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A high density linkage disequilibrium mapping in 14 noradrenergic genes: evidence of association between SLC6A2, ADRA1B and ADHD

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Abstract

Pharmacological evidence suggests the importance of noradrenergic and other monoaminergic neurotransmitters in the aetiology and treatment of attention deficit hyperactivity disorder (ADHD). Until recently, the genes of the noradrenergic pathway were not intensively investigated in ADHD compared to dopaminergic and serotonergic candidates. In this study, 91 SNP markers of 14 noradrenergic genes (an average density of one SNP per 4.5 kbp) were examined in ADHD samples from Ireland and Australia. Although suggestive evidence of association (nominal p ≤ 0.05) with the genes SLC6A2, ADRA1A, ADRA1B and ADRA2B was observed, none remained significant after permutation adjustments. In contrast, haplotype analyses demonstrated a significant association between ADHD and a SLC6A2 haplotype comprising the markers rs36009, rs1800887, rs8049681, rs2242447 and rs9930182 (χ2 = 9.39, p-corrected = 0.019, OR = 1.51). A rare ADRA1B haplotype made of six SNPs (rs2030373, rs6884105, rs756275, rs6892282, rs6888306 and rs13162302) was also associated (χ2 = 7.79, p-corrected = 0.042 OR = 2.74) with the disorder. These findings provide evidence of a contribution of the noradrenaline system to the genetic aetiology of ADHD. The observed haplotype association signals may be driven by as yet unidentified functional risk variants in or around the associated regions. Functional genomic analysis is warranted to determine the biological mechanism of the observed association.

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Acknowledgments

We would like to acknowledge the generous financial support of the Australian National Health and Medical Research Council (NHMRC) under grants 569636, 569533 and 1027526 and the Health Research Board of Ireland. MAB is supported by a Career Development Award from the Australian NHMRC. We would also like to thank the participating families and Dr. Tarrant Cummins for the comments on the manuscript.

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Authors and Affiliations

  1. Queensland Brain Institute and School of Psychology, The University of Queensland, Brisbane, Queensland, Australia

    Ziarih Hawi, Natasha Matthews, Joseph Wagner, Robyn H. Wallace & Mark A. Bellgrove

  2. Neuropsychiatric Genetics Research Group, Discipline of Psychiatry, Trinity College, Dublin, Ireland

    Edwina Barry & Michael Gill

  3. St. John of God Hospital, Stillorgan, County Dublin, Ireland

    Aiveen Kirley

  4. Mater Medical Research Institute, Brisbane, Australia

    Helen S. Heussler

  5. The Royal Children’s Hospital, University of Melbourne, Melbourne, Victoria, Australia

    Alasdair Vance

  6. School of Psychology and Psychiatry, Monash University, Building 17, Clayton Campus, Clayton, Melbourne, Victoria, 3800, Australia

    Ziarih Hawi & Mark A. Bellgrove

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  1. Ziarih Hawi
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  2. Natasha Matthews
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  3. Edwina Barry
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  9. Michael Gill
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Correspondence to Ziarih Hawi.

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Hawi, Z., Matthews, N., Barry, E. et al. A high density linkage disequilibrium mapping in 14 noradrenergic genes: evidence of association between SLC6A2, ADRA1B and ADHD. Psychopharmacology 225, 895–902 (2013). https://doi.org/10.1007/s00213-012-2875-x

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  • DOI: https://doi.org/10.1007/s00213-012-2875-x

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