| 21. |
- de Jong, S, et al.
(författare)
-
Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
-
Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 22. |
|
|
| 23. |
- Figlioli, G, et al.
(författare)
-
The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
-
Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
-
Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
- Haas, Brian J., et al.
(författare)
-
Genome sequence and analysis of the Irish potato famine pathogen Phytophthora infestans
- 2009
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 461:7262, s. 393-398
-
Tidskriftsartikel (refereegranskat)abstract
- Phytophthora infestans is the most destructive pathogen of potato and a model organism for the oomycetes, a distinct lineage of fungus-like eukaryotes that are related to organisms such as brown algae and diatoms. As the agent of the Irish potato famine in the mid-nineteenth century, P. infestans has had a tremendous effect on human history, resulting in famine and population displacement(1). To this day, it affects world agriculture by causing the most destructive disease of potato, the fourth largest food crop and a critical alternative to the major cereal crops for feeding the world's population(1). Current annual worldwide potato crop losses due to late blight are conservatively estimated at $6.7 billion(2). Management of this devastating pathogen is challenged by its remarkable speed of adaptation to control strategies such as genetically resistant cultivars(3,4). Here we report the sequence of the P. infestans genome, which at similar to 240 megabases (Mb) is by far the largest and most complex genome sequenced so far in the chromalveolates. Its expansion results from a proliferation of repetitive DNA accounting for similar to 74% of the genome. Comparison with two other Phytophthora genomes showed rapid turnover and extensive expansion of specific families of secreted disease effector proteins, including many genes that are induced during infection or are predicted to have activities that alter host physiology. These fast-evolving effector genes are localized to highly dynamic and expanded regions of the P. infestans genome. This probably plays a crucial part in the rapid adaptability of the pathogen to host plants and underpins its evolutionary potential.
|
|
| 27. |
- Hampsey, E, et al.
(författare)
-
Protocol for Rhapsody: a longitudinal observational study examining the feasibility of speech phenotyping for remote assessment of neurodegenerative and psychiatric disorders
- 2022
-
Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 12:6, s. e061193-
-
Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative and psychiatric disorders (NPDs) confer a huge health burden, which is set to increase as populations age. New, remotely delivered diagnostic assessments that can detect early stage NPDs by profiling speech could enable earlier intervention and fewer missed diagnoses. The feasibility of collecting speech data remotely in those with NPDs should be established.Methods and analysisThe present study will assess the feasibility of obtaining speech data, collected remotely using a smartphone app, from individuals across three NPD cohorts: neurodegenerative cognitive diseases (n=50), other neurodegenerative diseases (n=50) and affective disorders (n=50), in addition to matched controls (n=75). Participants will complete audio-recorded speech tasks and both general and cohort-specific symptom scales. The battery of speech tasks will serve several purposes, such as measuring various elements of executive control (eg, attention and short-term memory), as well as measures of voice quality. Participants will then remotely self-administer speech tasks and follow-up symptom scales over a 4-week period. The primary objective is to assess the feasibility of remote collection of continuous narrative speech across a wide range of NPDs using self-administered speech tasks. Additionally, the study evaluates if acoustic and linguistic patterns can predict diagnostic group, as measured by the sensitivity, specificity, Cohen’s kappa and area under the receiver operating characteristic curve of the binary classifiers distinguishing each diagnostic group from each other. Acoustic features analysed include mel-frequency cepstrum coefficients, formant frequencies, intensity and loudness, whereas text-based features such as number of words, noun and pronoun rate and idea density will also be used.Ethics and disseminationThe study received ethical approval from the Health Research Authority and Health and Care Research Wales (REC reference: 21/PR/0070). Results will be disseminated through open access publication in academic journals, relevant conferences and other publicly accessible channels. Results will be made available to participants on request.Trial registration numberNCT04939818.
|
|
| 28. |
|
|
| 29. |
- Lee, Christine J., et al.
(författare)
-
Clinical manifestations of COVID-19 breakthrough infections: A systematic review and meta-analysis
- 2022
-
Ingår i: Journal of Medical Virology. - : WILEY. - 0146-6615 .- 1096-9071. ; 94:9, s. 4234-4245
-
Forskningsöversikt (refereegranskat)abstract
- To provide a comparative meta-analysis and systematic review of the risk and clinical outcomes of coronavirus 2019 (COVID-19) infection between fully vaccinated and unvaccinated groups. Eighteen studies of COVID-19 infections in fully vaccinated ("breakthrough infections") and unvaccinated individuals were reviewed from Medline/PubMed, Scopus, Embase, and Web of Science databases. The meta-analysis examined the summary effects and between-study heterogeneity regarding differences in the risk of infection, hospitalization, treatments, and mortality between vaccinated and unvaccinated individuals. he overall risk of infection was lower for the fully vaccinated compared to that of the unvaccinated (relative risk [RR] 0.20, 95% confidence interval [CI]: 0.19-0.21), especially for variants other than Delta (Delta: RR 0.29, 95% CI: 0.13-0.65; other variants: RR 0.06, 95% CI: 0.04-0.08). The risk of asymptomatic infection was not statistically significantly different between fully vaccinated and unvaccinated (RR 0.56, 95% CI: 0.27-1.19). There were neither statistically significant differences in risk of hospitalization (RR 1.06, 95% CI: 0.38-2.93), invasive mechanical ventilation (RR 1.65, 95% CI: 0.90-3.06), or mortality (RR 1.19, 95% CI: 0.79-1.78). Conversely, the risk of supplemental oxygen during hospitalization was significantly higher for the unvaccinated (RR 1.40, 95% CI: 1.08-1.82). Unvaccinated people were more vulnerable to COVID-19 infection than fully vaccinated for all variants. Once infected, there were no statistically significant differences in the risk of hospitalization, invasive mechanical ventilation, or mortality. Still, unvaccinated showed an increased need for oxygen supplementation. Further prospective analysis, including patients risk factors, COVID-19 variants, and the utilized treatment strategies, would be warranted.
|
|
| 30. |
|
|
