Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10  × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD

TGFbeta depletion does neither modulate acute E. coli-induced inflammatory immune responses nor impair the protective effect by chronic filarial infection

TGFbeta is an anti-inflammatory molecule that suppresses pro-inflammatory immune responses. Previously, we demonstrated that chronic filarial infection has a beneficial impact on Escherichia coli -induced sepsis. In the present study, we investigated whether this protective effect is dependent on TGFbeta signaling and whether depletion of TGFbeta before E. coli challenge alters the early course of sepsis per se . In vivo depletion of TGFbeta before E. coli challenge did not alter levels of pro-inflammatory cytokines/chemokines and did neither increase the bacterial burden nor worsen E. coli -induced hypothermia six hours post E. coli challenge. Similarly, in the co-infection model, despite TGFbeta depletion, mice infected with the filarial nematode Litomosoides sigmodontis exhibited milder E. coli -induced hypothermia, reduced bacterial load and pro-inflammatory immune responses. Thus, we conclude that TGFbeta is not essentially modulating the initial pro-inflammatory phase during sepsis and that the protective effect of a chronic filarial infection against sepsis is independent of TGFbeta signaling