| 1. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 2. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 3. |
- Kong, Wan-Yee, et al.
(författare)
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Validation of Serial Alberta Stroke Program Early CT Score as an Outcome Predictor in Thrombolyzed Stroke Patients.
- 2017
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Ingår i: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057 .- 1532-8511. ; 26:10, s. 2264-2271
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Alberta Stroke Program Early CT Score (ASPECTS) on baseline imaging is an established predictor of functional outcome in anterior circulation acute ischemic stroke (AIS). We studied ASPECTS before intravenous thrombolysis (IVT) and at 24 hours to assess its prognostic value.METHODS: Data for consecutive anterior circulation AIS patients treated with IVT from 2006 to 2013 were extracted from a prospectively managed registry at our tertiary center. Pre-thrombolysis and 24-hour ASPECTS were evaluated by 2 independent neuroradiologists. Outcome measures included symptomatic intracranial hemorrhage (SICH), modified Rankin Scale (mRS) at 90 days, and mortality. Unfavorable functional outcome was defined by mRS >1. Dramatic ASPECTS progression (DAP) was defined as deterioration in ASPECTS by 6 points or more.RESULTS: Of 554 AIS patients thrombolyzed during the study period, 400 suffered from anterior circulation infarction. The median age was 65 years (interquartile range (IQR): 59-70) and the median National Institutes of Health Stroke Scale score was 18 points (IQR: 12-22). Compared with the pre-IVT ASPECTS (area under the curve [AUC] = .64, 95% confidence interval [CI]: .54-.65, P = .001), ASPECTS on the 24-hour CT scan (AUC = .78, 95% CI: .73-.82, P < .001), and change in ASPECTS (AUC = .69, 95% CI: .64-.74, P < .001) were better predictors of unfavorable functional outcome at 3 months. DAP, noted in 34 (14.4%) patients with good baseline ASPECTS (8-10 points), was significantly associated with unfavorable functional outcome (odds ratio [OR]: 9.91, 95% CI: 3.37-29.19, P ≤ .001), mortality (OR: 21.99, 95% CI: 7.98-60.58, P < .001), and SICH (OR: 8.57, 95% CI: 2.87-25.59, P < .001).CONCLUSION: Compared with the pre-thrombolysis score, ASPECTS measured at 24 hours as well as serial change in ASPECTS is a better predictor of 3-month functional outcome.
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| 4. |
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| 5. |
- Brolin, Kajsa, et al.
(författare)
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RIC3 variants are not associated with Parkinson's disease in large European, Latin American, or East Asian cohorts
- 2022
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 109, s. 264-268
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is a complex neurodegenerative disorder in which both rare and common genetic variants contribute to disease risk. Multiple genes have been reported to be linked to monogenic PD but these only explain a fraction of the observed familial aggregation. Rare variants in RIC3 have been suggested to be associated with PD in the Indian population. However, replication studies yielded inconsistent results. We further investigate the role of RIC3 variants in PD in European cohorts using individual-level genotyping data from 14,671 PD patients and 17,667 controls, as well as whole-genome sequencing data from 1,615 patients and 961 controls. We also investigated RIC3 using summary statistics from a Latin American cohort of 1,481 individuals, and from a cohort of 31,575 individuals of East Asian ancestry. We did not identify any association between RIC3 and PD in any of the cohorts. However, more studies of rare variants in non-European ancestry populations, in particular South Asian populations, are necessary to further evaluate the world-wide role of RIC3 in PD etiology.
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| 6. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 7. |
- Leonard, Hampton L., et al.
(författare)
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The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson’s disease data
- 2023
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Ingår i: npj Parkinson's Disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Open science and collaboration are necessary to facilitate the advancement of Parkinson’s disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD.
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| 8. |
- Manzoni, Claudia, et al.
(författare)
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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
- 2024
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Ingår i: American Journal of Human Genetics. - 0002-9297. ; 111:7, s. 1316-1329
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
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| 9. |
- Yeo, Leonard L L, et al.
(författare)
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Nongated Cardiac Computed Tomographic Angiograms for Detection of Embolic Sources in Acute Ischemic Stroke
- 2017
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 48:5, s. 1256-1261
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: axis coverage of a non-ECG-gated computed tomographic angiogram performed in the primary evaluation of acute stroke without increasing the contrast dose.METHODS: Twenty consecutive patients with acute ischemic stroke within the 4.5 hours of symptom onset were prospectively recruited. We increased the longitudinal coverage to the domes of the diaphragm to include the heart. Contrast administration (Omnipaque 350) remained unchanged (injected at 3-4 mL/s; total 60-80 mL, triggered by bolus tracking). Images of the heart and aorta, reconstructed at 5 mm slice thickness in 3 orthogonal planes, were read by a radiologist and cardiologist, findings conveyed to the treating neurologist, and correlated with the transthoracic or transesophageal echocardiogram performed within the next 24 hours.RESULTS: Of 20 patients studied, 3 (15%) had abnormal findings: a left ventricular thrombus, a Stanford type A aortic dissection, and a thrombus of the left atrial appendage. Both thrombi were confirmed by transesophageal echocardiography, and anticoagulation was started urgently the following day. None of the patients developed contrast-induced nephropathy on follow-up. The radiation dose was slightly increased from a mean of 4.26 mSV (range, 3.88-4.70 mSV) to 5.17 (range, 3.95 to 6.25 mSV).CONCLUSIONS: Including the heart and ascending aorta in a routine non-ECG-gated computed tomographic angiogram enhances an existing imaging modality, with no increased incidence of contrast-induced nephropathy and minimal increase in radiation dose. This may help in the detection of high-risk cardiac and aortic sources of embolism in acute stroke patients.
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| 10. |
- Yeo, Leonard L L, et al.
(författare)
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Synchronous cardiocerebral infarction in the era of endovascular therapy : which to treat first?
- 2017
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 44:1, s. 104-111
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Tidskriftsartikel (refereegranskat)abstract
- A cardiocerebral ischemic attack (CCI) or a concurrent acute ischemic stroke (AIS) and myocardial infarction (AMI) is a severe event with no clear recommendations for ideal management because of the rarity of the scenario. The narrow time window for treatment and complexity of the treatment decision puts immense pressure on the treating physician. We evaluated this challenging situation at our tertiary center. Using our prospective stroke database out of a total of 555 patients with acute ischemic stroke between 2009 and 2014, we identified five consecutive cases with CCI (incidence 0.009%). Demography, risk factor characteristics, vascular occlusions and treatment approach were recorded. Good functional outcome was defined by the modified Rankin scale (mRS) score of 0-2 points. Out of five patients, AIS was treated with endovascular treatment in three cases, while two were treated with intravenous thrombolysis only. One out of three patients had embolectomy of the brain performed prior to the coronary intervention, while the other two patients underwent coronary intervention first. One patient developed sudden cardiac arrest on day-2 and passed away. CCI is an uncommon and devastating clinical scenario, further research is needed for the ideal management strategy that provides the best outcomes. However, the rarity of the disease does not lend itself to the conduct of a trial easily. We have proposed a considered treatment algorithm based on the current literature and our experience.
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