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

Abstract

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental psychiatric disorders. Previous studies have shown that the disorder is highly heritable and associated with several different risk-taking behaviors. Additionally, brain-imaging studies have identified various brain regions such as the cerebellum and frontal cortex to be altered in ADHD.Large 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 conducted the largest ADHD transcriptome-wide association study (TWAS) to date consisting of 19,099 cases and 34,194 controls and identified 9 transcriptome-wide significant hits. We successfully demonstrate that several previous GWAS hits can be largely explained by expression. Probabilistic causal fine-mapping of TWAS signals prioritized 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 enrichments identified dopaminergic and norepinephrine pathways, which are highly relevant for ADHD. Finally, we used the top eQTLs associated with the TWAS genes to identify phenotypes relevant to ADHD and found an inverse genetic correlation with educational attainment and a positive correlation with "ever smoker", maternal smoking at birth, BMI, and schizophrenia. Overall, our findings highlight the power of TWAS to identify novel risk loci and prioritize putatively causal genes.

Biomarker discovery in attention deficit hyperactivity disorder: RNA sequencing of whole blood in discordant twin and case-controlled cohorts

“…A second possible match is between exome mutations in WDR83, and expression changes in WDR45B in discordant twins, and WDR74 in case control subjects. Also, we observed some similarity to transcripts identified in ADHD by Liao et al [ 97 ], whereby transcripts MED8 and ARTN had suggestive p values in our analysis.…”

Biomarker Discovery in Attention Deficit Hyperactivity Disorder: RNA sequencing of Whole Blood in Discordant Twin and Case-Controlled Cohorts

“…A second possible match is between exome mutations in WDR83, and expression changes in WDR45B in discordant twins, and WDR74 in case control subjects. Also, we observed some similarity to transcripts identi ed in ADHD by Liao et al [97], whereby transcripts MED8 and ARTN had suggestive p-values in our analysis.…”

Biomarker Discovery in Attention Deficit Hyperactivity Disorder: RNA sequencing of Whole Blood in Discordant Twin and Case-Controlled Cohorts

“…A second possible match is between exome mutations in WDR83, and expression changes in WDR45B in discordant twins, and WDR74 in case control subjects. Also, we observed some similarity to transcripts identi ed in ADHD by Liao et al [97], whereby transcripts MED8 and ARTN had suggestive p-values in our analysis. Limitations to the present study principally derive from the observational nature of the studies, a necessarily small samples for MZ discordant twins, and the necessity to use peripheral blood RNA, as opposed to a tissue more proximal to the presumed neural in uences on ADHD.…”