Search results for "Predisposition"
showing 10 items of 771 documents
The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.
2014
Item does not contain fulltext Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a mono…
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
2013
International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variant…
IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci
2010
A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significa…
The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis
2013
NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our stron…
Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease.
2014
Mutations in the GDAP1 gene cause different forms of Charcot-Marie-Tooth (CMT) disease, and the primary clinical expression of this disease is markedly variable in the dominant inheritance form (CMT type 2K; CMT2K), in which carriers of the GDAP1 p.R120W mutation can display a wide range of clinical severity. We investigated the JPH1 gene as a genetic modifier of clinical expression variability because junctophilin-1 (JPH1) is a good positional and functional candidate. We demonstrated that the JPH1-GDAP1 cluster forms a paralogon and is conserved in vertebrates. Moreover, both proteins play a role in Ca(2+) homeostasis, and we demonstrated that JPH1 is able to restore the store-operated Ca…
Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels
2011
Background— C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results— We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in p…
Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs
2013
AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in …
Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways
2015
G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an an…
IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice.
2009
Abstract Resistance to leishmaniasis in C57BL/6 mice depends on Th1/Tc1 cells. BALB/c mice preferentially develop Th2 immunity and succumb to infection. We now assessed the role of IL-17 in cutaneous leishmaniasis. During the course of Leishmania major infection, BALB/c CD4 cells and neutrophils produced increased amounts of IL-17 as compared with cells from C57BL/6 mice. This increase was associated with significantly increased IL-23 release from L. major-infected BALB/c dendritic cells (DC), whereas IL-6 and TGF-β1 production by BALB/c and C57BL/6 DC were comparable. Interestingly, lesion sizes in infected IL-17-deficient BALB/c mice were dramatically smaller and failed to progress as com…
Transplanting the genetic susceptibility to Crohn’s disease
2003
Susceptibility to Crohn’s disease may be transferred via haematopoietic stem cells, highlighting the pivotal role of genetic factors in the pathogenesis of Crohn’s disease Crohn’s disease (CD) is one of the two most common forms of inflammatory bowel disease (IBD). The prevalence of CD has increased in Western countries over the past decades and mainly young patients are affected, with a peak incidence between 15 and 35 years.1 The aetiology of IBD is still unclear and should be considered as multifactorial according to recent studies.2 Genetic factors seem to play a pathogenic role as well as environmental, infectious, and immunological factors. All of these different aetiological aspects …