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- Arranz, Belén
(author)
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Neurobiological aspects of human aging and suicide
- 1994
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Doctoral thesis (other academic/artistic)abstract
- This thesis addresses: 1) The involvement of the monoaminergic and neuropeptidergic neurotransmitter systems in the aging process, and 2) The contribution of these systems in the etiology of an age-related mental disorder: the depressive syndrome. Because of the evidence suggesting the efficacy of the SSRI in the treatment of some age-related symptoms, a comparison study of the binding characteristics of two SSRI, i.e. [3H]paroxetine and [3H]citalopram, to the human brain 5-HT uptake site was included.Neurochemical analysis, involving HPLC, binding assays and RIA methods, was performed in several brain regions from 23 control subjects and 18 suicides pooled according to the method of death and the prior existence of depressive symptoms.Both [3H]paroxetine and [3H]citalopram were found to label the same number of presynaptic 5-HT binding sites, which is in accordance to their ability to identify the same membrane protein. However, the 15 to 30-fold higher affinity displayed by [3H]paroxetine gives evidence to this SSRI having a more easily accesible binding domain in the 5-HT transport complex than [3H]citalopram, and hence being a better marker of thispresynaptic 5-HT carrier system.No statistical differences in either the monoamines 5-HT, NA and DA, their metabolites or the 5-HT binding sites were found between controls and overall suicides. However, a diminished number of 5-HTl D binding sites with advancing age, together with a significant decrease in the number of 5-HTl D binding sites and binding affinity was noticed in the nondepressed and depressed suicides, respectively. These results might indicate the involvement of this novel 5-HT receptor in both some of the physical disturbances present in the elderly population and in the mechanisms underlying the depressive syndrome. Advancing age was also found to be negatively correlated with brain NA, DA and HV A concentrations, thus supporting the increased likelihood of changes in feeding habits and in the hypothalamic-mediated endocrine dysfunctionscommonly observed in senescence.With regard to the neuropeptidergic neurotransmitter systems, age-related decreases in gyrus cinguli NPY and CRF concentrations were noted. In addition, although unchanged NPY, SOM and CRF concentrations were observed in the overall suicide group, the HPLC analysis revealed that the depressed suicides showed a different pattern of NPY-LI fragments, which is in agreement with depression being associated with an altered processing or metabolism of the intact NPY molecule.
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| 2. |
- Cruz, Raquel, et al.
(author)
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Novel genes and sex differences in COVID-19 severity
- 2022
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Journal article (peer-reviewed)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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