| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Turcot, Valerie, et al.
(author)
-
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
-
In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
|
|
| 6. |
- Veres, P., et al.
(author)
-
Observation of inverse Compton emission from a long gamma-ray burst
- 2019
-
In: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 575:7783, s. 459-
-
Journal article (peer-reviewed)abstract
- Long-duration gamma-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectron volt-to-mega electronvoltband, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission(1,2). Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands(1-6). The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock(7-9). Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C(10,11). Here we report multifrequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 x 10(-6) to 10(12) electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.
|
|
| 7. |
|
|
| 8. |
- Marouli, Eirini, et al.
(author)
-
Rare and low-frequency coding variants alter human adult height
- 2017
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
-
Journal article (peer-reviewed)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
- Clark, DW, et al.
(author)
-
Associations of autozygosity with a broad range of human phenotypes
- 2019
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
-
Journal article (peer-reviewed)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
|
|
| 12. |
- Justice, Anne E., et al.
(author)
-
Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
-
In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
-
Journal article (peer-reviewed)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
|
|
| 13. |
- Wessel, Jennifer, et al.
(author)
-
Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Journal article (peer-reviewed)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
|
|
| 14. |
- Witt, S. H., et al.
(author)
-
Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia
- 2017
-
In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7
-
Journal article (peer-reviewed)abstract
- Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P = 4.42 x 10(-7)) and PKP4 (P = 8.67 x 10(-7)); and gene-set analysis yielded a significant finding for exocytosis (GO: 0006887, PFDR = 0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (r(g) = 0.28 [P = 2.99 x 10(-3)]), SCZ (r(g) = 0.34 [P = 4.37 x 10(-5)]) and MDD (r(g) = 0.57 [P = 1.04 x 10(-3)]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
|
|
| 15. |
- de Jong, S, et al.
(author)
-
Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
-
In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
-
Journal article (peer-reviewed)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
|
|
| 16. |
|
|
| 17. |
- Mahajan, Anubha, et al.
(author)
-
Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
-
In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
-
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.
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
- Altenburger, R., et al.
(author)
-
Future water quality monitoring: improving the balance between exposure and toxicity assessments of real-world pollutant mixtures
- 2019
-
In: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4715 .- 2190-4707. ; 31
-
Journal article (peer-reviewed)abstract
- Environmental water quality monitoring aims to provide the data required for safeguarding the environment against adverse biological effects from multiple chemical contamination arising from anthropogenic diffuse emissions and point sources. Here, we integrate the experience of the international EU-funded project SOLUTIONS to shift the focus of water monitoring from a few legacy chemicals to complex chemical mixtures, and to identify relevant drivers of toxic effects. Monitoring serves a range of purposes, from control of chemical and ecological status compliance to safeguarding specific water uses, such as drinking water abstraction. Various water sampling techniques, chemical target, suspect and non-target analyses as well as an array of in vitro, in vivo and in situ bioanalytical methods were advanced to improve monitoring of water contamination. Major improvements for broader applicability include tailored sampling techniques, screening and identification techniques for a broader and more diverse set of chemicals, higher detection sensitivity, standardized protocols for chemical, toxicological, and ecological assessments combined with systematic evidence evaluation techniques. No single method or combination of methods is able to meet all divergent monitoring purposes. Current monitoring approaches tend to emphasize either targeted exposure or effect detection. Here, we argue that, irrespective of the specific purpose, assessment of monitoring results would benefit substantially from obtaining and linking information on the occurrence of both chemicals and potentially adverse biological effects. In this paper, we specify the information required to: (1) identify relevant contaminants, (2) assess the impact of contamination in aquatic ecosystems, or (3) quantify cause-effect relationships between contaminants and adverse effects. Specific strategies to link chemical and bioanalytical information are outlined for each of these distinct goals. These strategies have been developed and explored using case studies in the Danube and Rhine river basins as well as for rivers of the Iberian Peninsula. Current water quality assessment suffers from biases resulting from differences in approaches and associated uncertainty analyses. While exposure approaches tend to ignore data gaps (i.e., missing contaminants), effect-based approaches penalize data gaps with increased uncertainty factors. This integrated work suggests systematic ways to deal with mixture exposures and combined effects in a more balanced way, and thus provides guidance for future tailored environmental monitoring.
|
|
| 21. |
- Leloudas, G., et al.
(author)
-
The superluminous transient ASASSN-15lh as a tidal disruption event from a Kerr black hole
- 2016
-
In: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 1:1
-
Journal article (peer-reviewed)abstract
- When a star passes within the tidal radius of a supermassive black hole, it will be torn apart1. For a star with the mass of the Sun (M-circle dot) and a non-spinning black hole with a mass <10(8)M(circle dot), the tidal radius lies outside the black hole event horizon2 and the disruption results in a luminous flare(3-6). Here we report observations over a period of ten months of a transient, hitherto interpreted(7) as a superluminous supernova(8). Our data show that the transient rebrightened substantially in the ultraviolet and that the spectrum went through three different spectroscopic phases without ever becoming nebular. Our observations are more consistent with a tidal disruption event than a superluminous supernova because of the temperature evolution(6), the presence of highly ionized CNO gas in the line of sight(9) and our improved localization of the transient in the nucleus of a passive galaxy, where the presence of massive stars is highly unlikely(10,11). While the supermassive black hole has a mass >10(8)M(circle dot)(12,13), a star with the same mass as the Sun could be disrupted outside the event horizon if the black hole were spinning rapidly(14). The rapid spin and high black hole mass can explain the high luminosity of this event.
|
|
| 22. |
- Lyman, J. D., et al.
(author)
-
The optical afterglow of the short gamma-ray burst associated with GW170817
- 2018
-
In: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 2:9, s. 751-754
-
Journal article (peer-reviewed)abstract
- The binary neutron star merger GW170817 was the first multi-messenger event observed in both gravitational and electromagnetic waves(1,2). The electromagnetic signal began approximately two seconds post-merger with a weak, short burst of gamma rays(3), which was followed over the next hours and days by the ultraviolet, optical and near-infrared emission from a radioactively powered kilonova(4-11). Later, non-thermal rising X-ray and radio emission was observed(12,13). The low luminosity of the gamma rays and the rising non-thermal flux from the source at late times could indicate that we are outside the opening angle of the beamed relativistic jet. Alternatively, the emission could be arising from a cocoon of material formed from the interaction between a jet and the merger ejecta(13-15). Here we present late-time optical detections and deep near-infrared limits on the emission from GW170817 at 110 days post-merger. Our new observations are at odds with expectations of late-time emission from kilonova models, being too bright and blue(16,17). Instead, the emission arises from the interaction between the relativistic ejecta of GW170817 and the interstellar medium. We show that this emission matches the expectations of a Gaussian-structured relativistic jet, which would have launched a high-luminosity, short gamma-ray burst to an aligned observer. However, other jet structure or cocoon models can also match current data-the future evolution of the afterglow will directly distinguish the origin of the emission.
|
|
| 23. |
- Smartt, S. J., et al.
(author)
-
PESSTO : survey description and products from the first data release by the Public ESO Spectroscopic Survey of Transient Objects
- 2015
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 579
-
Journal article (peer-reviewed)abstract
- Context. The Public European Southern Observatory Spectroscopic Survey of Transient Objects (PESSTO) began as a public spectroscopic survey in April 2012. PESSTO classifies transients from publicly available sources and wide-field surveys, and selects science targets for detailed spectroscopic and photometric follow-up. PESSTO runs for nine months of the year, January - April and August - December inclusive, and typically has allocations of 10 nights per month. Aims. We describe the data reduction strategy and data products that are publicly available through the ESO archive as the Spectroscopic Survey data release 1 (SSDR1). Methods. PESSTO uses the New Technology Telescope with the instruments EFOSC2 and SOFI to provide optical and NIR spectroscopy and imaging. We target supernovae and optical transients brighter than 20.5(m) for classification. Science targets are selected for follow-up based on the PESSTO science goal of extending knowledge of the extremes of the supernova population. We use standard EFOSC2 set-ups providing spectra with resolutions of 13-18 angstrom between 3345-9995 angstrom. A subset of the brighter science targets are selected for SOFI spectroscopy with the blue and red grisms (0.935-2.53 mu m and resolutions 23-33 angstrom) and imaging with broadband JHK(s) filters. Results. This first data release (SSDR1) contains flux calibrated spectra from the first year (April 2012-2013). A total of 221 confirmed supernovae were classified, and we released calibrated optical spectra and classifications publicly within 24 h of the data being taken (via WISeREP). The data in SSDR1 replace those released spectra. They have more reliable and quantifiable flux calibrations, correction for telluric absorption, and are made available in standard ESO Phase 3 formats. We estimate the absolute accuracy of the flux calibrations for EFOSC2 across the whole survey in SSDR1 to be typically similar to 15%, although a number of spectra will have less reliable absolute flux calibration because of weather and slit losses. Acquisition images for each spectrum are available which, in principle, can allow the user to refine the absolute flux calibration. The standard NIR reduction process does not produce high accuracy absolute spectrophotometry but synthetic photometry with accompanying JHK(s) imaging can improve this. Whenever possible, reduced SOFI images are provided to allow this. Conclusions. Future data releases will focus on improving the automated flux calibration of the data products. The rapid turnaround between discovery and classification and access to reliable pipeline processed data products has allowed early science papers in the first few months of the survey.
|
|
| 24. |
- Tanvir, N. R., et al.
(author)
-
The Emergence of a Lanthanide-rich Kilonova Following the Merger of Two Neutron Stars
- 2017
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 848:2
-
Journal article (peer-reviewed)abstract
- We report the discovery and monitoring of the near-infrared counterpart (AT2017gfo) of a binary neutron-star merger event detected as a gravitational wave source by Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)/Virgo (GW170817) and as a short gamma-ray burst by Fermi Gamma-ray Burst Monitor (GBM) and Integral SPI-ACS (GRB 170817A). The evolution of the transient light is consistent with predictions for the behavior of a kilonova/ macronova powered by the radioactive decay of massive neutron-rich nuclides created via r-process nucleosynthesis in the neutron-star ejecta. In particular, evidence for this scenario is found from broad features seen in Hubble Space Telescope infrared spectroscopy, similar to those predicted for lanthanide-dominated ejecta, and the much slower evolution in the near-infrared K-s-band compared to the optical. This indicates that the late-time light is dominated by high-opacity lanthanide-rich ejecta, suggesting nucleosynthesis to the third r-process peak (atomic masses A approximate to 195). This discovery confirms that neutron-star mergers produce kilo-/macronovae and that they are at least a major-if not the dominant-site of rapid neutron capture nucleosynthesis in the universe.
|
|
| 25. |
|
|
| 26. |
- Anderson, J. P., et al.
(author)
-
A nearby super-luminous supernova with a long pre-maximum plateau and strong C (II) features
- 2018
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 620
-
Journal article (peer-reviewed)abstract
- Context. Super-luminous supernovae (SLSNe) are rare events defined as being significantly more luminous than normal terminal stellar explosions. The source of the additional power needed to achieve such luminosities is still unclear. Discoveries in the local Universe (i.e. z < 0.1) are scarce, but afford dense multi-wavelength observations. Additional low-redshift objects are therefore extremely valuable.Aims. We present early-time observations of the type I SLSN ASASSN-18km/SN 2018bsz. These data are used to characterise the event and compare to literature SLSNe and spectral models. Host galaxy properties are also analysed.Methods. Optical and near-IR photometry and spectroscopy were analysed. Early-time ATLAS photometry was used to constrain the rising light curve. We identified a number of spectral features in optical-wavelength spectra and track their time evolution. Finally, we used archival host galaxy photometry together with H( II )region spectra to constrain the host environment.Results. ASASSN-18km/SN 2018bsz is found to be a type I SLSN in a galaxy at a redshift of 0.0267 (111 Mpc), making it the lowest-redshift event discovered to date. Strong C- II lines are identified in the spectra. Spectral models produced by exploding a Wolf-Rayet progenitor and injecting a magnetar power source are shown to be qualitatively similar to ASASSN-18km/SN 2018bsz, contrary to most SLSNe-I that display weak or non-existent C (II) lines. ASASSN-18km/SN 2018bsz displays along, slowly rising, red plateau of >26 days, before a steeper, faster rise to maximum. The host has an absolute magnitude of -19.8 mag (r), a mass of M-* = 1.5(-0.33)(+0.08) x 10(9) M-circle dot, and a star formation rate of =0.50(-0.19)(+2.22) M-circle dot yr(-1). A nearby H (II) region has an oxygen abundance (O3N2) of 8.31 +/- 0.01 dex.
|
|
| 27. |
- Arnau-Soler, A, et al.
(author)
-
Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland
- 2019
-
In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 14-
-
Journal article (peer-reviewed)abstract
- Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10−6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10−9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10−8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10−8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10−6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10−3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.
|
|
| 28. |
- Bennett, A. I., et al.
(author)
-
Contact Measurements of Randomly Rough Surfaces
- 2017
-
In: Tribology letters. - : Springer Science and Business Media, LLC. - 1023-8883 .- 1573-2711. ; 65:4
-
Journal article (peer-reviewed)abstract
- This manuscript presents an experimental effort to directly measure contact areas and the details behind these scaled experiments on a randomly rough model surface used in the “Contact Mechanics Challenge” (2017). For these experiments, the randomly rough surface model was scaled up by a factor of 1000× to give a 100 mm square sample that was 3D printed from opaque polymethylmethacrylate (PMMA). This sample was loaded against various optically smooth and transparent samples of PDMS that were approximately 15 mm thick and had a range in elastic modulus from 14 kPa to 2.1 MPa. During loading, a digital camera recorded contact locations by imaging the scattering of light that occurs off of the PMMA rough surface when it was in contact with the PDMS substrate. This method of illuminating contact areas is called frustrated total internal reflection and is performed by creating a condition of total internal reflection within the unperturbed PDMS samples. Contact or deformation of the surface results in light being diffusely transmitted from the PDMS and detected by the camera. For these experiments, a range of reduced pressure (nominal pressure/elastic modulus) from below 0.001 to over 1.0 was examined, and the resulting relative contact area (real area of contact/apparent area of contact) was found to increase from below 0.1% to over 60% at the highest pressures. The experimental uncertainties associated with experiments are discussed, and the results are compared to the numerical results from the simulation solution to the “Contact Mechanics Challenge.” The simulation results and experimental results of the relative contact areas as a function of reduced pressure are in agreement (within experimental uncertainties).
|
|
| 29. |
- Bennett, A. I., et al.
(author)
-
Deformation Measurements of Randomly Rough Surfaces
- 2017
-
In: Tribology letters. - : Springer Science and Business Media, LLC. - 1023-8883 .- 1573-2711. ; 65:4
-
Journal article (peer-reviewed)abstract
- Measurements of surface deformations as part of the “Contact Mechanics Challenge” were collected using digital image correlation (DIC). For these experiments, a scaled version (1000×) of the periodic and random roughness surface provided for the “Contact Mechanics Challenge” was used. A 100 mm × 100 mm scale replica of the surface, approximately 10 mm thick, was 3D-printed using an opaque polymethylmethacrylate and pressed into contact against flat, transparent polydimethylsiloxane (PDMS) sheets with dead weight loads. Four different formulations of PDMS were used, and the resulting elastic moduli ranged from 64 kPa to 2.1 MPa. The DIC technique was used in situ to measure the deformation of the PDMS surface at each load increment from 22.5 to 450 N. Surface deformations in and out of contact were measured across the entire apparent area of contact and overlaid with the measurements of contact area to provide a complete description of the surface profile during loading. A direct comparison between these experiments and the simulations regarding the gap within the contact at a reduced pressure of 0.164 agrees to within ±10% when normalized to the maximum gap.
|
|
| 30. |
- Buijsse, B, et al.
(author)
-
Consumption of fatty foods and incident type 2 diabetes in populations from eight European countries.
- 2015
-
In: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 1476-5640 .- 0954-3007. ; 69:4, s. 455-461
-
Journal article (peer-reviewed)abstract
- Background/Objectives:Diets high in saturated and trans fat and low in unsaturated fat may increase type 2 diabetes (T2D) risk, but studies on foods high in fat per unit weight are sparse. We assessed whether the intake of vegetable oil, butter, margarine, nuts and seeds and cakes and cookies is related to incident T2D.Subjects/Methods:A case-cohort study was conducted, nested within eight countries of the European Prospective Investigation into Cancer (EPIC), with 12 403 incident T2D cases and a subcohort of 16 835 people, identified from a cohort of 340 234 people. Diet was assessed at baseline (1991-1999) by country-specific questionnaires. Country-specific hazard ratios (HRs) across four categories of fatty foods (nonconsumers and tertiles among consumers) were combined with random-effects meta-analysis.Results:After adjustment not including body mass index (BMI), nonconsumers of butter, nuts and seeds and cakes and cookies were at higher T2D risk compared with the middle tertile of consumption. Among consumers, cakes and cookies were inversely related to T2D (HRs across increasing tertiles 1.14, 1.00 and 0.92, respectively; P-trend <0.0001). All these associations attenuated upon adjustment for BMI, except the higher risk of nonconsumers of cakes and cookies (HR 1.57). Higher consumption of margarine became positively associated after BMI adjustment (HRs across increasing consumption tertiles: 0.93, 1.00 and 1.12; P-trend 0.03). Within consumers, vegetable oil, butter and nuts and seeds were unrelated to T2D.Conclusions:Fatty foods were generally not associated with T2D, apart from weak positive association for margarine. The higher risk among nonconsumers of cakes and cookies needs further explanation.European Journal of Clinical Nutrition advance online publication, 26 November 2014; doi:10.1038/ejcn.2014.249.
|
|
| 31. |
- Czamara, D, et al.
(author)
-
Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
- 2019
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2548-
-
Journal article (peer-reviewed)abstract
- Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
|
|
| 32. |
- De Cia, Annalisa, et al.
(author)
-
Light Curves of Hydrogen-poor Superluminous Supernovae from the Palomar Transient Factory
- 2018
-
In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 860:2
-
Journal article (peer-reviewed)abstract
- We investigate the light-curve properties of a sample of 26 spectroscopically confirmed hydrogen- poor superluminous supernovae (SLSNe-I) in the Palomar Transient Factory survey. These events are brighter than SNe Ib/c and SNe Ic-BL, on average, by about 4 and 2. mag, respectively. The peak absolute magnitudes of SLSNe-I in rest-frame g band span -22 less than or similar to M-g less than or similar to -20 mag, and these peaks are not powered by radioactive Ni-56, unless strong asymmetries are at play. The rise timescales are longer for SLSNe than for normal SNe Ib/c, by roughly 10 days, for events with similar decay times. Thus, SLSNe-I can be considered as a separate population based on photometric properties. After peak, SLSNe-I decay with a wide range of slopes, with no obvious gap between rapidly declining and slowly declining events. The latter events show more irregularities (bumps) in the light curves at all times. At late times, the SLSN-I light curves slow down and cluster around the 56Co radioactive decay rate. Powering the late-time light curves with radioactive decay would require between 1 and 10M(circle dot) of Ni masses. Alternatively, a simple magnetar model can reasonably fit the majority of SLSNe-I light curves, with four exceptions, and can mimic the radioactive decay of 56Co, up to similar to 400 days from explosion. The resulting spin values do not correlate with the host-galaxy metallicities. Finally, the analysis of our sample cannot strengthen the case for using SLSNe-I for cosmology.
|
|
| 33. |
|
|
| 34. |
- Geisler, Anja, et al.
(author)
-
Pain management after total hip arthroplasty at five different Danish hospitals : A prospective, observational cohort study of 501 patients
- 2019
-
In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 63:7, s. 923-930
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The available literature does not present a "gold standard" for post-operative pain treatment after total hip arthroplasty (THA). The aim of this prospective observational study was to explore and document post-operative pain treatment, including outcomes, in a large cohort of patients undergoing THA at five different Danish hospitals.METHODS: This prospective, multicentre, observational cohort study of 501 THA patients was performed at five different hospitals in the Capital Region and at the Region Zealand in Denmark, from April 2014 to April 2016. The study had two co-primary outcomes: Pain during mobilisation at 6 hours post-operatively (numeric rating scale [NRS] [0-10]) and morphine consumption 0-24 hours post-operatively.RESULTS: A large variety of analgesic treatments were used at the included hospitals and none of the hospitals used the same non-opioid basic analgesic regimen. For all patients at all hospitals, the NRS-pain level during mobilisation at 6 hours was 5 (3-6), (median [interquartile range]) and the 24-hour intravenous morphine (eqv) consumption was 25 mg (18-35). Although some statistically significant differences between hospitals were found for morphine use, no non-opioid analgesic regimen demonstrated consistent clinically relevant superior efficacy. In general, pain levels at rest were low to moderate and pain during mobilisation was moderate.CONCLUSIONS: Analgesic treatment routines differed between hospitals. Pain levels, however, did not differ substantially and were in general low at rest and moderate during mobilisation. No non-opioid analgesic treatment demonstrated consistent analgesic superiority.
|
|
| 35. |
- Hou, Liping, et al.
(author)
-
Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
-
In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
-
Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
|
|
| 36. |
|
|
| 37. |
- Leblanc, K. J., et al.
(author)
-
Stability of High Speed 3D Printing in Liquid-Like Solids
- 2016
-
In: ACS Biomaterials Science & Engineering. - : American Chemical Society. - 2373-9878. ; 2:10, s. 1796-1799
-
Journal article (peer-reviewed)abstract
- Fluid instabilities limit the ability of features to hold their shape in many types of 3D printing as liquid inks solidify into written structures. By 3D printing directly into a continuum of jammed granular microgels, these instabilities are circumvented by eliminating surface tension and body forces. However, this type of 3D printing process is potentially limited by inertial instabilities if performed at high speeds where turbulence may destroy features as they are written. Here, we design and test a high-speed 3D printing experimental system to identify the instabilities that arise when an injection nozzle translates at 1 m/s. We find that the viscosity of the injected material can control the Reynold's instability, and we discover an additional, unanticipated instability near the top surface of the granular microgel medium.
|
|
| 38. |
- Levan, A. J., et al.
(author)
-
The Environment of the Binary Neutron Star Merger GW170817
- 2017
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 848:2
-
Journal article (peer-reviewed)abstract
- We present Hubble Space Telescope (HST) and Chandra imaging, combined with Very Large Telescope MUSE integral field spectroscopy of the counterpart and host galaxy of the first binary neutron star merger detected via gravitational-wave emission by LIGO and Virgo, GW170817. The host galaxy, NGC 4993, is an S0 galaxy at z - 0.009783. There is evidence for large, face-on spiral shells in continuum imaging, and edge-on spiral features visible in nebular emission lines. This suggests that NGC 4993 has undergone a relatively recent (less than or similar to 1 Gyr) dry merger. This merger may provide the fuel for a weak active nucleus seen in Chandra imaging. At the location of the counterpart, HST imaging implies there is no globular or young stellar cluster, with a limit of a few thousand solar masses for any young system. The population in the vicinity is predominantly old with less than or similar to 1% of any light arising from a population with ages <500 Myr. Both the host galaxy properties and those of the transient location are consistent with the distributions seen for short-duration gamma-ray bursts, although the source position lies well within the effective radius (r(e) similar to 3 kpc), providing an r(e)-normalized offset that is closer than similar to 90% of short GRBs. For the long delay time implied by the stellar population, this suggests that the kick velocity was significantly less than the galaxy escape velocity. We do not see any narrow host galaxy interstellar medium features within the counterpart spectrum, implying low extinction, and that the binary may lie in front of the bulk of the host galaxy.
|
|
| 39. |
- Marklund, Matti, et al.
(author)
-
Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
- 2019
-
In: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
-
Journal article (peer-reviewed)abstract
- Background:Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.Methods:We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).Results:In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.Conclusions:In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
|
|
| 40. |
- McGhee, A. J., et al.
(author)
-
Contact and Deformation of Randomly Rough Surfaces with Varying Root-Mean-Square Gradient
- 2017
-
In: Tribology letters. - : Springer New York LLC. - 1023-8883 .- 1573-2711. ; 65:4
-
Journal article (peer-reviewed)abstract
- The “Contact Mechanics Challenge” posed to the tribology community by Müser and Dapp in 2015 detailed a 100 µm × 100 µm randomly rough surface with a root-mean-square gradient of unity, g ¯ = 1. Many surfaces, both natural and synthetic, can be described as randomly rough, but rarely with a root-mean-square gradient as steep as g ¯ = 1. The selection of such a challenging surface parameter was intentional, but potentially limiting for broad comparisons across existing models and theories which may be limited by small-slope approximations. In this manuscript, the root-mean-square gradients (g ¯) of the “Contact Mechanics Challenge” surface were produced on 1000 × scaled models such that there were three different surfaces for study with g¯=0.2,0.5, and 1. In situ measurements of the real area of contact and contact area distributions were performed using frustrated total internal reflectance along with surface deformation measurements performed using digital image correlation. These optical in situ experiments used the scaled 3D-printed rough surfaces that were loaded into contact with smooth, flat, and elastic samples that were made from unfilled PDMS: (10:1) E* = 2.1 MPa Δγ = 4 mJ/m2; (20:1) E* = 0.75 MPa Δγ = 3 mJ/m2; (30:1) E* = 0.24 MPa Δγ = 2 mJ/m2. All of the loading was performed using a uniaxial load frame under force control. A Green’s function molecular dynamics simulation assuming the small-slope approximation was compared to all experimental data. These measurements reveal that decreasing root-mean-square gradient noticeably increases real area of contact area under conditions of “equal” applied load, but variations in the root-mean-square gradient did not significantly alter the contact patch geometry under conditions of nearly equal real area of contact. Including g ¯ in the reduced pressure (p= P/ (E∗ g ¯)) reduced the root-mean-square error between the simulation (g ¯ = 1) and all experimental data for the relative area of contact as a function of reduced pressure over the entire range of surfaces, materials, and loads tested.
|
|
| 41. |
- Mullins, Niamh, et al.
(author)
-
GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
- 2019
-
In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
-
Journal article (peer-reviewed)abstract
- Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
|
|
| 42. |
- Müser, M. H., et al.
(author)
-
Meeting the Contact-Mechanics Challenge
- 2017
-
In: Tribology letters. - : Springer New York LLC. - 1023-8883 .- 1573-2711. ; 65:4
-
Journal article (peer-reviewed)abstract
- This paper summarizes the submissions to a recently announced contact-mechanics modeling challenge. The task was to solve a typical, albeit mathematically fully defined problem on the adhesion between nominally flat surfaces. The surface topography of the rough, rigid substrate, the elastic properties of the indenter, as well as the short-range adhesion between indenter and substrate, were specified so that diverse quantities of interest, e.g., the distribution of interfacial stresses at a given load or the mean gap as a function of load, could be computed and compared to a reference solution. Many different solution strategies were pursued, ranging from traditional asperity-based models via Persson theory and brute-force computational approaches, to real-laboratory experiments and all-atom molecular dynamics simulations of a model, in which the original assignment was scaled down to the atomistic scale. While each submission contained satisfying answers for at least a subset of the posed questions, efficiency, versatility, and accuracy differed between methods, the more precise methods being, in general, computationally more complex. The aim of this paper is to provide both theorists and experimentalists with benchmarks to decide which method is the most appropriate for a particular application and to gauge the errors associated with each one..
|
|
| 43. |
- Noguchi, S, et al.
(author)
-
FANTOM5 CAGE profiles of human and mouse samples
- 2017
-
In: Scientific data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4, s. 170112-
-
Journal article (peer-reviewed)abstract
- In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
|
|
| 44. |
|
|
| 45. |
- Reinbold, C. S., et al.
(author)
-
Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
- 2018
-
In: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 9
-
Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen) Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD associated miRNAs However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
|
|
| 46. |
|
|
| 47. |
|
|
| 48. |
- Tchebakova, N. M., et al.
(author)
-
Energy and Mass Exchange and the Productivity of Main Siberian Ecosystems (from Eddy Covariance Measurements). 2. Carbon Exchange and Productivity
- 2015
-
In: Biology Bulletin of the Russian Academy of Science. - 1062-3590. ; 42:6, s. 579-588
-
Journal article (peer-reviewed)abstract
- Direct measurements of CO2 fluxes by the eddy covariance method have demonstrated that the examined middle-taiga pine forest, raised bog, true steppe, and southern tundra along the Yenisei meridian (similar to 90 degrees E) are carbon sinks of different capacities according to annual output. The tundra acts as a carbon sink starting from June; forest and bog, from May; and steppe, from the end of April. In transitional seasons and winter, the ecosystems are a weak source of carbon; this commences from September in the tundra, from October in the forest and bog, and from November in the steppe. The photosynthetic productivity of forest and steppe ecosystems, amounting to 480-530 g C/(m(2) year), exceeds by 2-2.5 times that of bogs and tundras, 200-220 g C/(m(2) year). The relationships between the heat balance structure and CO2 exchange are shown. Possible feedback of carbon exchange between the ecosystems and atmosphere as a result of climate warming in the region are assessed.
|
|
| 49. |
|
|
| 50. |
- Weismuller, T. J., et al.
(author)
-
Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis
- 2017
-
In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 152:8
-
Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P <.001 and HR, 0.90; P =.03, respectively) and malignancy (HR, 0.68; P =.008 and HR, 0.77; P =.004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P <.001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P =.002 and HR, 0.68; P <.001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P <.001 and adjusted HR for women, 0.48; P =.003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P <.001) or no IBD (HR, 1.15; P =.002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.
|
|
