University of Leicester
Browse

Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis

Download all (5.42 MB)
journal contribution
posted on 2018-04-19, 09:20 authored by Kimm J. E. van Hulzen, Claus J. Scholz, Barbara Franke, Stephan Ripke, Marieke Klein, Andrew McQuillin, Edmund J. Sonuga-Barke, PGC ADHD Working Group, John R. Kelsoe, Mikael Landén, Ole A. Andreassen, PGC Bipolar Disorder Working Group, Klaus-Peter Lesch, Heike Weber, Stephen V. Faraone, Alejandro Arias-Vasquez, Andreas Reif
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 (r Gfull =.64, p = 3.13 × 10 –14 ; r Grestricted =.71, p = 4.09 × 10 –16 ). The meta-analysis between the full BPD sample identified two genome-wide significant (p rs7089973 = 2.47 × 10 –8 ; p rs11756438 = 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 (p rs58502974 = 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.

Funding

This work was supported by core funding for the Psychiatric Genomics Consortium provided by the National Institute of Mental Health (NIMH) (Grant No. U01 MH094421). This work was also supported by grants from the NIMH (Grant Nos. MH081804, MH078151, and MH59567 to JRK). This work was carried out on the Dutch national e-infrastructure with the support of the SURF Foundation. We especially thank Willem Vermin (SURF Foundation, Amsterdam, the Netherlands) for his valuable support in the creating computer codes that fulfilled our needs for an efficient analysis of the data. 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 No. 602805 and NIMH Grant Nos. R13MH059126 and R01MH094469. JRK is supported by National Institutes of Health Grant Nos. MH078151, MH081804, MH59567, and MH094483. AR is supported by the Deutsche Forschungsgemeinschaft (Grant Nos. KFO 125, TRR 58/B06 and Z02, RE1632/5-1, and RTG 1256) and the European Community‘s Seventh Framework Programme (FP7/2007-2013) under Grant No. 602805 (“AGGRESSOTYPE”). CJS and HW are supported by Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Grant No. Z-6. KJEvH, BF, and AA-V are supported by grants from the Netherlands Organization for Scientific Research (NWO), i.e., the NWO Brain & Cognition Excellence Program (Grant No. 433-09-229) and a Vici grant to BF (Grant No. 016-130-669), and by grants from the Netherlands Brain Foundation (Grant No. 15F07[2]27) and BBMRI-NL (Grant No. CP2010-33). The research leading to these results also received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant Nos. 602805 (AGGRESSOTYPE), 278948 (TACTICS), and 602450 (IMAGEMEND), and from the European Community’s Horizon 2020 Programme (H2020/2014-2020) under Grant Nos. 643051 (MiND) and 667302 (CoCA). In addition, thei

History

Citation

Biological Psychiatry, 2017, 82 (9), pp. 634-641

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Version

  • AM (Accepted Manuscript)

Published in

Biological Psychiatry

Publisher

Elsevier for Society of Biological Psychiatry

issn

0006-3223

eissn

1873-2402

Acceptance date

2016-08-08

Copyright date

2017

Available date

2018-04-19

Publisher DOI

Publisher version

https://www.sciencedirect.com/science/article/pii/S0006322316329201?via=ihub

Notes

Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.biopsych.2016.08.040.

Language

en

Administrator link

Usage metrics

    University of Leicester Publications

    Categories

    No categories selected

    Keywords

    Attention-deficit/hyperactivity disorderbipolar disordercross-disorder meta-analysisgenetic correlationgenetic overlapGWAS

    Licence

    CC BY-NC-ND 4.0

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC