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Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD

Molecular Psychiatry volume 21, pages 1589–1598 (2016)Cite this article

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Abstract

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations (‘the wheat’ from ‘the chaff’) will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools—genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)—that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.

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Acknowledgements

We acknowledge the financial support of the following agencies: the Australian National Health and Medical Research Council (NHMRC) (Project IDs 1064591 and 1065677, and Fellowship ID 520574 (KCP)), Australian Research Council (Future Fellowship (MAB)), Royal Australasian College of Physicians and the Menzies Foundation. We would also like to acknowledge the Queensland Brain Bank and the Victorian Brain Bank for providing the non-pathological brain tissue samples. These centres are funded by the NHMRC. Tissues were also obtained from the New South Wales Tissue Resource Centre at the University of Sydney, which is supported by the NHMRC, Schizophrenia Research Institute and National Institute of Alcohol Abuse and Alcoholism (NIH (NIAAA) R24AA012725).

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Author notes

  1. M A Bellgrove and K C Pang: These two authors contributed equally to this work.

Authors and Affiliations

  1. School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia

    J H S Tong, Z Hawi, C Dark, T D R Cummins, B P Johnson, D P Newman, R Lau & M A Bellgrove

  2. Department of Paediatrics, Academic Child Psychiatry Unit, University of Melbourne, Royal Children’s Hospital, Melbourne, VIC, Australia

    A Vance

  3. Mater Research Institute, University of Queensland, Brisbane, QLD, Australia

    H S Heussler

  4. Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia

    N Matthews

  5. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    K C Pang

  6. Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia

    K C Pang

  7. Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia

    K C Pang

  8. Murdoch Children’s Research Institute, Parkville, VIC, Australia

    K C Pang

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Tong, J., Hawi, Z., Dark, C. et al. Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD. Mol Psychiatry 21, 1589–1598 (2016). https://doi.org/10.1038/mp.2016.2

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