Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Molecular Psychiatry volume 22, pages 580–584 (2017)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Polanczyk GV, Willcutt EG, Salum GA, Kieling C, Rohde LA . ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol 2014; 43: 434–442.

    Article  Google Scholar 

  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Association: Washington, DC, 2013.

  3. Dalsgaard S, Østergaard SD, Leckman JF, Mortensen PB, Pedersen MG . Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015; 385: 2190–2196.

    Article  Google Scholar 

  4. Stergiakouli E, Thapar A . Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatr Dis Treat 2010; 6: 551–560.

    Article  CAS  Google Scholar 

  5. Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45: 984–994.

    Article  Google Scholar 

  6. Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 2010; 376: 1401–1408.

    Article  CAS  Google Scholar 

  7. Williams NM, Franke B, Mick E, Anney RJL, Freitag CM, Gill M et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 5q13.3. Am J Psychiatry 2012; 169: 195–204.

    Article  Google Scholar 

  8. Hawi Z, Cummins TDR, Tong J, Johnson B, Lau R, Samarrai W et al. The molecular genetic architecture of attention deficit hyperactivity disorder. Mol Psychiatry 2015; 20: 289–297.

    Article  CAS  Google Scholar 

  9. Kenny EM, Cormican P, Furlong S, Heron E, Kenny G, Fahey C et al. Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Mol Psychiatry 2014; 19: 872–879.

    Article  CAS  Google Scholar 

  10. Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D et al. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 2012; 44: 78–84.

    Article  CAS  Google Scholar 

  11. Stergiakouli E, Hamshere M, Holmans P, Langley K, Zaharieva I, deCODE Genetics et al. Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD. Am J Psychiatry 2012; 169: 186–194.

    Article  Google Scholar 

  12. Lasky-Su J, Neale BM, Franke B, Anney RJL, Zhou K, Maller JB et al. Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1345–1354.

    Article  CAS  Google Scholar 

  13. Neale BM, Lasky-Su J, Anney R, Franke B, Zhou K, Maller JB et al. Genome-wide association scan of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1337–1344.

    Article  CAS  Google Scholar 

  14. Neale BM, Medland S, Ripke S, Anney RJL, Asherson P, Buitelaar J et al. Case control genome-wide association study of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010; 49: 906–920.

    Article  Google Scholar 

  15. Mick E, Todorov A, Smalley S, Hu X, Loo S, Todd RD et al. Family-based genomewide association scan of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010; 2010: 898–905.

    Article  Google Scholar 

  16. Irish Schizophrenia Genomics Consortium and the Wellcome Trust Case Control Consortium 2. Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biol Psychiatry 2012; 72: 620–628.

    Article  Google Scholar 

  17. Hawi Z, Matthews N, Barry E, Kirley A, Wagner J, Wallace RH et al. A high density linkage disequilibrium mapping in 14 noradrenergic genes: evidence of association between SLC6A2, ADRA1B and ADHD. Psychopharmacology (Berl) 2013; 225: 895–902.

    Article  CAS  Google Scholar 

  18. Hawi Z, Matthews N, Wagner J, Wallace RH, Butler TJ, Vance A et al. DNA variation in the SNAP25 gene confers risk to ADHD and is associated with reduced expression in prefrontal cortex. Plos One 2013; 8: e60274.

    Article  CAS  Google Scholar 

  19. Angold A, Prendergast M, Cox A, Harrington R, Simonoff E, Rutter M . The Child and Adolescent Psychiatric Assessment (CAPA). Psychol Med 1995; 25: 739–753.

    Article  CAS  Google Scholar 

  20. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington DC, 1994.

  21. World Health Organization The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization: Geneva, 1992.

  22. Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009; 25: 1754–1760.

    Article  CAS  Google Scholar 

  23. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 2011; 43: 491–498.

    Article  CAS  Google Scholar 

  24. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010; 20: 1297–1303.

    Article  CAS  Google Scholar 

  25. Lemire M . Defining rare variants by their frequencies in controls may increase type I error. Nat Genet 2011; 43: 391–392.

    Article  CAS  Google Scholar 

  26. Pearson RD . Bias due to selection of rare variants using frequency in controls. Nat Genet 2011; 43: 394–395.

    Article  Google Scholar 

  27. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J . A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 2014; 46: 310–315.

    Article  CAS  Google Scholar 

  28. Liu DJ, Leal SM . A novel adaptive method for the analysis of next-generation sequencing data to detect complex trait associations with rare variants due to gene main effects and interactions. PLOS Genet 2010; 6: e1001156.

    Article  Google Scholar 

  29. MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 2012; 335: 823–828.

    Article  CAS  Google Scholar 

  30. Madsen B, Browning S . A groupwise association test for rare mutations using a weighted sum statistic. PLOS Genet 2009; 5: e1000384.

    Article  Google Scholar 

  31. The Encode Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74.

    Article  Google Scholar 

  32. Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol 2010; 28: 1045–1048.

    Article  CAS  Google Scholar 

  33. Kiezun A, Garimella K, Do R, Stitziel NO, Neale BM, McLaren PJ et al. Exome sequencing and the genetic basis of complex traits. Nat Genet 2012; 44: 623–630.

    Article  CAS  Google Scholar 

  34. Notaras M, Hill R, van den Buuse M . The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. Mol Psychiatry 2015; 20: 916–930.

    Article  CAS  Google Scholar 

  35. Notaras M, Hill R, van den Buuse M . A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev 2015; 51: 15–30.

    Article  CAS  Google Scholar 

  36. Chourbaji S, Hellweg R, Brandis D, Zorner B, Zacher C, Lang UE et al. Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior. Brain Res Mol Brain Res 2004; 121: 28–36.

    Article  CAS  Google Scholar 

  37. Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 2001; 15: 1748–1757.

    Article  CAS  Google Scholar 

  38. Eaton MJ, Staley JK, Globus MY, Whittemore SR . Developmental regulation of early serotonergic neuronal differentiation: the role of brain-derived neurotrophic factor and membrane depolarization. Dev Biol 1995; 170: 169–182.

    Article  CAS  Google Scholar 

  39. Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991; 350: 230–232.

    Article  CAS  Google Scholar 

  40. Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 1999; 96: 15239–15244.

    Article  CAS  Google Scholar 

  41. Andersen SL, Sonntag KC . Juvenile methylphenidate reduces prefrontal cortex plasticity via D3 receptor and BDNF in adulthood. Front Synaptic Neurosci 2014; 6: 1–8.

    Article  Google Scholar 

  42. Meredith GE, Callen S, Scheuer DA . Brain-derived neurotrophic factor expression is increased in the rat amygdala, piriform cortex and hypothalamus following repeated amphetamine administration. Brain Res 2002; 949: 218–227.

    Article  CAS  Google Scholar 

  43. Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N et al. Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD. Mol Psychiatry 2005; 10: 939–943.

    Article  CAS  Google Scholar 

  44. Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T . Dissecting the human BDNF locus: Bidirectional transcription, complex splicing, and multiple promoters. Genomics 2007; 90: 397–406.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; APP1065677; Bellgrove, Hawi and Cummins) and an NHMRC fellowship (1078901; Wray).

Author information

Author notes

  1. Z Hawi and T D R Cummins: These authors contributed equally and should both be considered as first author.

Authors and Affiliations

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

    Z Hawi, T D R Cummins, J Tong, D P Newman, B Johnson & M A Bellgrove

  2. John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

    M Arcos-Burgos & S Easteal

  3. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia

    Q Zhao, N Matthews, N R Wray & M A Bellgrove

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

    A Vance

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

    H S Heussler

  6. School of Psychiatry, University of New South Wales, Sydney, NSW, Australia

    F Levy

  7. Child and Family East, Prince of Wales Hospital, Randwick, NSW, Australia

    F Levy

  8. Department of Psychiatry and Institute of Molecular Medicine, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin, Ireland

    E Kenny & M Gill

  9. Department of Biochemistry, National University of Ireland Galway, Galway, Ireland

    D Morris

  10. School of Medicine, University of St Andrews, St Andrews, Scotland, UK

    L Kent

Authors
  1. Z Hawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T D R Cummins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Arcos-Burgos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Q Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Matthews
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D P Newman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Vance
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H S Heussler
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Easteal
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. N R Wray
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. E Kenny
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. D Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. L Kent
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. M A Bellgrove
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M A Bellgrove.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hawi, Z., Cummins, T., Tong, J. et al. Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study. Mol Psychiatry 22, 580–584 (2017). https://doi.org/10.1038/mp.2016.117

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2016.117

This article is cited by

Search

Advanced search

Quick links