supernovae (SNe). Spectra during the outburst show a red continuum, Balmer emission with a velocity width of approximate to 400 km s(-1), Ca II and [Ca II] emission, and absorption features characteristic of an F-type supergiant. The spectra and multiband light curves are similar to the so-called SN impostors and intermediate-luminosity red transients (ILRTs). We directly identify the likely progenitor in archival Spitzer Space Telescope imaging with a 4.5 mu m luminosity of M-[4.5] approximate to -12.2 mag and a [3.6]-[4.5] color redder than 0.74 mag, similar to those of the prototype ILRTs SN 2008S and NGC 300 OT2008-1. Intensive monitoring of M51 with Spitzer further reveals evidence for variability of the progenitor candidate at [ 4.5] in the years before the OT. The progenitor is not detected in pre-outburst Hubble Space Telescope optical and near-IR images. The optical colors during outburst combined with spectroscopic temperature constraints imply a higher reddening of E(B - V) approximate to 0.7 mag and higher intrinsic luminosity of M-r approximate to -14.9 mag (nu L-nu = 5.3 x 10(7) L-circle dot) near peak than seen in previous ILRT candidates. Moreover, the extinction estimate is higher on the rise than on the plateau, suggestive of an extended phase of circumstellar dust destruction. These results, enabled by the early discovery of M51. OT2019-1 and extensive pre-outburst archival coverage, offer new clues about the debated origins of ILRTs and may challenge the hypothesis that they arise from the electron-capture induced collapse of extreme asymptotic giant branch stars.
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| 8. |
- Sung, Yun Ju, et al.
(författare)
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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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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Tidskriftsartikel (refereegranskat)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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| 9. |
- Kounenis, Charlampos, et al.
(författare)
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Investigations of the Rear-End Flow Structures on a Sedan Car
- 2016
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Ingår i: SAE Technical Papers. - 400 Commonwealth Drive, Warrendale, PA, United States : SAE International. - 0148-7191 .- 2688-3627.
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Tidskriftsartikel (refereegranskat)abstract
- The aerodynamic drag, fuel consumption and hence CO2 emissions, of a road vehicle depend strongly on its flow structures and the pressure drag generated. The rear end flow which is an area of complex three-dimensional flow structures, contributes to the wake development and the overall aerodynamic performance of the vehicle. This paper seeks to provide improved insight into this flow region to better inform future drag reduction strategies. Using experimental and numerical techniques, two vehicle shapes have been studied; a 30% scale model of a Volvo S60 representing a 2003MY vehicle and a full scale 2010MY S60. First the surface topology of the rear end (rear window and trunk deck) of both configurations is analysed, using paint to visualise the skin friction pattern. By means of critical points, the pattern is characterized and changes are identified studying the location and type of the occurring singularities. The flow field away from the surface is then analysed using PIV measurements and CFD for the scale model and CFD simulations for the full scale vehicle. The flow field is investigated regarding its singular points in cross-planes and the correlation between the patterns for the two geometries is analysed. Furthermore, it is discussed how the occurring structures can be described in more generalized terms to be able to compare different vehicle geometries regarding their flow field properties. The results show the extent to which detailed flow structures on similar but distinct vehicles are comparable; as well as providing insight into the complex 3D wake flow.
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| 10. |
- Sims, Emily K., et al.
(författare)
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Who is enrolling? The path to monitoring in type 1 diabetes trialnet’s pathway to prevention
- 2019
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 42:12, s. 2228-2236
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To better understand potential facilitators of individual engagement in type 1 diabetes natural history and prevention studies through analysis of enrollment data in the TrialNet Pathway to Prevention (PTP) study. RESEARCH DESIGN AND METHODS We used multivariable logistic regression models to examine continued engagement of eligible participants at two time points: 1) the return visit after screening to confirm an initial autoantibody-positive (Ab1) test result and 2) the initial oral glucose tolerance test (OGTT) for enrollment into the monitoring protocol. RESULTS Of 5,387 subjects who screened positive for a single autoantibody (Ab), 4,204 (78%) returned for confirmatory Ab testing. Younger age was associated with increased odds of returning for Ab confirmation (age <12 years vs. >18 years: odds ratio [OR] 2.12, P < 0.0001). Racial and ethnic minorities were less likely to return for confirmation, particularly nonwhite non-Hispanic (OR 0.50, P < 0.0001) and Hispanic (OR 0.69, P 5 0.0001) relative to non-Hispanic white subjects. Of 8,234 subjects, 5,442 (66%) were identified as eligible to be enrolled in PTP OGTT monitoring. Here, younger age and identification as multiple Ab1 were associated with increased odds of returning for OGTT monitoring (age <12 years vs. >18 years: OR 1.43, P < 0.0001; multiple Ab1: OR 1.36, P < 0.0001). Parents were less likely to enroll into monitoring than other relatives (OR 0.78, P 5 0.004). Site-specific factors, including site volume and U.S. site versus international site, were also associated with differences in rates of return for Ab1 confirmation and enrollment into monitoring. CONCLUSIONS These data confirm clear differences between successfully enrolled populations and those lost to follow-up, which can serve to identify strategies to increase ongoing participation.
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