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 and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD-associated genetic variants and to investigate genetic overlap between these phenotypes. A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n=328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA. Identified single nucleotide polymorphisms (SNPs) were tested for association in an independent population-based study of ADHD symptoms (n=17,666). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation. At levels of condFDR<0.01 and conjFDR<0.05, we identified 5 ADHD-associated loci, 3 of these being shared between ADHD and EA. None of these loci had been identified in the primary ADHD GWAS, demonstrating the increased power provided by the condFDR/conjFDR analysis. Leading SNPs for 4 of 5 identified regions are in introns of protein coding genes (KDM4A, MEF2C, PINK1, RUNX1T1), whereas the remaining one is an intergenic SNP on chromosome 2 at 2p24. Consistent direction of effects in the independent study of ADHD symptoms was shown for 4 of 5 identified loci. A polygenic overlap between ADHD and EA was supported by significant genetic correlation (rg=-0.403, p=7.90×10-8) and >10-fold mutual enrichment of SNPs associated with both traits. We identified 5 novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and EA. These findings could aid understanding of the genetic risk architecture of ADHD and its relation to EA.