Transcriptome-wide association study of attention deficit hyperactivity disorder identifies associated genes and phenotypes

Nat Commun. 2019 Oct 1;10(1):4450. doi: 10.1038/s41467-019-12450-9.

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental psychiatric disorder. Genome-wide association studies (GWAS) have identified several loci associated with ADHD. However, understanding the biological relevance of these genetic loci has proven to be difficult. Here, we conduct an ADHD transcriptome-wide association study (TWAS) consisting of 19,099 cases and 34,194 controls and identify 9 transcriptome-wide significant hits, of which 6 genes were not implicated in the original GWAS. We demonstrate that two of the previous GWAS hits can be largely explained by expression regulation. Probabilistic causal fine-mapping of TWAS signals prioritizes KAT2B with a posterior probability of 0.467 in the dorsolateral prefrontal cortex and TMEM161B with a posterior probability of 0.838 in the amygdala. Furthermore, pathway enrichment identifies dopaminergic and norepinephrine pathways, which are highly relevant for ADHD. Overall, our findings highlight the power of TWAS to identify and prioritize putatively causal genes.

MeSH terms

  • Amygdala
  • Attention Deficit Disorder with Hyperactivity / genetics*
  • Dopamine Agents / isolation & purification
  • Dopamine Agents / metabolism
  • Fatty Acid Elongases / genetics
  • Gene Expression
  • Genetic Loci
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study*
  • Genomics
  • Genotype
  • Humans
  • Membrane Proteins / genetics
  • Nerve Tissue Proteins / genetics
  • Norepinephrine / genetics
  • Norepinephrine / isolation & purification
  • Norepinephrine / metabolism
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Probability
  • Transcriptome*
  • p300-CBP Transcription Factors / genetics

Substances

  • ARTN protein, human
  • Dopamine Agents
  • ELOVL1 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins
  • TMEM161B protein, human
  • Fatty Acid Elongases
  • KAT2B protein, human
  • p300-CBP Transcription Factors
  • Norepinephrine