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- 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
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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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| 2. |
- Holmes, Robin B., et al.
(author)
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Creation of an anthropomorphic CT head phantom for verification of image segmentation
- 2020
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In: Medical physics (Lancaster). - : Wiley-Blackwell. - 0094-2405 .- 2473-4209. ; 47:6, s. 2380-2391
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Journal article (peer-reviewed)abstract
- Purpose: Many methods are available to segment structural magnetic resonance (MR) images of the brain into different tissue types. These have generally been developed for research purposes but there is some clinical use in the diagnosis of neurodegenerative diseases such as dementia. The potential exists for computed tomography (CT) segmentation to be used in place of MRI segmentation, but this will require a method to verify the accuracy of CT processing, particularly if algorithms developed for MR are used, as MR has notably greater tissue contrast.Methods: To investigate these issues we have created a three-dimensional (3D) printed brain with realistic Hounsfield unit (HU) values based on tissue maps segmented directly from an individual T1 MRI scan of a normal subject. Several T1 MRI scans of normal subjects from the ADNI database were segmented using SPM12 and used to create stereolithography files of different tissues for 3D printing. The attenuation properties of several material blends were investigated, and three suitable formulations were used to print an object expected to have realistic geometry and attenuation properties. A skull was simulated by coating the object with plaster of Paris impregnated bandages. Using two CT scanners, the realism of the phantom was assessed by the measurement of HU values, SPM12 segmentation and comparison with the source data used to create the phantom.Results: Realistic relative HU values were measured although a subtraction of 60 was required to obtain equivalence with the expected values (gray matter 32.9-35.8 phantom, 29.9-34.2 literature). Segmentation of images acquired at different kVps/mAs showed excellent agreement with the source data (Dice Similarity Coefficient 0.79 for gray matter). The performance of two scanners with two segmentation methods was compared, with the scanners found to have similar performance and with one segmentation method clearly superior to the other.Conclusion: The ability to use 3D printing to create a realistic (in terms of geometry and attenuation properties) head phantom has been demonstrated and used in an initial assessment of CT segmentation accuracy using freely available software developed for MRI.
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| 3. |
- 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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