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Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

Molecular Psychiatry volume 16, pages 491–503 (2011)Cite this article

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterized by hyperactivity, inattention and increased impulsivity. To detect micro-deletions and micro-duplications that may have a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array comparative genomic hybridization (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise 4 deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolizing butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domain-containing protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 α subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6) and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a ∼3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical family-based association test, P=0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by functional magnetic resonance imaging links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. These findings implicate CNVs of behaviour-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome.

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References

  1. Lesch KP . Attention-deficit/hyperactivity disorder (ADHD). In: Lang F (ed). Encyclopedia of Molecular Mechanisms of Disease. Springer: Heidelberg, New York, 2009 pp 188–191.

    Google Scholar 

  2. Jacob CP, Romanos J, Dempfle A, Heine M, Windemuth-Kieselbach C, Kruse A et al. Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 2007; 257: 309–317.

    Article  Google Scholar 

  3. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1313–1323.

    Article  CAS  Google Scholar 

  4. Friedel S, Saar K, Sauer S, Dempfle A, Walitza S, Renner T et al. Association and linkage of allelic variants of the dopamine transporter gene in ADHD. Mol Psychiatry 2007; 12: 923–933.

    Article  CAS  Google Scholar 

  5. Romanos M, Freitag C, Jacob C, Craig DW, Dempfle A, Nguyen TT et al. Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Mol Psychiatry 2008; 13: 522–530.

    Article  CAS  Google Scholar 

  6. Zhou K, Dempfle A, Arcos-Burgos M, Bakker SC, Banaschewski T, Biederman J et al. Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1392–1398.

    Article  CAS  Google Scholar 

  7. Thapar A, Langley K, Owen MJ, O’Donovan MC . Advances in genetic findings on attention deficit hyperactivity disorder. Psychol Med 2007; 37: 1681–1692.

    Article  Google Scholar 

  8. Lee JA, Lupski JR . Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 2006; 52: 103–121.

    Article  CAS  Google Scholar 

  9. Stankiewicz P, Beaudet AL . Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev 2007; 17: 182–192.

    Article  CAS  Google Scholar 

  10. Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–328.

    Article  CAS  Google Scholar 

  11. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T et al. Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449.

    Article  CAS  Google Scholar 

  12. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008; 82: 477–488.

    Article  CAS  Google Scholar 

  13. Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M . Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 2008; 40: 880–885.

    Article  CAS  Google Scholar 

  14. Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008; 320: 539–543.

    Article  CAS  Google Scholar 

  15. Friedman JI, Vrijenhoek T, Markx S, Janssen IM, van der Vliet WA, Faas BH et al. CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol Psychiatry 2008; 13: 261–266.

    Article  CAS  Google Scholar 

  16. Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M et al. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet 2008; 17: 458–465.

    Article  CAS  Google Scholar 

  17. Wilson GM, Flibotte S, Chopra V, Melnyk BL, Honer WG, Holt RA . DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling. Hum Mol Genet 2006; 15: 743–749.

    Article  CAS  Google Scholar 

  18. St Clair D . Copy number variation and schizophrenia. Schizophr Bull 2009; 35: 9–12.

    Article  Google Scholar 

  19. Vrijenhoek T, Buizer-Voskamp JE, van der Stelt I, Strengman E, Sabatti C, Geurts van Kessel A et al. Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am J Hum Genet 2008; 83: 504–510.

    Article  CAS  Google Scholar 

  20. Elia J, Gai X, Xie HM, Perin JC, Geiger E, Glessner JT et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 2009, June 23 [e-pub ahead of print].

  21. Ionita-Laza I, Rogers AJ, Lange C, Raby BA, Lee C . Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. Genomics 2009; 93: 22–26.

    Article  CAS  Google Scholar 

  22. Barkley RA, Shelton TL, Crosswait C, Moorehouse M, Fletcher K, Barrett S et al. Preschool children with disruptive behavior: three-year outcome as a function of adaptive disability. Dev Psychopathol 2002; 14: 45–67.

    Article  Google Scholar 

  23. Shelton TL, Barkley RA, Crosswait C, Moorehouse M, Fletcher K, Barrett S et al. Multimethod psychoeducational intervention for preschool children with disruptive behavior: two-year post-treatment follow-up. J Abnorm Child Psychol 2000; 28: 253–266.

    Article  CAS  Google Scholar 

  24. Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 1998; 20: 207–211.

    Article  CAS  Google Scholar 

  25. Solinas-Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Dohner H et al. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 1997; 20: 399–407.

    Article  CAS  Google Scholar 

  26. Erdogan F, Chen W, Kirchhoff M, Kalscheuer VM, Hultschig C, Muller I et al. Impact of low copy repeats on the generation of balanced and unbalanced chromosomal aberrations in mental retardation. Cytogenet Genome Res 2006; 115: 247–253.

    Article  CAS  Google Scholar 

  27. Ishkanian AS, Malloff CA, Watson SK, DeLeeuw RJ, Chi B, Coe BP et al. A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet 2004; 36: 299–303.

    Article  CAS  Google Scholar 

  28. Krzywinski M, Bosdet I, Smailus D, Chiu R, Mathewson C, Wye N et al. A set of BAC clones spanning the human genome. Nucleic Acids Res 2004; 32: 3651–3660.

    Article  CAS  Google Scholar 

  29. Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Scott CE et al. DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 2003; 36: 361–374.

    Article  CAS  Google Scholar 

  30. Chen W, Erdogan F, Ropers HH, Lenzner S, Ullmann R . CGHPRO—a comprehensive data analysis tool for array CGH. BMC Bioinformatics 2005; 6: 85.

    Article  Google Scholar 

  31. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y et al. Detection of large-scale variation in the human genome. Nat Genet 2004; 36: 949–951.

    Article  CAS  Google Scholar 

  32. Shaikh TH, Gai X, Perin JC, Glessner JT, Xie H, Murphy K et al. High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res 2009; 19: 1682–1690.

    Article  CAS  Google Scholar 

  33. Knutson B, Adams CM, Fong GW, Hommer D . Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci 2001; 21: RC159.

    Article  CAS  Google Scholar 

  34. Hahn T, Dresler T, Ehlis AC, Plichta MM, Heinzel S, Polak T et al. Neural response to reward anticipation is modulated by Gray’s impulsivity. Neuroimage 2009; 46: 1148–1153.

    Article  Google Scholar 

  35. Fox PT, Lancaster JL . Opinion: mapping context and content: the BrainMap model. Nat Rev Neurosci 2002; 3: 319–321.

    Article  CAS  Google Scholar 

  36. Laird NM, Horvath S, Xu X . Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000; 19 (Suppl 1): S36–S42.

    Article  Google Scholar 

  37. Rabinowitz D, Laird N . A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000; 50: 211–223.

    Article  CAS  Google Scholar 

  38. Darvesh S, Hopkins DA, Geula C . Neurobiology of butyrylcholinesterase. Nat Rev Neurosci 2003; 4: 131–138.

    Article  CAS  Google Scholar 

  39. Raveh L, Grunwald J, Marcus D, Papier Y, Cohen E, Ashani Y . Human butyrylcholinesterase as a general prophylactic antidote for nerve agent toxicity. In vitro and in vivo quantitative characterization. Biochem Pharmacol 1993; 45: 2465–2474.

    Article  CAS  Google Scholar 

  40. Koetzner L, Woods JH . Characterization of butyrylcholinesterase antagonism of cocaine-induced hyperactivity. Drug Metab Dispos 2002; 30: 716–723.

    Article  CAS  Google Scholar 

  41. Manoharan I, Kuznetsova A, Fisk JD, Boopathy R, Lockridge O, Darvesh S . Comparison of cognitive functions between people with silent and wild-type butyrylcholinesterase. J Neural Transm 2007; 114: 939–945.

    Article  CAS  Google Scholar 

  42. Hokfelt T, Broberger C, Diez M, Xu ZQ, Shi T, Kopp J et al. Galanin and NPY, two peptides with multiple putative roles in the nervous system. Horm Metab Res 1999; 31: 330–334.

    Article  CAS  Google Scholar 

  43. Herzog H . Neuropeptide Y and energy homeostasis: insights from Y receptor knockout models. Eur J Pharmacol 2003; 480: 21–29.

    Article  CAS  Google Scholar 

  44. Zhou Z, Zhu G, Hariri AR, Enoch MA, Scott D, Sinha R et al. Genetic variation in human NPY expression affects stress response and emotion. Nature 2008; 452: 997–1001.

    Article  CAS  Google Scholar 

  45. Karl T, Herzog H . Behavioral profiling of NPY in aggression and neuropsychiatric diseases. Peptides 2007; 28: 326–333.

    Article  CAS  Google Scholar 

  46. Zhu G, Pollak L, Mottagui-Tabar S, Wahlestedt C, Taubman J, Virkkunen M et al. NPY Leu7Pro and alcohol dependence in Finnish and Swedish populations. Alcohol Clin Exp Res 2003; 27: 19–24.

    Article  CAS  Google Scholar 

  47. Ruohonen ST, Pesonen U, Moritz N, Kaipio K, Roytta M, Koulu M et al. Transgenic mice overexpressing neuropeptide Y in noradrenergic neurons: a novel model of increased adiposity and impaired glucose tolerance. Diabetes 2008; 57: 1517–1525.

    Article  CAS  Google Scholar 

  48. Bannon AW, Seda J, Carmouche M, Francis JM, Norman MH, Karbon B et al. Behavioral characterization of neuropeptide Y knockout mice. Brain Res 2000; 868: 79–87.

    Article  CAS  Google Scholar 

  49. Painsipp E, Wultsch T, Edelsbrunner ME, Tasan RO, Singewald N, Herzog H et al. Reduced anxiety-like and depression-related behavior in neuropeptide Y Y4 receptor knockout mice. Genes Brain Behav 2008; 7: 532–542.

    Article  CAS  Google Scholar 

  50. Greco B, Carli M . Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: relation to anxiolytic-like phenotype. Behav Brain Res 2006; 169: 325–334.

    Article  CAS  Google Scholar 

  51. Scheres A, Milham MP, Knutson B, Castellanos FX . Ventral striatal hyporesponsiveness during reward anticipation in attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 61: 720–724.

    Article  Google Scholar 

  52. Strohle A, Stoy M, Wrase J, Schwarzer S, Schlagenhauf F, Huss M et al. Reward anticipation and outcomes in adult males with attention-deficit/hyperactivity disorder. Neuroimage 2008; 39: 966–972.

    Article  Google Scholar 

  53. Oades RD, Daniels R, Rascher W . Plasma neuropeptide-Y levels, monoamine metabolism, electrolyte excretion and drinking behavior in children with attention-deficit hyperactivity disorder. Psychiatry Res 1998; 80: 177–186.

    Article  CAS  Google Scholar 

  54. Agranat-Meged AN, Deitcher C, Goldzweig G, Leibenson L, Stein M, Galili-Weisstub E . Childhood obesity and attention deficit/hyperactivity disorder: a newly described comorbidity in obese hospitalized children. Int J Eat Disord 2005; 37: 357–359.

    Article  Google Scholar 

  55. Ogilvie I, Kennaway NG, Shoubridge EA . A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J Clin Invest 2005; 115: 2784–2792.

    Article  CAS  Google Scholar 

  56. Xu S, Wang Y, Zhao H, Zhang L, Xiong W, Yau KW et al. PHR1, a PH domain-containing protein expressed in primary sensory neurons. Mol Cell Biol 2004; 24: 9137–9151.

    Article  CAS  Google Scholar 

  57. Sullivan PG, Dube C, Dorenbos K, Steward O, Baram TZ . Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death. Ann Neurol 2003; 53: 711–717.

    Article  CAS  Google Scholar 

  58. Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003; 9: 1062–1068.

    Article  CAS  Google Scholar 

  59. Wang D, Deng C, Bugaj-Gaweda B, Kwan M, Gunwaldsen C, Leonard C et al. Cloning and characterization of novel PDE4D isoforms PDE4D6 and PDE4D7. Cell Signal 2003; 15: 883–891.

    Article  Google Scholar 

  60. Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Roser C, Nguyen TT et al. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm 2008; 115: 1573–1585.

    Article  CAS  Google Scholar 

  61. Uhl GR, Drgon T, Johnson C, Fatusin OO, Liu QR, Contoreggi C et al. ‘Higher order’ addiction molecular genetics: convergent data from genome-wide association in humans and mice. Biochem Pharmacol 2008; 75: 98–111.

    Article  CAS  Google Scholar 

  62. Roeske D, Ludwig KU, Neuhoff N, Becker J, Bartling J, Bruder J et al. First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children. Mol Psychiatry 2009, September 29 [e-pub ahead of print].

  63. Mitchell KJ, Porteous DJ . GWAS for psychiatric disease: is the framework built on a solid foundation? Mol Psychiatry 2009; 14: 740–741.

    Article  CAS  Google Scholar 

  64. Franke B, Neale BM, Faraone SV . Genome-wide association studies in ADHD. Hum Genet 2009; 126: 13–50.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the patients and their families for their participation and support. We greatly appreciate the input from co-workers, who contributed to organization of the study, data management and technical assistance: Annette Nowak, Gabriele Ortega, Nicole Steigerwald, Nicole Döring and Theresia Töpner. This study was supported by the Deutsche Forschungsgemeinschaft (KFO 125, SFB 581, SFB TRR 58, GRK 1156, GRK 1253) and the Bundesministerium für Bildung und Forschung (BMBF 01GV0605).

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Author notes

  1. K-P Lesch, S Selch and T J Renner: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, ADHD Clinical Research Network, Unit for Molecular Psychiatry, Laboratory of Translational Neuroscience, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

    K-P Lesch, S Selch, C Jacob, T Hahn, M Heine, A Boreatti-Hümmer, J Romanos, S Gross-Lesch, T Wultsch, S Heinzel, A Fallgatter & A Reif

  2. Department of Child and Adolescent Psychiatry, ADHD Clinical Research Network, Psychosomatics, and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

    T J Renner, M Romanos, S Walitza & A Warnke

  3. Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany

    T T Nguyen, A Dempfle & H Zerlaut

  4. Max Planck Institute for Molecular Genetics, Berlin, Germany

    S Shoichet, H Schäfer, H-H Ropers & R Ullmann

  5. Department of Endocrinology and Diabetes, Internal Medicine I, University of Wuerzburg, Wuerzburg, Germany

    M Fassnacht & B Allolio

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  1. K-P Lesch
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  2. S Selch
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Correspondence to K-P Lesch.

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Additional information

Author contributions: The study was conceptualized and supervised by KPL, AW, HHR and RU. MR, JR and CJ ascertained and clinically characterized the patients. SW, TR, MH, AB-H and CJ contributed to clinical characterization of family members. SS, SS and RU carried out the genetic analysis. KPL, SS, RU and TR evaluated the genomic data. MF and BA determined NPY plasma concentrations. TH, SH and AF conducted and analysed the fMRI. TW and AR contributed expertise on genetic analyses and NPY animal models. TN, AD, HZ, and HS performed statistical analyses. KPL, TR, SS, AR and RU wrote and revised the paper.

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Lesch, KP., Selch, S., Renner, T. et al. Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree. Mol Psychiatry 16, 491–503 (2011). https://doi.org/10.1038/mp.2010.29

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