Original Article

Molecular Psychiatry (2017) 22, 580–584; doi:10.1038/mp.2016.117 published online 26 July 2016

Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study

Z Hawi1,11, T D R Cummins1,11, J Tong1, M Arcos-Burgos2, Q Zhao3, N Matthews3, D P Newman1, B Johnson1, A Vance4, H S Heussler5, F Levy6,7, S Easteal2, N R Wray3, E Kenny8, D Morris9, L Kent10, M Gill8 and M A Bellgrove1,3

  1. 1School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, Melbourne, VIC, Australia
  2. 2John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
  3. 3Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
  4. 4Academic Child Psychiatry Unit, Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, VIC, Australia
  5. 5Mater Research Institute, University of Queensland, Brisbane, QLD, Australia
  6. 6School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
  7. 7Child and Family East, Prince of Wales Hospital, Randwick, NSW, Australia
  8. 8Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
  9. 9Department of Biochemistry, National University of Ireland Galway, Galway, Ireland
  10. 10School of Medicine, University of St Andrews, St Andrews, Scotland, UK

Correspondence: Professor MA Bellgrove, School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, 18 Innovation Walk, Clayton Campus, Wellington Road, Melbourne, VIC 3800, Australia. E-mail: mark.bellgrove@monash.edu

11These authors contributed equally and should both be considered as first author.

Received 27 October 2015; Revised 14 April 2016; Accepted 6 May 2016
Advance online publication 26 July 2016

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Abstract

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.