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

Panic disorder (PD) has a lifetime prevalence of 2–4% and heritability estimates of 40%. Thecontributory genetic variants remainlargely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide associationstudy (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden).Standard GWAS quality control procedureswere conducted on each individual dataset, and imputation was performed using the 1000Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locuswas 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 was28.0–34.2%. After correction for multiple testing, a significant genetic correlation was foundbetween PD and major depressivedisorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) withp<1×10−4werefollowed up in an independent sample of 2408 PD patients and 228,470controls from Denmark, Iceland and the Netherlands. In thecombined analysis, SNP rs144783209 showed the strongest association with PD (pcomb=3.10 × 10−7). Sign tests revealed asignificant enrichment of SNPs with a discoveryp-value of