Genetic Factors For Adhd Risk Overlap With Those Influencing Intracranial Volume

Abstract

Abstract Attention Deficit Hyperactivity Disorder(ADHD) is a common neurodevelopmental disorder that has a complex genetic background. Several brain structures have been found to be smaller in people with ADHD compared to healthy individuals. Since both ADHD risk and brain volumes are highly heritable, we hypothesized that both traits are genetically linked by shared common variant architecture. We integrated genome-wide association results from the largest publicly available studies of ADHD (N=55,374; PGC+iPSYCH ADHD working groups) and regional brain volumes (N=11,221-24,704; ENIGMA and CHARGE consortium). To investigate overlap between common genetic variation associated with ADHD risk and brain volume measures (intracranial volume (ICV), accumbens, amygdala, caudate, hippocampus, and putamen), we used a set of complementary methods, extending a recent analysis of schizophrenia. Linkage disequilibrium score regression revealed a negative genetic correlation between ADHD and ICV (-0.206; P=1.98x10-10). Genetic correlations between ADHD risk and subcortical brain volumes were low and non-significant. SNP effect concordance analysis showed significant pleiotropy and concordance of allelic effects between ADHD risk variants and variants associated with ICV (both P=0.0009). Significant concordant genetic effects were also seen for the accumbens (P=0.0009). Meta-analysis of single variants revealed significant loci of interest associated with both ADHD risk and ICV volume. Gene-set analysis, using the ADHD-ICV meta-analytic summary statistics, showed significant association with a neurite outgrowth gene-set (Ngenes=44; P=0.0025). This first genome-wide study of genetic overlap between brain volume measures and ADHD revealed significant genetic covariation between ADHD and ICV, both on the global as well as single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. Neurite outgrowth variation seemed to be involved in this effect in gene-set and single variant analyses. These findings can help us to develop new hypotheses about biological mechanisms, by which brain structure alterations may be involved in ADHD disease etiology.