Genetic overlap between attention-deficit/hyperactivity disorder and bipolar disorder: evidence from genome-wide association study meta-analysis

PGC ADHD Working Group, PGC Bipolar Disorder Working Group, Kimm J.E. van Hulzen, Claus J. Scholz, Barbara Franke, Stephan Ripke, Marieke Klein, Andrew McQuillin, Edmund J. Sonuga-Barke, John R. Kelsoe, Mikael Landén, Ole A. Andreassen, Klaus-Peter Lesch, Heike Weber, Stephen V. Faraone, Alejandro Arias-Vasquez, Andreas Reif, Lindsey Kent

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Abstract

Background 

Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD. 

Methods 

Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks. 

Results 

We found a significant single nucleotide polymorphism–based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull =.64, p = 3.13 × 10–14; rGrestricted =.71, p = 4.09 × 10–16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10–8; prs11756438 = 4.36 × 10–8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10–8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue. 

Conclusions 

The single nucleotide polymorphism–based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

Original languageEnglish
Pages (from-to)634-641
Number of pages8
JournalBiological Psychiatry
Volume82
Issue number9
Early online date18 Oct 2016
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • Attention-deficit/hyperactivity disorder
  • Bipolar disorder
  • Cross-disorder meta-analysis
  • Genetic correlation
  • Genetic overlap
  • GWAS

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