| 1. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 2. |
- Sangeorzan, Irina, et al.
(författare)
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Toward Shared Decision-Making in Degenerative Cervical Myelopathy : Protocol for a Mixed Methods Study
- 2023
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Ingår i: JMIR Research Protocols. - : JMIR Publications. - 1929-0748. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Health care decisions are a critical determinant in the evolution of chronic illness. In shared decision-making (SDM), patients and clinicians work collaboratively to reach evidence-based health decisions that align with individual circumstances, values, and preferences. This personalized approach to clinical care likely has substantial benefits in the oversight of degenerative cervical myelopathy (DCM), a type of nontraumatic spinal cord injury. Its chronicity, heterogeneous clinical presentation, complex management, and variable disease course engenders an imperative for a patient-centric approach that accounts for each patient's unique needs and priorities. Inadequate patient knowledge about the condition and an incomplete understanding of the critical decision points that arise during the course of care currently hinder the fruitful participation of health care providers and patients in SDM. This study protocol presents the rationale for deploying SDM for DCM and delineates the groundwork required to achieve this.Objective: The study's primary outcome is the development of a comprehensive checklist to be implemented upon diagnosis that provides patients with essential information necessary to support their informed decision-making. This is known as a core information set (CIS). The secondary outcome is the creation of a detailed process map that provides a diagrammatic representation of the global care workflows and cognitive processes involved in DCM care. Characterizing the critical decision points along a patient's journey will allow for an effective exploration of SDM tools for routine clinical practice to enhance patient-centered care and improve clinical outcomes.Methods: Both CISs and process maps are coproduced iteratively through a collaborative process involving the input and consensus of key stakeholders. This will be facilitated by Myelopathy.org, a global DCM charity, through its Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy community. To develop the CIS, a 3-round, web-based Delphi process will be used, starting with a baseline list of information items derived from a recent scoping review of educational materials in DCM, patient interviews, and a qualitative survey of professionals. A priori criteria for achieving consensus are specified. The process map will be developed iteratively using semistructured interviews with patients and professionals and validated by key stakeholders.Results: Recruitment for the Delphi consensus study began in April 2023. The pilot-testing of process map interview participants started simultaneously, with the formulation of an initial baseline map underway.Conclusions: This protocol marks the first attempt to provide a starting point for investigating SDM in DCM. The primary work centers on developing an educational tool for use in diagnosis to enable enhanced onward decision-making. The wider objective is to aid stakeholders in developing SDM tools by identifying critical decision junctures in DCM care. Through these approaches, we aim to provide an exhaustive launchpad for formulating SDM tools in the wider DCM community.
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| 3. |
- Su, Zhan, et al.
(författare)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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| 4. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)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.
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| 5. |
- Anney, Richard, et al.
(författare)
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A genome-wide scan for common alleles affecting risk for autism.
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
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Tidskriftsartikel (refereegranskat)abstract
- Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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| 6. |
- Beekman, Jan, et al.
(författare)
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Long-term population trends and shifts in distribution of Bewick's swans cygnus columbianus bewickii wintering in northwest Europe
- 2020
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Ingår i: Wildfowl. - 0954-6324. ; :69, s. 73-102
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Tidskriftsartikel (refereegranskat)abstract
- Coordinated international censuses of the Northwest European Bewick's Swan Cygnus columbianus bewickii population have been undertaken across the swans' wintering range at c. 5-year intervals since 1984. During the early years of the study, numbers increased steadily to a peak of 29,780 individuals in January 1995, but then declined by 39.4% to 18,057 swans counted in January 2010 before showing a partial recovery to 20,149 recorded in January 2015. Changes in distribution across the wintering range were also recorded; a higher proportion of the population now remains in more easterly countries (notably Germany) in mid-winter, whilst only a handful of birds migrated to Ireland (at the western edge of the range) during the 2000s compared to >1,000 wintering there at the start of the study. Variation between censuses in the proportion of swans recorded in different parts of the range were attributable to weather conditions, with more swans wintering further north in warmer years. The overall percentage of cygnets recorded in each of the census years ranged from 9.6% in 2010 to 13.2% in 2005, with no obvious consistency over time in the distribution of cygnets across the wintering range. There were however changes between 1990 and 2015 in the swans' use of feeding habitats, with a decline in the proportion of birds on pasture and a corresponding increase in those on arable land. Decreases in the total population size and changes in distribution in the 21st century have implications for the designation and resultant protection of sites of international importance for the species.
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| 7. |
- Brout, Dillon, et al.
(författare)
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The Pantheon+ analysis : cosmological constraints
- 2022
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Ingår i: Astrophysical Journal. - : Institute of Physics (IOP). - 0004-637X .- 1538-4357. ; 938:2
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Tidskriftsartikel (refereegranskat)abstract
- We present constraints on cosmological parameters from the Pantheon+ analysis of 1701 light curves of 1550 distinct Type Ia supernovae (SNe Ia) ranging in redshift from z = 0.001 to 2.26. This work features an increased sample size from the addition of multiple cross-calibrated photometric systems of SNe covering an increased redshift span, and improved treatments of systematic uncertainties in comparison to the original Pantheon analysis, which together result in a factor of 2 improvement in cosmological constraining power. For a flat ΛCDM model, we find ΩM = 0.334 ± 0.018 from SNe Ia alone. For a flat w0CDM model, we measure w0 = −0.90 ± 0.14 from SNe Ia alone, H0 = 73.5 ± 1.1 km s−1 Mpc−1 when including the Cepheid host distances and covariance (SH0ES), and w0 = -0.978-+0.0310.024 when combining the SN likelihood with Planck constraints from the cosmic microwave background (CMB) and baryon acoustic oscillations (BAO); both w0 values are consistent with a cosmological constant. We also present the most precise measurements to date on the evolution of dark energy in a flat w0waCDM universe, and measure wa = -0.1-+2.00.9 from Pantheon+ SNe Ia alone, H0 = 73.3 ± 1.1 km s−1 Mpc−1 when including SH0ES Cepheid distances, and wa = -0.65-+0.320.28 when combining Pantheon+ SNe Ia with CMB and BAO data. Finally, we find that systematic uncertainties in the use of SNe Ia along the distance ladder comprise less than one-third of the total uncertainty in the measurement of H0 and cannot explain the present “Hubble tension” between local measurements and early universe predictions from the cosmological model.
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| 8. |
- Brout, Dillon, et al.
(författare)
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The Pantheon+ analysis : supercal-fragilistic cross calibration, retrained SALT2 light-curve model, and calibration systematic uncertainty
- 2022
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Ingår i: Astrophysical Journal. - : Institute of Physics (IOP). - 0004-637X .- 1538-4357. ; 938:2
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Tidskriftsartikel (refereegranskat)abstract
- We present a recalibration of the photometric systems in the Pantheon+ sample of Type Ia supernovae (SNe Ia) including those in the SH0ES distance-ladder measurement of H0. We utilize the large and uniform sky coverage of the public Pan-STARRS stellar photometry catalog to cross calibrate against tertiary standards released by individual SN Ia surveys. The most significant updates over the “SuperCal” cross calibration used for the previous Pantheon and SH0ES analyses are: (1) expansion of the number of photometric systems (now 25) and filters (now 105), (2) solving for all filter offsets in all systems simultaneously to produce a calibration uncertainty covariance matrix for cosmological-model constraints, and (3) accounting for the change in the fundamental flux calibration of the Hubble Space Telescope CALSPEC standards from previous versions on the order of 1.5% over a Δλ of 4000 Å. We retrain the SALT2 model and find that our new model coupled with the new calibration of the light curves themselves causes a net distance modulus change (dμ/dz) of 0.04 mag over the redshift range 0 < z < 1. We introduce a new formalism to determine the systematic impact on cosmological inference by propagating the covariance in the fitted calibration offsets through retraining simultaneously with light-curve fitting and find a total calibration uncertainty impact of σw = 0.013; roughly half the size of the sample statistical uncertainty. Similarly, we find the systematic SN calibration contribution to the SH0ES H0 uncertainty is less than 0.2 km s−1 Mpc−1, suggesting that SN Ia calibration cannot resolve the current level of the “Hubble Tension.”
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| 9. |
- Fodarella, Cristina, et al.
(författare)
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The importance of detailed context reinstatement for the production of identifiable composite faces from memory
- 2021
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Ingår i: Visual cognition (Print). - : Taylor & Francis. - 1350-6285 .- 1464-0716. ; 29:3, s. 180-200
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Tidskriftsartikel (refereegranskat)abstract
- Memory is facilitated by reflecting upon, or revisiting, the environment in which information was encoded. We investigated these “context reinstatement” (CR) techniques to improve the effectiveness of facial composites – visual likenesses of a perpetrator’s face constructed by eyewitnesses. Participant-constructors viewed a face and, after a one-day-delay, revisited (Physical CR) or recalled the environmental context (Mental/Detailed CR) before recalling the face and constructing an EvoFIT or a PRO-fit composite. Detailed CR increased correct naming of ensuing composites, but only when participant-constructors suitably encoded the environment. Detailed CR was also effective when combined with another interviewing technique (Holistic-Cognitive Interview), with focus on a target’s character; it was no more effective prompting constructors to engage in greater environmental recall. Analyses indicate that the Detailed CR advantage was mediated by an increase in face recall. Results are applicable by forensic practitioners to aid eyewitness memory, thereby potentially increasing suspect identification and subsequent arrest rates.
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| 10. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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