Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Contains fulltext : 97006.pdf (publisher's version ) (Open Access)The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc

The impact of intrinsic and extrinsic features on delay discounting

International audienceDelay discounting refers to the tendency of people to evaluate immediate rewards as being more valuable than those that are distant in time. Several models explain this phenomenon by a set of intrinsic and extrinsic features. Intrinsic features are related to the inherent traits and neurological conditions of the individual, whereas extrinsic features are related to the characteristics of the reward. In this study, we refer to extraversion and attention-deficit/hyperactivity disorder symptoms (attention and hyperactivity-impulsivity) as intrinsic features, and to fungibility, perishability, and magnitude of the reward as extrinsic features. Whereas there is a known main effect to these intrinsic and extrinsic features, the current research examines their additive and interactive contributions to delay discounting. A total of 222 participants filled out an online questionnaire measuring intrinsic features and presenting decision tasks with different types of rewards. The scores of the intrinsic variables and the delay discounting rate for each reward were calculated and analyzed. The results replicated previous findings showing main effects of hyperactivity, fungibility, perishability, and magnitude. They also provided new findings on an interaction between fungibility-perishability and hyperactivity—the effect of hyperactivity on delay discounting was larger when the rewards were fungible and nonperishable than when the rewards were perishable and nonfungible. This interaction has practical implications that can help in moderating delay discounting in clinical treatments of impulsivity as well as in constructing efficient economic models for consumers

Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Funded by EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (115565), The Spanish Ministry of Economy Industry and Competitiveness (SAF2015-66761-P), The Regional Ministry of Innovation, Science and Technologies of the Andalusian Regional Government (P12-BIO-1395) and Juan de la Cierva fellowship (FJCI-2015-24028). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences