The relative contribution of common and rare genetic variants to ADHD.

J Martin,A Thapar,K Langley,N Williams,M C O'Donovan

doi:10.1038/tp.2015.5

Abstract

Attention deficit hyperactivity disorder (ADHD) is highly heritable. Genome-wide molecular studies show an increased burden of large, rare copy-number variants (CNVs) in children with ADHD compared with controls. Recent polygenic risk score analyses have also shown that en masse common variants are enriched in ADHD cases compared with population controls. The relationship between these common and rare variants has yet to be explored. In this study, we tested whether children with ADHD with (N=60) a large (>500 kb), rare (<1% frequency) CNV differ by polygenic risk scores for ADHD to children with ADHD without such CNVs (N=421). We also compared ADHD polygenic scores in ADHD children with and without CNVs with a group of population controls (N=4670; of whom N=397 had CNVs). The results show that children with ADHD with large, rare CNVs have lower polygenic scores than children without such CNVs (odds ratio (OR)=0.73, P=0.023). Although ADHD children without CNVs had higher scores than controls (OR=1.18, P=0.0031), this difference was not observed for ADHD children with CNVs (OR=0.86, P=0.27). These results are consistent with a polygenic liability threshold model of ADHD with both common and rare variants involved.

Highlights

Attention deficit hyperactivity disorder (ADHD) is a childhoodonset neurodevelopmental disorder characterized by developmentally inappropriate levels of hyperactivity, impulsivity and inattention
Controls were provided by The main analyses the Wellcome Trust Case Control Consortium-Phase 2, consisting of 3000 were re-run using polygenic scores based on the different thresholds
We have previously shown that children with ADHD have higher polygenic risk scores for ADHD than population controls,[8] limiting the analysis to children with copy-number variants (CNVs) (N = 60) shows no difference between cases and controls (OR = 0.86, 95% CI = 0.67–1.12, P = 0.27, R2 = 0.002), this may be due to the small sample size of children with ADHD with large, rare CNVs

Summary

INTRODUCTION

Attention deficit hyperactivity disorder (ADHD) is a childhoodonset neurodevelopmental disorder characterized by developmentally inappropriate levels of hyperactivity, impulsivity and inattention. Twin studies consistently indicate that it is highly heritable.[1] Molecular genetic studies are beginning to suggest that the genetic architecture of ADHD is complex, with multiple common and rare genetic variants involved.[2,3] Recent molecular genetic studies using a method called ‘genomic-relationshipmatrix restricted maximum likelihood’ as implemented by the software Genome-wide Complex Trait Analysis confirm that additive common genetic variants contribute to estimates of heritability.[4,5] genome-wide association studies (GWAS) far have not reported any significantly associated singlenucleotide polymorphisms (SNPs), these studies have been relatively small and underpowered for detecting individual loci significant at a genome-wide level,[2,6] compared with GWAS of adult psychiatric conditions such as schizophrenia.[7] Other factors, including use of ‘pseudo-controls’ in trio-based analyses[4] and sample heterogeneity (in terms of phenotype, as well as ancestry), may have had a role. We hypothesized that children without a CNV would have a higher polygenic risk score for ADHD than those carrying a large and rare deletion or duplication

MATERIALS AND METHODS

Findings

DISCUSSION