Genetic overlap between attention-deficit/hyperactivity disorder and bipolar disorder : evidence from genome-wide association study meta-analysis
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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.
PGC ADHD Working Group , PGC Bipolar Disorder Working Group , van Hulzen , K J E , Scholz , C J , Franke , B , Ripke , S , Klein , M , McQuillin , A , Sonuga-Barke , E J , Kelsoe , J R , Landén , M , Andreassen , O A , Lesch , K-P , Weber , H , Faraone , S V , Arias-Vasquez , A , Reif , A & Kent , L 2017 , ' Genetic overlap between attention-deficit/hyperactivity disorder and bipolar disorder : evidence from genome-wide association study meta-analysis ' , Biological Psychiatry , vol. 82 , no. 9 , pp. 634-641 . https://doi.org/10.1016/j.biopsych.2016.08.040
Copyright © 2016 Society of Biological Psychiatry. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1016/j.biopsych.2016.08.040.
DescriptionFunding: SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders,University of Bergen, Bergen, Norway, the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 602805 and NIMH grants R13MH059126 and R01MH094469. JRK is supported by NIH grants MH078151, MH081804, MH59567 and MH094483. AR is supported by the Deutsche Forschungsgemeinschaft (KFO 125, TRR 58/B06 and Z02 to AR, RE1632/5-1, RTG 1256 AR) and the European Community‘s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 602805 (“AGGRESSOTYPE”). CJS and HW are supported by Interdisziplinäres Zentrum für Klinische Forschung (IZKF) grant Z-6. The research leading to these results also received funding from the European Community’s Seventh Framework Programme (FP7/2007 –2013) under grant agreements n° 602805 (AGGRESSOTYPE), n° 278948 (TACTICS), and n° 60245 (IMAGEMEND) and from the European Community’s Horizon 2020 Programme (H2020/2014 –2020) under grant agreement n° 643051 (MiND) and n° 667302( CoCA). In addition, their work is supported by the ECNP for the Research Network ‘ADHD across the Lifespan’.
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