M1 - FIVE NOVEL LOCI ASSOCIATED WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ARE REVEALED BY LEVERAGING POLYGENIC OVERLAP WITH EDUCATIONAL ATTAINMENT

Abstract

Attention-Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition that affects about 5% of children and adolescents worldwide. Despite its high heritability little is known about underlying genetic factors. Among other things ADHD is tightly associated with educational failure. However, potential genetic overlap between ADHD and educational attainment has not been examined in detail so far. Exploiting epidemiological similarity between ADHD and educational attainment we aimed to improve discovery of ADHD-associated genetic factors and investigated genetic overlap between these phenotypes. We used ADHD data from the PGC (2064 trios, 896 cases, 2455 controls) and educational attainment data from the SSGAC (N=328917). To investigate polygenic overlap between ADHD and educational attainment we constructed fold-enrichment plots and conditional QQ plots in both directions: conditioning ADHD on educational attainment and vice versa. To explore the nature of the polygenic overlap and test a hypothesis that investigated traits correlate genetically we calculated correlations between z-scores of ADHD and educational attainment variants for nested strata of variants, representing subsets of SNPs with increasing significance of p-values in one of the traits. Additionally we supported this hypothesis by estimating genetic correlation between ADHD and educational attainment using LD score regression. We applied condFDR/conjFDR method to identify specific loci associated with ADHD and loci associated with both ADHD and educational attainment simultaneously. Consistency of effect directions for top association signals detected in our condFDR/conjFDR analyses was tested in the independent GWAS of ADHD symptoms from EAGLE consortium (N=17666). Using condFDR/conjFDR method we identified five novel loci associated with ADHD, three of these being shared between ADHD and educational attainment. Leading variants for four of five identified regions are located in introns of protein coding genes: KDM4A, MEF2C, PINK1, RUNX1T1, while the remaining one is an intergenic SNP on chromosome 2 at 2p24. Four of five loci have opposite directions of effect in ADHD and educational attainment and consistent directions of effect in the independent GWAS of ADHD symptoms from the EAGLE consortium. A hypothesis of polygenic overlap between ADHD and educational attainment was supported by significant genetic correlation (rg=-0.403, p=7.90E-8), consistent pleiotropic enrichment in conditional QQ plots, >10-fold mutual enrichment of SNPs associated with both traits and growing negative correlation of association z-scores for the nested SNP strata with increasing significance in both phenotypes. We found five novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and educational attainment, implicating three genetic loci in this overlap. Four of five identified loci showed consistent effects in the independent data set of ADHD symptoms, and inverse correlation with educational attainment. The latter is in line with prior epidemiological and genetic studies. We belive that altogether these findings provide new insights into the relationship between ADHD and educational attainment, suggesting shared molecular genetic mechanisms. Further research is required to clarify the biological effects of the identified genetic variants and how these may influence educational attainment and ADHD pathogenesis.