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- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 6. |
- Coomans, Emma M., et al.
(författare)
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Genetically identical twins show comparable tau PET load and spatial distribution
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:10, s. 3571-3581
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Tidskriftsartikel (refereegranskat)abstract
- Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in (i) tau load; and (ii) spatial distribution of tau, measured with 18F-flortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6 years), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic 18F-flortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18F-flortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial 18F-flortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18F-flortaucipir BPND. On visual inspection, Alzheimer's disease-like 18F-flortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18F-flortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; P = 0.01), neocortical (r = 0.59; P < 0.01) and global (r = 0.56; P < 0.01) regions, but not in the temporal region (r = 0.20; P = 0.10). The 18F-flortaucipir distribution pattern was significantly more similar between twins of the same pair [mean r = 0.27; standard deviation (SD) = 0.09] than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (P < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18F-flortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18F-flortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37 < β < 0.56), physical activity (-0.41 < β < -0.42) and social activity (-0.32 < β < -0.36) (all P < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies.
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| 7. |
- Visser, Denise, et al.
(författare)
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Longitudinal Tau PET Using 18F-Flortaucipir : The Effect of Relative Cerebral Blood Flow on Quantitative and Semiquantitative Parameters
- 2023
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 64:2, s. 281-286
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Tidskriftsartikel (refereegranskat)abstract
- Semiquantitative PET measures such as SUV ratio (SUVr) have several advantages over quantitative measures, such as practical applicability and relative computational simplicity. However, SUVr may potentially be affected by changes in blood flow, whereas quantitative measures such as nondisplaceable binding potential (BPND) are not. For 18F-flortaucipir PET, the sensitivity of SUVr for changes in blood flow is currently unknown. Therefore, we compared semiquantitative (SUVr) and quantitative (BPND) parameters of longitudinal 18F-flortaucipir PET scans and assessed their vulnerability to changes in blood flow. Methods: Subjects with subjective cognitive decline (n = 38) and Alzheimer disease patients (n = 24) underwent baseline and 2-y follow-up dynamic 18F-flortaucipir PET scans. BPND and relative tracer delivery were estimated using receptor parametric mapping, and SUVr at 80-100 min was calculated. Regional SUVrs were compared with corresponding distribution volume ratio (BPND + 1) using paired t tests. Additionally, simulations were performed to model effects of larger flow changes in different binding categories. Results: Results in subjective cognitive decline and Alzheimer disease showed only minor differences between SUVr and BPND changes over time. Relative tracer delivery changes were small in all groups. Simulations illustrated a variable bias for SUVr depending on the amount of binding. Conclusion: SUVr provided an accurate estimate of changes in specific binding for 18F-flortaucipir over a 2-y follow-up during which changes in flow were small. Notwithstanding, simulations showed that large(r) flow changes may affect 18F-flortaucipir SUVr. Given that it is currently unknown to what order of magnitude pharmacotherapeutic interventions may induce changes in cerebral blood flow, caution may be warranted when changes in flow are potentially large(r), as in clinical trials.
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- de Jong, Sarah, et al.
(författare)
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Effect of rare coding variants in the CFI gene on Factor I expression levels
- 2020
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 29:14, s. 2313-2324
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Tidskriftsartikel (refereegranskat)abstract
- Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg, p.Gly188Ala and c.772G>A (r.685_773del), significantly reduced FI plasma levels were detected. Furthermore, recombinant FI expression levels were determined for 126 rare coding variants. Of these variants 68 (54%) resulted in significantly reduced FI expression in supernatant compared to wildtype (WT). The recombinant protein expression levels correlated significantly with the FI level in plasma of carriers of CFI variants. In this study, we performed the most comprehensive FI expression level analysis of rare coding variants in CFI to date. More than half of CFI variants lead to reduced FI expression, which might impair complement regulation in vivo. Our study will aid the interpretation of rare coding CFI variants identified in clinical practice, which is in particular important in light of patient inclusion in ongoing clinical trials for CFI gene supplementation in AMD.
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| 9. |
- de Jong, Sarah, et al.
(författare)
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Functional Analysis of Variants in Complement Factor I Identified in Age-Related Macular Degeneration and Atypical Hemolytic Uremic Syndrome
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Complement factor I (FI) is a central inhibitor of the complement system, and impaired FI function increases complement activation, contributing to diseases such as age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (aHUS). Genetic variation in complement factor I (CFI) has been identified in both AMD and aHUS, with more than half of these variants leading to reduced FI secretion levels. For many of the variants with normal FI secretion, however, functional implications are not yet known. Here we studied 11 rare missense variants, with FI secretion levels comparable to wildtype, but a predicted damaging effects based on the Combined Annotation Dependent Depletion (CADD) score. Three variants (p.Pro50Ala, p.Arg339Gln, and p.Ser570Thr) were analyzed in plasma and serum samples of carriers affected by AMD. All 11 variants (nine for the first time in this study) were recombinantly expressed and the ability to degrade C3b was studied with the C3b degradation assay. The amount of degradation was determined by measuring the degradation product iC3b with ELISA. Eight of 11 (73%) mutant proteins (p.Pro50Ala, p.Arg339Gln, p.Ile340Thr, p.Gly342Glu, p.Gly349Arg, p.Arg474Gln, p.Gly487Cys, and p.Gly512Ser) showed significantly impaired C3b degradation, and were therefore classified as likely pathogenic. Our data indicate that genetic variants in CFI with a CADD score >20 are likely to affect FI function, and that monitoring iC3b in a degradation assay is a useful tool to establish the pathogenicity of CFI variants in functional studies.
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| 10. |
- Mansell, G., et al.
(författare)
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A Person-Centred Prehabilitation Program based on Cognitive Behavioural Physical Therapy for patients scheduled for Lumbar Fusion surgery: A mediation analysis to assess fear of movement (kinesiophobia), self-efficacy and catastrophizing as mediators of health outcomes
- 2022
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Ingår i: European Journal of Pain (United Kingdom). - : Wiley. - 1090-3801 .- 1532-2149. ; 26:8, s. 1790-1799
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate whether early changes in fear of movement (kinesiophobia), self-efficacy and catastrophizing were mediators of the relationship between allocation to the pre-habilitation intervention and later changes in health outcomes. Methods: The original pre-habilitation trial (PREPARE, ISRCTN17115599) recruited 118 participants awaiting lumbar fusion surgery, half of whom received a prehabilitation intervention designed based on the modified fear-avoidance model and half of whom received usual care. Mediation analysis was performed to test each mediator separately. Analysis was performed on each outcome of interest separately (Oswestry disability index, patient-specific function, EQ general health and moderate/vigorous physical activity). Mediation analysis was carried out using PROCESS. Beta coefficients and bootstrapped 95% CIs were used to interpret the results. Results: None of the potential mediators was found to mediate the relationship between allocation to the intervention and 3-month scores on any of the health outcomes tested. Conclusions: Screening patients for higher levels of catastrophizing and fear avoidance and lower levels of self-efficacy could help ensure only the patients who are most likely to benefit from the intervention are included. Significance: Prehabilitation interventions for spinal fusion surgery have been found to improve health outcomes for patients. Theory-based interventions that target key mechanisms are more effective at improving outcomes than non-theory-based interventions. While no mediating effects were found for this particular intervention, the analysis suggests that the underlying theoretical model and treatment targets are appropriate and could drive improvement if more strongly targeted. © 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.
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| 11. |
- Lotzke, Hanna, et al.
(författare)
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Developing an evidence-based prehabilitation programme designed to improve functional outcomes after lumbar fusion surgery-A feasibility study using the Medical Research Council framework
- 2020
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Ingår i: European Journal of Physiotherapy. - : Informa UK Limited. - 2167-9169 .- 2167-9177. ; 22:1, s. 51-61
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A prehabilitation phase is suggested as the ideal way to prepare patients for optimal outcomes from surgery. Our aim was to describe the lessons we learned from developing PREPARE, an evidence-based prehabilitation programme based on a cognitive behavioural approach designed to improve functional outcomes after lumbar fusion surgery. Methods: We used the Medical Research Council (MRC) framework approach for developing and designing a complex intervention, specifically the two phases; 'Development' and 'Feasibility and Piloting'. Various aspects of treatment fidelity were evaluated during the phase 'Feasibility and Piloting'. As part of the feasibility element, a pilot Single Subject Research Design study was performed. Eleven patients awaiting lumbar fusion surgery participated in the study. We evaluated in particular the use and application of outcome measures. Results: Significant lessons were learned which we used to adjust the prehabilitation programme to better fit a surgical context. The original treatment manual was elaborated on, the outcome measures adjusted, and the content of the intervention altered. Finally, the PREPARE programme was published in the form of a study protocol. Conclusions: There are significant lessons to be learned from testing a study protocol before it is implemented in a large-scale randomised controlled trial (RCT).
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| 12. |
- van Engelen, Marie Paule E., et al.
(författare)
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Altered brain metabolism in frontotemporal dementia and psychiatric disorders : involvement of the anterior cingulate cortex
- 2023
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Ingår i: EJNMMI Research. - 2191-219X. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Behavioural symptoms and frontotemporal hypometabolism overlap between behavioural variant of frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), hampering diagnostic distinction. Voxel-wise comparisons of brain metabolism might identify specific frontotemporal-(hypo)metabolic regions between bvFTD and PPD. We investigated brain metabolism in bvFTD and PPD and its relationship with behavioural symptoms, social cognition, severity of depressive symptoms and cognitive functioning. Results: Compared to controls, bvFTD showed decreased metabolism in the dorsal anterior cingulate cortex (dACC) (p < 0.001), orbitofrontal cortex (OFC), temporal pole, dorsolateral prefrontal cortex (dlPFC) and caudate, whereas PPD showed no hypometabolism. Compared to PPD, bvFTD showed decreased metabolism in the dACC (p < 0.001, p < 0.05FWE), insula, Broca’s area, caudate, thalamus, OFC and temporal cortex (p < 0.001), whereas PPD showed decreased metabolism in the motor cortex (p < 0.001). Across bvFTD and PPD, decreased metabolism in the temporal cortex (p < 0.001, p < 0.05FWE), dACC and frontal cortex was associated with worse social cognition. Decreased metabolism in the dlPFC was associated with compulsiveness (p < 0.001). Across bvFTD, PPD and controls, decreased metabolism in the PFC and motor cortex was associated with executive dysfunctioning (p < 0.001). Conclusions: Our findings indicate subtle but distinct metabolic patterns in bvFTD and PPD, most strongly in the dACC. The degree of frontotemporal and cingulate hypometabolism was related to impaired social cognition, compulsiveness and executive dysfunctioning. Our findings suggest that the dACC might be an important region to differentiate between bvFTD and PPD but needs further validation.
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