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- 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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- Bjartmar, Carl
(author)
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On the relation between nerve fibres and glial cells
- 1996
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Doctoral thesis (other academic/artistic)abstract
- The general aim of this study is to generate knowledge on the normal axo-glial relations in developing and adult vertebrate white matter. CNS and PNS specimens from developing and mature rats and from chickens of various ages were analysed through electron microscopy of single and serial sections, or through immunohistochemistry. Sections from fish, frog and turtle were examined by immunohistochemistry. Teased nerves from adult rats were subjected to light microscopic analysis. In addition, Western blot analysis was performed on material from adult chicken spinal cord.At onset of myelination, oligodendrocytes related to prospective large myelinated axons in the ventral funiculus of the spinal cord contact fewer axons than oligodendrocytes related to axons in the cotpus callosum, which are destined to remain small. This difference increases with time. In addition, the data suggest that some spinal oligodendrocytes in the rat reduce the number of sheaths initially elaborated, before formation of compact myelin. In the chicken, the T4-0 antiserum recognizes a single 50 kDa protein. Staining with different markers for glial cells indicate that the T4-0 immunoreactivity is located mainly to a subgtoup of white matter oligodendrocytes in the ventral funiculus, being colocalized with large fibres which myelinate early during development. The T4-0 molecule is expressed after onset of myelination. It can not be detected in fish, amphibian, reptile and mammalian white matter. These results suggest that oligodendrocytes in the rat and in the chicken form a heterogeneous population and that this heterogeneity is related to time of onset of myelination and prospective axon diameter.In the ventral root L5 of newborn rats, the average Schwann cell sheath is 60-70 Jlm long at onset of myelination. The corresponding adult myelin sheath length is 1250 Jlm. While the sheaths exhibit a developmental elongation of 17 times, the root elongates 11 times only. In developing rat white matter, uncompacted oligodendroglia! sheaths are 21-33 Jlm long, many sheaths being <10 Jlm. The average sheath containing cytoplasmic segments and compact myelin is 102 Jlm long in the spinal cord and 69 Jlm long in the cotpus callosum. The intercalated naked axon portions present are too short to accomodate the developmental sheath elongation. These data show that PNS and CNS initial sheath lengths are markedly different, and indicate that both sheath types undergo an early remodelling.Nodes along thin callosal axons possess tiny node gaps with few or no astrocytic processes. Nodes along thick spinal axons have large node gaps containing scattered astrocytic processes. Antibodies against HNK-1, chondroitin sulfate (CS), tenascin or NSP-4labellarge but not small nodes. These data indicate that the relation between nodal complexity and fibre size is less strict in the CNS than in the PNS and that CS occurs at CNS nodes.
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