| 1. |
- Mishra, A., et al.
(författare)
-
Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611
-
Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Graff, M., et al.
(författare)
-
Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
-
Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
-
Tidskriftsartikel (refereegranskat)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
|
|
| 5. |
- Justice, A. E., et al.
(författare)
-
Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
|
|
| 6. |
- Aktas, A., et al.
(författare)
-
Measurement of event shape variables in deep-inelastic scattering at HERA
- 2006
-
Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 46:2, s. 343-356
-
Tidskriftsartikel (refereegranskat)abstract
- Deep-inelastic ep scattering data taken with the H1 detector at HERA and corresponding to an integrated luminosity of 106 pb(-1) are used to study the differential distributions of event shape variables. These include thrust, jet broadening, jet mass and the C-parameter. The four-momentum transfer Q is taken to be the relevant energy scale and ranges between 14 GeV and 200 GeV. The event shape distributions are compared with perturbative QCD predictions, which include resummed contributions and analytical power law corrections, the latter accounting for non-perturbative hadronisation effects. The data clearly exhibit the running of the strong coupling alpha(s)(Q) and are consistent with a universal power correction parameter alpha(0) for all event shape variables. A combined QCD fit using all event shape variables yields alpha(s)(m(Z)) = 0.1198 +/- 0.0013 (+0.0056)(-0.0043) and alpha(0) = 0.476 +/- 0.008 (+0.018)(-0.059).
|
|
| 7. |
- Aktas, A., et al.
(författare)
-
Photoproduction of dijets with high transverse momenta at HERA
- 2006
-
Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 639:1, s. 21-31
-
Tidskriftsartikel (refereegranskat)abstract
- Differential dijet cross sections are measured in photoproduction in the region of photon virtualities Q(2) < 1 GeV2 with the H1 detector at the HERA ep collider using an integrated luminosity of 66.6 pb(-1). Jets are defined with the inclusive k perpendicular to algorithm and a minimum transverse momentum of the leading jet of 25 GeV is required. Dijet cross sections are measured indirect and resolved photon enhanced regions separately. Longitudinal proton momentum fractions up to 0.7 are reached. The data compare well with predictions from Monte Carlo event generators based on leading order QCD and parton showers and with next-to-leading order QCD calculations corrected for hadronisation effects.
|
|
| 8. |
- Aktas, A, et al.
(författare)
-
A direct search for stable magnetic monopoles produced in positron-proton collisions at HERA
- 2005
-
Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 41, s. 133-141
-
Tidskriftsartikel (refereegranskat)abstract
- A direct search has been made for magnetic monopoles produced in e(+)p collisions at a centre of mass energy of 300 GeV at HERA. The beam pipe surrounding the interaction region in 1995-1997 was investigated using a SQUID magnetometer to look for stopped magnetic monopoles. During this time an integrated luminosity of 62 pb(-1) was delivered. No magnetic monopoles were observed and charge and mass dependent upper limits on the e(+)p production cross section are set.
|
|
| 9. |
- Aktas, A, et al.
(författare)
-
A general search for new phenomena in ep scattering at HERA
- 2004
-
Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - 0370-2693. ; 602:1-2, s. 14-30
-
Tidskriftsartikel (refereegranskat)abstract
- A model-independent search for deviations from the Standard Model prediction is performed in e(+) p and e(-) p collisions at HERA using H1 data corresponding to an integrated luminosity of 117 pb(-1). For the first time all event topologies involving isolated electrons, photons, muons, neutrinos and jets with high transverse momenta are investigated in a single analysis. Events are assigned to exclusive classes according to their final state. A statistical algorithm is developed to search for deviations from the Standard Model in the distributions of the scalar sum of transverse momenta or invariant mass of final state particles and to quantify their significance. A good agreement with the Standard Model prediction is observed in most of the event classes. The most significant deviation is found for a topology containing an isolated muon, missing transverse momentum and a jet, consistent with a previously reported observation.
|
|
| 10. |
- Aktas, A., et al.
(författare)
-
Elastic J/psi production at HERA
- 2006
-
Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 46:3, s. 585-603
-
Tidskriftsartikel (refereegranskat)abstract
- Cross sections for elastic production of J/psi mesons in photoproduction and electroproduction are measured in electron proton collisions at HERA using an integrated luminosity of 55 pb(-1). Results are presented for photon virtualities Q(2) up to 80 GeV2. The dependence on the photon-proton centre of mass energy W-gamma p is analysed in the range 40 <= W-gamma p <= 305 GeV in photoproduction and 40 <= W-gamma p <= 160 GeV in electroproduction. The W-gamma p dependences of the cross sections do not change significantly with Q(2) and can be described by models based on perturbative QCD. Within such models, the data show a high sensitivity to the gluon density of the proton in the domain of low Bjorken x and low Q(2). Differential cross sections d sigma/dt, where t is the squared four-momentum transfer at the proton vertex, are measured in the range vertical bar t vertical bar < 1.2 GeV2 as functions of W-gamma p and Q(2). Effective Pomeron trajectories are determined for photoproduction and electroproduction. The J/psi production and decay angular distributions are consistent with s-channel helicity conservation. The ratio of the cross sections for longitudinally and transversely polarised photons is measured as a function of Q(2) and is found to be described by perturbative QCD based models.
|
|
