scholarly journals Covariance of Interdependent Samples with Application to GWAS

2021 ◽  
Author(s):  
Daniel Krefl ◽  
Sven Bergmann
Keyword(s):  
Bone Structure ◽  
Association Studies ◽  
Covariance Structure ◽  
Surface Expression ◽  
Significance Test ◽  
Cumulative Distribution ◽  
Cell Surface Expression ◽  
Genome Wide Association Studies ◽  
Positive And Negative Coefficients ◽  
Sample Covariance

We devise a significance test for covariance of samples not drawn independently, but with known inter-sample covariance structure. The test distribution we propose is a linear combination of χ2 distributions, with positive and negative coefficients. The corresponding cumulative distribution function can be efficiently calculated with Davies algorithm at high precision. As an application, we propose a test for dependence between SNP-wise effect sizes of two genome-wide association studies at the level of genes. The test can be extended to detect gene-wise causal links. We illustrate this method by uncovering potential shared genetic links between severity of Covid-19, taking of class M05B medication (drugs affecting bone structure and mineralization), Vitamin D (25OHD) and Calcium concentrations. In particular, our method detects a potential role played by chemokine receptor genes linked to TH1 versus TH2 immune reaction, a gene related to integrin beta-1 cell surface expression, and other genes potentially impacting severity of Covid-19.

scholarly journals Relevance of the COPI complex for Alzheimer’s disease progression in vivo

2016 ◽  
Vol 113 (19) ◽  
pp. 5418-5423 ◽  
Author(s):  
Karima Bettayeb ◽  
Basaraj V. Hooli ◽  
Antonio R. Parrado ◽  
Lisa Randolph ◽  
Dante Varotsis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Retrograde Transport ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Memory Impairments ◽  
Ad Mouse Model

Cellular trafficking and recycling machineries belonging to late secretory compartments have been associated with increased Alzheimer’s disease (AD) risk. We have shown that coat protein complex I (COPI)-dependent trafficking, an early step in Golgi-to-endoplasmic reticulum retrograde transport, affects amyloid precursor protein subcellular localization, cell-surface expression, as well as its metabolism. We present here a set of experiments demonstrating that, by targeting subunit δ-COP function, the moderation of the COPI-dependent trafficking in vivo leads to a significant decrease in amyloid plaques in the cortex and hippocampus of neurological 17 mice crossed with the 2xTg AD mouse model. Remarkably, an improvement of the memory impairments was also observed. Importantly, human genetic association studies of different AD cohorts led to the identification of 12 SNPs and 24 mutations located in COPI genes linked to an increased AD risk. These findings further demonstrate in vivo the importance of early trafficking steps in AD pathogenesis and open new clinical perspectives.

scholarly journals FAM210A is a novel determinant of bone and muscle structure and strength

2018 ◽  
Vol 115 (16) ◽  
pp. E3759-E3768 ◽  
Author(s):  
Ken-ichiro Tanaka ◽  
Yingben Xue ◽  
Loan Nguyen-Yamamoto ◽  
John A. Morris ◽  
Ippei Kanazawa ◽  
...  
Keyword(s):  
Lean Mass ◽  
Knockout Mice ◽  
Bone Structure ◽  
Association Studies ◽  
Whole Body ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
Genome Wide ◽  
Fracture Bone ◽  
And Function

Osteoporosis and sarcopenia are common comorbid diseases, yet their shared mechanisms are largely unknown. We found that genetic variation near FAM210A was associated, through large genome-wide association studies, with fracture, bone mineral density (BMD), and appendicular and whole body lean mass, in humans. In mice, Fam210a was expressed in muscle mitochondria and cytoplasm, as well as in heart and brain, but not in bone. Grip strength and limb lean mass were reduced in tamoxifen-inducible Fam210a homozygous global knockout mice (TFam210a−/−), and in tamoxifen-inducible Fam210 skeletal muscle cell-specific knockout mice (TFam210aMus−/−). Decreased BMD, bone biomechanical strength, and bone formation, and elevated osteoclast activity with microarchitectural deterioration of trabecular and cortical bones, were observed in TFam210a−/− mice. BMD of male TFam210aMus−/− mice was also reduced, and osteoclast numbers and surface in TFam210aMus−/− mice increased. Microarray analysis of muscle cells from TFam210aMus−/− mice identified candidate musculoskeletal modulators. FAM210A, a novel gene, therefore has a crucial role in regulating bone structure and function, and may impact osteoporosis through a biological pathway involving muscle as well as through other mechanisms.

scholarly journals Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wei Chou Tseng ◽  
Veronica Reinhart ◽  
Thomas A. Lanz ◽  
Mark L. Weber ◽  
Jincheng Pang ◽  
...  
Keyword(s):  
Association Studies ◽  
Missense Variant ◽  
Synaptic Cleft ◽  
Surface Expression ◽  
Genome Wide Association Studies ◽  
Zinc Transport ◽  
Loss Of Function ◽  
Glutamate Signaling ◽  
Inflammatory Signals ◽  
The Impact

AbstractSchizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8A391T) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8A391T mutation resulted in reduced zinc transport into the cell, suggesting a loss in the tight control of zinc in the synaptic cleft. Electrophysiological recordings from perturbed neurons revealed a significant reduction in NMDA- and AMPA-mediated spontaneous EPSCs (sEPSCs) and a reduction in GluN2A and GluA1/2/3 receptor surface expression. All phenotypes were rescued by re-expression of wild-type ZIP8 (ZIP8WT) or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also resulted in decreased BBB integrity, increased IL-6/IL-1β protein expression, and increased NFκB following TNFα stimulation, indicating that ZIP8 loss-of-function may exacerbate immune and inflammatory signals. Together, our findings demonstrate that the A391T missense mutation results in alterations in glutamate and immune function and provide novel therapeutic targets relevant to schizophrenia.

Increased Expression of u-PA and u-PAR on Monocytes by LDL and Lp(a) Lipoproteins – Consequences for Plasmin Generation and Monocyte Adhesion

1999 ◽  
Vol 81 (04) ◽  
pp. 594-560 ◽  
Author(s):  
Florence Ganné ◽  
Marc Vasse ◽  
Jean-Louis Beaudeu ◽  
Jacqueline Peynet ◽  
Arnaud François ◽  
...  
Keyword(s):  
Fold Increase ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Atheromatous Plaque ◽  
Monocyte Adhesion ◽  
Blood Monocytes ◽  
Proteolytic Cascade ◽  
Ecm Degradation ◽  
Dose Dependent Increase ◽  
Dose Dependent

SummaryMonocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaque. As urokinase/urokinase-receptor (u-PA/u-PAR) is the trigger of a proteolytic cascade responsible for ECM degradation, we have examined the effect of atherogenic lipoproteins on monocyte surface expression of u-PAR and u-PA. Peripheral blood monocytes, isolated from 10 healthy volunteers, were incubated with 10 to 200 µg/ml of native or oxidised (ox-) atherogenous lipoproteins for 18 h and cell surface expression of u-PA and u-PAR was analysed by flow cytometry. Both LDL and Lp(a) induced a dose-dependent increase in u-PA (1.6-fold increase with 200 μg/ml of ox-LDL) and u-PAR [1.7-fold increase with 200 μg/ml of ox-Lp(a)]. There is a great variability of the response among the donors, some of them remaining non-responders (absence of increase of u-PA or u-PAR) even at 200 μg/ml of lipoproteins. In positive responders, enhanced u-PA/u-PAR is associated with a significant increase of plasmin generation (1.9-fold increase with 200 μg/ml of ox-LDL), as determined by an amidolytic assay. Furthermore, monocyte adhesion to vitronectin and fibrinogen was significantly enhanced by the lipoproteins [respectively 2-fold and 1.7-fold increase with 200 μg/ml of ox-Lp(a)], due to the increase of u-PAR and ICAM-1, which are receptors for vitronectin and fibrinogen. These data suggest that atherogenous lipoproteins could contribute to the development of atheromatous plaque by increasing monocyte adhesion and trigger plaque weakening by inducing ECM degradation.

TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer

2018 ◽  
Vol 27 (4) ◽  
pp. 363-369 ◽  
Author(s):  
Gintare Dargiene ◽  
Greta Streleckiene ◽  
Jurgita Skieceviciene ◽  
Marcis Leja ◽  
Alexander Link ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Atrophic Gastritis ◽  
Genetic Polymorphisms ◽  
Association Studies ◽  
Control Group ◽  
Similar Distribution ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Infection Susceptibility ◽  
H Pylori

Background & Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H.pylori infection, atrophic gastritis (AG) or GC in the European population.Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26–2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26–2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

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