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Mental problems are written in your face

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Background​

Schizophrenia is a severe mental disorder that affects about 1% of the world population. The core features of schizophrenia are positive symptoms including delusions and hallucinations, negative symptoms (especially impaired motivation, reduction in spontaneous speech, and social withdrawal) and cognitive impairment [1, 2]. The first episode of schizophrenia usually occurs in late adolescence or early adulthood [3, 4]. Around 20% of schizophrenia patients have chronic symptoms and disability, and over 50% have intermittent but long-term psychiatric problems [5]. The etiology and pathogenesis of schizophrenia are not very clear, but genetic and environmental synergistic pathogeneses are generally accepted. The estimated heritability of schizophrenia is about 70–85% [6].

Schizophrenia is highly polygenic, as predicted by several genetic epidemiological researches many years ago [7]. Previous genome-wide association studies (GWASs) have revealed more than 100 distinct genetic loci are genome-wide associated with schizophrenia, which have en masse effects [1, 8, 9]. In 2017, Li et al. reported 30 new susceptibility loci of schizophrenia including rs73219805 locus near BNIP3L gene and predicting that the BNIP3L gene may be a susceptibility gene of schizophrenia [10]. Recent research about comparative genetic architectures of schizophrenia also revealed that intron variant of BNIP3L gene, rs117325001, was significantly associated with schizophrenia in a fixed-effect meta-analysis including individuals from East Asian and European ancestries [11].

The BNIP3L gene is located on chromosome 8p21.2 and harbors 6 exons, which encodes a 23.8-kDa protein called BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (NIP3L/NIX) and containing a transmembrane domain and a BH3 domain in the C-terminal region. NIP3L, which belongs to the NIP3 family, has two isoforms produced by alternative splicing (Fig. (Fig.1).1). The protein was a single-pass, transmembrane protein, located in the nuclear envelope, endoplasmic reticulum (ER) region, and outer mitochondrial membrane (OMM) [12, 13]. The transmembrane domain of NIP3L is glycine zipper, and every two NIP3L molecules form detergent-resistant homodimers [12]. Ney stated that mitochondrial clearance in reticulocytes was affected by disruption of NIP3L’s glycine zipper, which suggested that the function realization of NIP3L requires dimerization. The majority of NIP3L protein is cytoplasmic, which contains an LC3-interacting region (LIR) motif and a novel short linear motif (SLiM) [12, 14]. LIR motif may recruit LC3 which bridges cargo with autophagy-generated membrane [15]. SLiM was inferred to interact with a hydrophobic pocket in another protein [12].
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Methionine sulfoxide reductase (MSRA) is an antioxidant enzyme implicated in protection against oxidative stress and protein maintenance. We have previously reported the association of marker D8S542, located within the MSRA gene, with schizophrenia in the Central Valley of Costa Rica (CVCR). By performing fine mapping analysis, we have now identified a potential 3-marker at risk haplotype within MSRA in the same CVCR sample, with a global P value slightly above nominal significance (P = 0.0526). By sequencing the MSRA gene in individuals carrying this haplotype, we identified a novel four-base pair deletion 1792 bases upstream of the MSRA transcription start site. This deletion was significantly under-transmitted to schizophrenia patients in the CVCR sample (P = 0.0292) using FBAT, and this was replicated in a large independent sample of 321 schizophrenia families from the Hispanic population (P = 0.0367). These findings suggest a protective effect of the deletion against schizophrenia. Further, MSRA mRNA levels were significantly lower in lymphoblastoid cell lines of individuals homozygous for the deletion compared to carriers of the normal allele (P = 0.0135), although significance was only evident when genotypes were collapsed. This suggests that the deleted sequence may play a role in regulating MSRA expression. In conclusion, this work points towards MSRA as a novel schizophrenia candidate gene. Further studies into the mechanisms by which MSRA is involved in schizophrenia pathophysiology may shed light into the biological underpinnings of this disorder.
Keywords: linkage disequilibrium, Central Valley of Costa Rica, deletion variant, protection, under-
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Methods​

We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole‐exome sequencing. Prioritized variants were selected by a three‐step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool.

Results​

We identified 42 rare, non‐synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome.

Conclusion​

Next‐generation sequencing approaches in family‐based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.
Keywords: Mendelian, polygenic, schizophrenia, bipolar disorder, rare variant

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Background: The human dystrobrevin binding protein 1 (DTNBP1) gene has been linked to risk for schizophrenia. Recent studies indicate that several single nucleotide polymorphisms (SNPs) in the DTNBP1 gene may also influence general cognitive ability in both schizophrenic patients and healthy control subjects. We examined the relationship between DTNBP1 SNPs and general cognitive ability in nonpsychiatric healthy samples via meta-analysis.

Results: Pooled effect sizes from two of the nine SNPs (rs1018381 and rs2619522) were -.123 and -.083, ps < .01, respectively, suggesting that the minor allele carriers of these SNPs had lower cognitive ability scores than the major allele homozygotes. Results remained significant after examining heterogeneity among samples and potential publication biases. Other SNPs did not show significant effects on general cognitive ability.


Conclusions: Genetic variation in DTNBP1 modestly influences general cognitive ability. Further studies are needed to elucidate the biological mechanisms that may account for this relationship.
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However, studies on clinical phenotypes or endo-phenotypes could offer additional clues or suggestions for the mechanisms of complex diseases. Ma et al. suggested that the GWAS-identified risk gene, methionine sulfoxide reductase A (MSRA), may be associated with fluid intelligence in schizophrenia.65 Fluid intelligence is the capacity to reason and solve novel problems, independent of any knowledge from the past which usually be assessed with Cattell’s Culture-Free Intelligence Test (CCFIT). Wang et al. reported that reduced gray matter (GM) volume was associated with polymorphisms in thromboxane A synthase 1 (TBXAS1), phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma (PIK3C2G) and heparan sulfate-glucosamine 3-sulfotransferase 5 (HS3ST5) in first-episode treatment-naïve patients with schizophrenia.66 Liu et al. evaluated the effects of polygenic risk on cortical gyrification and provided some implications regarding differences in the genetic risk of individuals for schizophrenia to cortical morphology and brain development in Han Chinese population.67 Furthermore, some GWASs have been conducted to assess treatment or side effects in Han Chinese populations.
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www.nature.com

Progress in genome-wide association studies of schizophrenia in Han Chinese populations - Schizophrenia

Since 2006, genome-wide association studies of schizophrenia have led to the identification of numerous novel risk loci for this disease. However, there remains a geographical imbalance in genome-wide association studies, which to date have primarily focused on Western populations. During the...
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