| 1. |
- Surendran, Praveen, et al.
(author)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Journal article (peer-reviewed)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 2. |
- Erzurumluoglu, A. Mesut, et al.
(author)
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
- 2020
-
In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
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Journal article (peer-reviewed)abstract
- Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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| 3. |
- Eikelboom, Willem S., et al.
(author)
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The reporting of neuropsychiatric symptoms in electronic health records of individuals with Alzheimer’s disease : a natural language processing study
- 2023
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In: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
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Journal article (peer-reviewed)abstract
- Background: Neuropsychiatric symptoms (NPS) are prevalent in the early clinical stages of Alzheimer’s disease (AD) according to proxy-based instruments. Little is known about which NPS clinicians report and whether their judgment aligns with proxy-based instruments. We used natural language processing (NLP) to classify NPS in electronic health records (EHRs) to estimate the reporting of NPS in symptomatic AD at the memory clinic according to clinicians. Next, we compared NPS as reported in EHRs and NPS reported by caregivers on the Neuropsychiatric Inventory (NPI). Methods: Two academic memory clinic cohorts were used: the Amsterdam UMC (n = 3001) and the Erasmus MC (n = 646). Patients included in these cohorts had MCI, AD dementia, or mixed AD/VaD dementia. Ten trained clinicians annotated 13 types of NPS in a randomly selected training set of n = 500 EHRs from the Amsterdam UMC cohort and in a test set of n = 250 EHRs from the Erasmus MC cohort. For each NPS, a generalized linear classifier was trained and internally and externally validated. Prevalence estimates of NPS were adjusted for the imperfect sensitivity and specificity of each classifier. Intra-individual comparison of the NPS classified in EHRs and NPS reported on the NPI were conducted in a subsample (59%). Results: Internal validation performance of the classifiers was excellent (AUC range: 0.81–0.91), but external validation performance decreased (AUC range: 0.51–0.93). NPS were prevalent in EHRs from the Amsterdam UMC, especially apathy (adjusted prevalence = 69.4%), anxiety (adjusted prevalence = 53.7%), aberrant motor behavior (adjusted prevalence = 47.5%), irritability (adjusted prevalence = 42.6%), and depression (adjusted prevalence = 38.5%). The ranking of NPS was similar for EHRs from the Erasmus MC, although not all classifiers obtained valid prevalence estimates due to low specificity. In both cohorts, there was minimal agreement between NPS classified in the EHRs and NPS reported on the NPI (all kappa coefficients < 0.28), with substantially more reports of NPS in EHRs than on NPI assessments. Conclusions: NLP classifiers performed well in detecting a wide range of NPS in EHRs of patients with symptomatic AD visiting the memory clinic and showed that clinicians frequently reported NPS in these EHRs. Clinicians generally reported more NPS in EHRs than caregivers reported on the NPI.
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| 4. |
- Hutchinson, David K., et al.
(author)
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The Eocene-Oligocene transition : a review of marine and terrestrial proxy data, models and model data comparisons
- 2021
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In: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 17:1, s. 269-315
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Research review (peer-reviewed)abstract
- The Eocene-Oligocene transition (EOT) was a climate shift from a largely ice-free greenhouse world to an icehouse climate, involving the first major glaciation of Antarctica and global cooling occurring similar to 34 million years ago (Ma) and lasting similar to 790 kyr. The change is marked by a global shift in deep-sea delta O-18 representing a combination of deep-ocean cooling and growth in land ice volume. At the same time, multiple independent proxies for ocean temperature indicate sea surface cooling, and major changes in global fauna and flora record a shift toward more cold-climateadapted species. The two principal suggested explanations of this transition are a decline in atmospheric CO2 and changes to ocean gateways, while orbital forcing likely influenced the precise timing of the glaciation. Here we review and synthesise proxy evidence of palaeogeography, temperature, ice sheets, ocean circulation and CO2 change from the marine and terrestrial realms. Furthermore, we quantitatively compare proxy records of change to an ensemble of climate model simulations of temperature change across the EOT. The simulations compare three forcing mechanisms across the EOT: CO2 decrease, palaeogeographic changes and ice sheet growth. Our model ensemble results demonstrate the need for a global cooling mechanism beyond the imposition of an ice sheet or palaeogeographic changes. We find that CO2 forcing involving a large decrease in CO2 of ca. 40 % (similar to 325 ppm drop) provides the best fit to the available proxy evidence, with ice sheet and palaeogeographic changes playing a secondary role. While this large decrease is consistent with some CO2 proxy records (the extreme endmember of decrease), the positive feedback mechanisms on ice growth are so strong that a modest CO2 decrease beyond a critical threshold for ice sheet initiation is well capable of triggering rapid ice sheet growth. Thus, the amplitude of CO2 decrease signalled by our data-model comparison should be considered an upper estimate and perhaps artificially large, not least because the current generation of climate models do not include dynamic ice sheets and in some cases may be undersensitive to CO2 forcing. The model ensemble also cannot exclude the possibility that palaeogeographic changes could have triggered a reduction in CO2.
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| 5. |
- Hutchinson, David K., et al.
(author)
-
The Eocene-Oligocene transition: a review of marine and terrestrial proxy data, models and model-data comparisons
- 2021
-
In: Climate of the Past. - : European Geosciences Union (EGU). - 1814-9324 .- 1814-9332. ; 17:1, s. 269-315
-
Journal article (peer-reviewed)abstract
- The Eocene–Oligocene transition (EOT) was a climate shift from a largely ice-free greenhouse world to an icehouse climate, involving the first major glaciation of Antarctica and global cooling occurring ∼ 34 million years ago (Ma) and lasting ∼ 790 kyr. The change is marked by a global shift in deep-sea δ18O representing a combination of deep-ocean cooling and growth in land ice volume. At the same time, multiple independent proxies for ocean tempera- ture indicate sea surface cooling, and major changes in global fauna and flora record a shift toward more cold-climate- adapted species. The two principal suggested explanations of this transition are a decline in atmospheric CO2 and changes to ocean gateways, while orbital forcing likely influenced the precise timing of the glaciation. Here we review and synthesise proxy evidence of palaeogeography, temperature, ice sheets, ocean circulation and CO2 change from the marine and terrestrial realms. Furthermore, we quantitatively com- pare proxy records of change to an ensemble of climate model simulations of temperature change across the EOT. The simulations compare three forcing mechanisms across the EOT: CO2 decrease, palaeogeographic changes and ice sheet growth. Our model ensemble results demonstrate the need for a global cooling mechanism beyond the imposition of an ice sheet or palaeogeographic changes. We find that CO2 forcing involving a large decrease in CO2 of ca. 40 % (∼ 325 ppm drop) provides the best fit to the available proxy evidence, with ice sheet and palaeogeographic changes play- ing a secondary role. While this large decrease is consistent with some CO2 proxy records (the extreme endmember of decrease), the positive feedback mechanisms on ice growth are so strong that a modest CO2 decrease beyond a critical threshold for ice sheet initiation is well capable of triggering rapid ice sheet growth. Thus, the amplitude of CO2 decrease signalled by our data–model comparison should be consid- ered an upper estimate and perhaps artificially large, not least because the current generation of climate models do not in- clude dynamic ice sheets and in some cases may be under- sensitive to CO2 forcing. The model ensemble also cannot exclude the possibility that palaeogeographic changes could have triggered a reduction in CO2.
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| 6. |
- van der Veldt, Astrid A. M., et al.
(author)
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Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy : Implications for Scheduling of Anti-Angiogenic Drugs
- 2012
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In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 21:1, s. 82-91
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Journal article (peer-reviewed)abstract
- Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([11C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [11C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.
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