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.

Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder

Abstract

The study of monozygotic twins discordant for attention deficit hyperactivity disorder can elucidate mechanisms that contribute to the disorder, which affects ~7% of children. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, s.d. 1.9 years), we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we found a significant enrichment of epigenetic differences in genes expressed in these ‘discordant’ brain structures. Specifically, there is differential methylation of probes lying in the shore and shelf and enhancer regions of striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs—such as copy number and rare, single-nucleotide variants—did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated γ-aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  1. ADHD. Data and Statistics, 2011. Available at: http://www.cdc.gov/ncbddd/adhd/data.html (last accessed on 1 September 2016).

  2. Hawi Z, Cummins T, 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.

    CAS  Article  Google Scholar 

  3. Franke B, Faraone SV, Asherson P, Buitelaar J, Bau CHD, Ramos-Quiroga JA et al. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 2012; 17: 960–987.

    CAS  Article  Google Scholar 

  4. Wong C, Meaburn EL, Ronald A, Price T, Jeffries A, Schalkwyk L et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol Psychiatry 2014; 19: 495–503.

    CAS  Article  Google Scholar 

  5. Cordova-Palomera A, Fatjo-Vilas M, Gasto C, Navarro V, Krebs M, Fananas L . Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins. Transl Psychiatry 2015; 5: e557.

    CAS  Article  Google Scholar 

  6. Fisher HL, Murphy TM, Arseneault L, Caspi A, Moffitt TE, Viana J et al. Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms. Epigenetics 2015; 10: 1014–1023.

    Article  Google Scholar 

  7. Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet 2011; 20: 4786–4796.

    CAS  Article  Google Scholar 

  8. Oh G, Wang S-C, Pal M, Chen ZF, Khare T, Tochigi M et al. DNA modification study of major depressive disorder: beyond locus-by-locus comparisons. Biol psychiatry 2015; 77: 246–255.

    CAS  Article  Google Scholar 

  9. Wilmot B, Fry R, Smeester L, Musser ED, Mill J, Nigg JT . Methylomic analysis of salivary DNA in childhood ADHD identifies altered DNA methylation in VIPR2. J Child Psychol Psychiatry 2015; 57: 152–160.

    Article  Google Scholar 

  10. Castellani CA, Awamleh Z, Melka MG, O'Reilly RL, Singh SM . Copy number variation distribution in six monozygotic twin pairs discordant for schizophrenia. Twin Res Hum Genet 2014; 17: 108–120.

    Article  Google Scholar 

  11. Ono S, Imamura A, Tasaki S, Kurotaki N, Ozawa H, Yoshiura K-I et al. Failure to confirm CNVs as of aetiological significance in twin pairs discordant for schizophrenia. Twin Res Hum Genet 2010; 13: 455–460.

    Article  Google Scholar 

  12. Bloom RJ, Kahler AK, Collins AL, Chen G, Cannon TD, Hultman C et al. Comprehensive analysis of copy number variation in monozygotic twins discordant for bipolar disorder or schizophrenia. Schizophr Res 2013; 146: 289–290.

    Article  Google Scholar 

  13. Bruder CE, Piotrowski A, Gijsbers AA, Andersson R, Erickson S, de Ståhl TD et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 2008; 82: 763–771.

    CAS  Article  Google Scholar 

  14. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014; 506: 179–184.

    CAS  Article  Google Scholar 

  15. Ronemus M, Iossifov I, Levy D, Wigler M . The role of de novo mutations in the genetics of autism spectrum disorders. Nat Rev Genet 2014; 15: 133–141.

    CAS  Article  Google Scholar 

  16. Castellanos FX, Sharp WS, Gottesman RF, Greenstein DK, Giedd JN, Rapoport JL . Anatomic brain abnormalities in monozygotic twins discordant for attention deficit hyperactivity disorder. Am J Psychiatry 2003; 160: 1693–1696.

    Article  Google Scholar 

  17. Nakao T, Radua J, Rubia K, Mataix-Cols D . Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. Am J Psychiatry 2011; 2011: 24.

    Google Scholar 

  18. Valera EM, Faraone SV, Murray KE, Seidman LJ . Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 61: 1361–1369.

    Article  Google Scholar 

  19. Frodl T, Skokauskas N . Meta‐analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. Acta Psychiatr Scand 2012; 125: 114–126.

    CAS  Article  Google Scholar 

  20. Xia S, Li X, Kimball AE, Kelly MS, Lesser I, Branch C . Thalamic shape and connectivity abnormalities in children with attention-deficit/hyperactivity disorder. Psychiatry Res 2012; 204: 161–167.

    Article  Google Scholar 

  21. Castellanos FX, Proal E . Large-scale brain systems in ADHD: beyond the prefrontal–striatal model. Trends Cogn Sci 2012; 16: 17–26.

    Article  Google Scholar 

  22. Reich W . Diagnostic interview for children and adolescents (DICA). J Am Acad Child Adolesc Psychiatry 2000; 39: 59–66.

    CAS  Article  Google Scholar 

  23. Galwey NW . A new measure of the effective number of tests, a practical tool for comparing families of non‐independent significance tests. Genet Epidemiol 2009; 33: 559–568.

    Article  Google Scholar 

  24. Morris TJ, Butcher LM, Feber A, Teschendorff AE, Chakravarthy AR, Wojdacz TK et al. ChAMP: 450k Chip Analysis Methylation Pipeline. Bioinformatics 2014; 30: 428–430.

    CAS  Article  Google Scholar 

  25. Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet 2011; 20: 4786–4796.

    CAS  Article  Google Scholar 

  26. Jones PA . Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012; 13: 484–492.

    CAS  Article  Google Scholar 

  27. Dempster EL, Wong CC, Lester KJ, Burrage J, Gregory AM, Mill J et al. Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression. Biol Psychiatry 2014; 76: 977–983.

    CAS  Article  Google Scholar 

  28. Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu X, Li M et al. Spatio-temporal transcriptome of the human brain. Nature 2011; 478: 483–489.

    CAS  Article  Google Scholar 

  29. 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.

    CAS  Article  Google Scholar 

  30. 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.

    CAS  Article  Google Scholar 

  31. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009; 25: 2078–2079.

    Article  Google Scholar 

  32. Hansen NF, Gartner JJ, Mei L, Samuels Y, Mullikin JC . Shimmer: detection of genetic alterations in tumors using next-generation sequence data. Bioinformatics 2013; 29: 1498–1503.

    CAS  Article  Google Scholar 

  33. Larson DE, Harris CC, Chen K, Koboldt DC, Abbott TE, Dooling DJ et al. SomaticSniper: identification of somatic point mutations in whole genome sequencing data. Bioinformatics 2012; 28: 311–317.

    CAS  Article  Google Scholar 

  34. Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 2013; 31: 213–219.

    CAS  Article  Google Scholar 

  35. Wang K, Li M, Hakonarson H . ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38: e164.

    Article  Google Scholar 

  36. 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 2008; 147B: 1345–1354.

    CAS  Article  Google Scholar 

  37. Friedman LA, Rapoport JL . Brain development in ADHD. Curr Opin Neurobiol 2015; 30: 106–111.

    CAS  Article  Google Scholar 

  38. Shaw P, De Rossi P, Watson B, Wharton A, Greenstein D, Raznahan A et al. Mapping the development of the basal ganglia in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2014; 53: 780–789.

    Article  Google Scholar 

  39. Stoodley CJ . Distinct regions of the cerebellum show gray matter decreases in autism, ADHD, and developmental dyslexia. Front Systems Neurosci 2014; 8: 92.

    Article  Google Scholar 

  40. Ivanov I . Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. Am J Psychiatry 2010; 167: 397.

    Article  Google Scholar 

  41. Mackie S, Shaw P, Lenroot R, Pierson R, Greenstein DK, Nugent TF 3rd et al. Cerebellar development and clinical outcome in attention deficit hyperactivity disorder [see comment]. Am J Psychiatry 2007; 164: 647–655.

    Article  Google Scholar 

  42. Rossi R, Pievani M, Järvenpää T, Testa C, Koskenvuo M, Räihä I et al. Voxel‐based morphometry study on monozygotic twins discordant for Alzheimer's disease. Acta Neurol Scand 2015; 133: 427–433.

    Article  Google Scholar 

  43. Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR . Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 1990; 322: 789–794.

    CAS  Article  Google Scholar 

  44. Pol HEH, Schnack HG, Mandl RC, Brans RG, van Haren NE, Baaré WF et al. Gray and white matter density changes in monozygotic and same-sex dizygotic twins discordant for schizophrenia using voxel-based morphometry. NeuroImage 2006; 31: 482–488.

    Article  Google Scholar 

  45. Kates WR, Burnette CP, Eliez S, Strunge LA, Kaplan D, Landa R et al. Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism. Am J Psychiatry 2004; 161: 539–546.

    Article  Google Scholar 

  46. Ronald A, Simonoff E, Kuntsi J, Asherson P, Plomin R . Evidence for overlapping genetic influences on autistic and ADHD behaviours in a community twin sample. J Child Psychol Psychiatry 2008; 49: 535–542.

    Article  Google Scholar 

  47. Taurines R, Schwenck C, Westerwald E, Sachse M, Siniatchkin M, Freitag C . ADHD and autism: differential diagnosis or overlapping traits? A selective review. Atten Defic Hyperact Disord 2012; 4: 115–139.

    Article  Google Scholar 

  48. Davies MN, Volta M, Pidsley R, Lunnon K, Dixit A, Lovestone S et al. Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biol 2012; 13: R43.

    CAS  Article  Google Scholar 

  49. Kaminsky Z, Tochigi M, Jia P, Pal M, Mill J, Kwan A et al. A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder. Mol psychiatry 2012; 17: 728–740.

    CAS  Article  Google Scholar 

  50. Lv J, Xin Y, Zhou W, Qiu Z . The epigenetic switches for neural development and psychiatric disorders. J Genet Genomics 2013; 40: 339–346.

    Article  Google Scholar 

  51. Ma DK, Marchetto MC, Guo JU, Ming G-l, Gage FH, Song H . Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat Neurosci 2010; 13: 1338–1344.

    CAS  Article  Google Scholar 

  52. Pidsley R, Dempster E, Mill J . Brain weight in males is correlated with DNA methylation at IGF2. Mol Psychiatry 2010; 15: 880–881.

    CAS  Article  Google Scholar 

  53. Peña CJ, Bagot RC, Labonté B, Nestler EJ . Epigenetic signaling in psychiatric disorders. J Mol Biol 2014; 426: 3389–3412.

    Article  Google Scholar 

  54. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA et al. Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 2002; 5: 308–315.

    CAS  Article  Google Scholar 

  55. Graziano C, D'Elia AV, Mazzanti L, Moscano F, Guidelli Guidi S, Scarano E et al. A de novo nonsense mutation of PAX6 gene in a patient with aniridia, ataxia, and mental retardation. Am J Med Genet A 2007; 143A: 1802–1805.

    CAS  Article  Google Scholar 

  56. Nakamura T, Jenkins NA, Copeland NG . Identification of a new family of Pbx-related homeobox genes. Oncogene 1996; 13: 2235–2242.

    CAS  PubMed  Google Scholar 

  57. Matsui A, Tran M, Yoshida AC, Kikuchi SS, Mami U, Ogawa M et al. BTBD3 controls dendrite orientation toward active axons in mammalian neocortex. Science 2013; 342: 1114–1118.

    CAS  Article  Google Scholar 

  58. Sofroniew MV, Howe CL, Mobley WC . Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001; 24: 1217–1281.

    CAS  Article  Google Scholar 

  59. Ribases M, Hervas A, Ramos-Quiroga JA, Bosch R, Bielsa A, Gastaminza X et al. Association study of 10 genes encoding neurotrophic factors and their receptors in adult and child attention-deficit/hyperactivity disorder. Biol Psychiatry 2008; 63: 935–945.

    CAS  Article  Google Scholar 

  60. Gassó P, Ortiz AE, Mas S, Morer A, Calvo A, Bargalló N et al. Association between genetic variants related to glutamatergic, dopaminergic and neurodevelopment pathways and white matter microstructure in child and adolescent patients with obsessive–compulsive disorder. J Affect Disord 2015; 186: 284–292.

    Article  Google Scholar 

  61. Scott LJ, Muglia P, Kong XQ, Guan W, Flickinger M, Upmanyu R et al. Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry. Proc Natl Acad Sci USA 2009; 106: 7501–7506.

    CAS  Article  Google Scholar 

  62. Kunugi H, Hashimoto R, Yoshida M, Tatsumi M, Kamijima K . A missense polymorphism (S205L) of the low‐affinity neurotrophin receptor p75NTR gene is associated with depressive disorder and attempted suicide. Am J Med Genet B 2004; 129: 44–46.

    Article  Google Scholar 

  63. Levy F, de Leon J . Dopamine ADHD/OCD theories: is glutamine part of the story? Neurotransmitter 2015; 2: e891; doi:10.14800/nt.891.

    CAS  Article  Google Scholar 

  64. Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P . Amplification of dopaminergic signaling by a positive feedback loop. Proc Natl Acad Sci USA 2000; 97: 12840–12845.

    CAS  Article  Google Scholar 

  65. Krab LC, Goorden SM, Elgersma Y . Oncogenes on my mind: ERK and MTOR signaling in cognitive diseases. Trends Genet 2008; 24: 498–510.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The study was funded by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Mental Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P Shaw.

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

Verify currency and authenticity via CrossMark

Cite this article

Chen, YC., Sudre, G., Sharp, W. et al. Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder. Mol Psychiatry 23, 683–690 (2018). https://doi.org/10.1038/mp.2017.45

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2017.45

Further reading

Search

Quick links