Genetische Grundlagen der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung

ZUSAMMENFASSUNG

Die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) zeigt eine hohe Erblichkeit in formalgenetischen Studien. Auch im Vergleich zu anderen psychiatrischen Erkrankungen ist die Heritabilität mit fast 80 % sehr hoch. Die Symptomatik der ADHS scheint jedoch graduell in der Normalbevölkerung vorzukommen. Neuere Arbeiten schätzen den Anteil der auf Einzelnukleotidvarianten beruhenden Heritabilität auf 22 %. Welcher Bereich der molekularen Genetik diese Differenz erklärt, ist unklar. In dem vorgelegten Übersichtsartikel geben wir einen Überblick über die Analyse häufiger und seltener Varianten. Während häufige Varianten in ersten Megaanalysen mit vielen tausend Patienten erste genomweite Ergebnisse bringen, die jedoch nur wenig Varianz erklären, zeigen sich die methodisch immer noch schwierigeren Analysen von seltenen Varianten erst in ihren Anfängen. Sie erklären in einigen wenigen individuellen Fällen jedoch eine beträchtliche Varianz. Hierzu werden Beispiele gegeben und diskutiert. Für die Praxis ist die kritische Kenntnis der Genetik der ADHS weder für Therapie noch Diagnostik zwingend. Möglicherweise werden in Zukunft auch seltene Varianten häufiger diagnostiziert werden. Um eine kompetente Beratung zu gewährleisten, ist die Kenntnis des aktuellen Forschungsstandes jedoch auch für den Praktiker von Belang.

ABSTRACT

Attention Deficit/Hyperactivity Disorder (ADHD) shows high heritability in formal genetic studies. Heritability is also very high compared to other psychiatric diseases, with almost 80 %. The symptoms of ADHD, however, seem to occur gradually in the normal population. Recent studies estimate the proportion of heritability based on single nucleotide variants at about 22 %. It is still unclear how this discrepancy can be explained. In this review, we give an overview of recent studies of frequent as well as rare DNA variants. While frequent variants provided first genome-wide results in recent mega-analyses with many thousands patients only little variance is explained so far. The analysis of rare variants is methodically still difficult. However, in a few individual cases they can explain considerable variance. Some recent studies as case examples are discussed. In clinical practice, a critical knowledge of ADHD genetics is not yet mandatory for therapy or diagnosis. However, it is possible that rare variants will also be diagnosed more frequently in the future. In order to ensure competent advice, knowledge of the current state of research is also important for practitioners.

Schlüsselwörter

ADHS - Genetik

Key Words

ADHD - genetics

• Literatur

• 1 Franke B, Michelini B, Asherson P. et al Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan. Eur Neuropsychopharmacol 2018; 28: 1059-1088 doi.org/10.1016/J.EURONEURO.2018.08.001
• 2 Polanczyk G, de Lima MS, Horta BL. et al The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis. Am J Psychiatry 2007; 164: 942-948
• 3 Larsson H, Dilshad R, Lichtenstein P. et al Developmental trajectories of DSM-IV symptoms of attention-deficit/hyperactivity disorder: Genetic effects, family risk and associated psychopathology. J Child Psychol Psychiatry Allied Discip 2011; 52: 954-63 doi.org/10.1111/j.1469-7610.2011.02379.x
• 4 Simon V, Czobor P, Bálint S. et al Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry 2009; 194: 204-211
• 5 Faraone S V, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol Med 2006; 36: 159-165
• 6 Lo-Castro A, D’Agati E, Curatolo P. ADHD and genetic syndromes. Brain Dev 2011; 33: 456-461
• 7 Sullivan PF, Daly MJ, O’Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537-551
• 8 Capusan AJ, Bendtsen P, Marteinsdottir I. et al Comorbidity of Adult ADHD and Its Subtypes With Substance Use Disorder in a Large Population-Based Epidemiological Study. J Atten Disord 2016; 108705471562651 doi.org/10.1177/1087054715626511
• 9 Franke B, Michelini G, Asherson P. et al Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan. Eur Neuropsychopharmacol 2018; 28: 1059-1088
• 10 Faraone S V., Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry 2019; 24: 562-575 www.nature.com/articles/s41380-018-0070-0
• 11 Demontis D, Walters RK, Martin J. et al Discovery of the first genome-wide significant risk loci for ADHD. Nat Genet 2019; 51: 63-75
• 12 Hong EP, Park JW. Sample size and statistical power calculation in genetic association studies. Genomics Inform 2012; 10: 117-122 www.ncbi.nlm.nih.gov/pubmed/23105939
• 13 Visscher PM, Wray NR, Zhang Q. et al 10 Years of GWAS Discovery: Biology, Function, and Translation. Am J Hum Genet 2017; 101: 5-22 http://www.ncbi.nlm.nih.gov/pubmed/28686856
• 14 Franke B, Faraone S V, Asherson P. et al The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 2012; 17: 960-987
• 15 Bonvicini C, Faraone S V., Scassellati C. Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Nature Publishing Group 20167
• 16 Lee SH, Ripke S, Neale BM. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45: 984-994 http://www.nature.com/articles/ng.2711
• 17 Lasky-Su J, Neale BM, Franke B. 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
• 18 Lesch K-PP, Timmesfeld N, Renner TJ. 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
• 19 Neale BM, Lasky-Su J, Anney R. et al Genome-wide association scan of attention deficit hyperactivity disorder. Am J Med Genet Part B Neuropsychiatr Genet 2008; 147B: 1337-1344 http://doi.wiley.com/10.1002/ajmg.b.30866
• 20 Neale BM, Medland SE, Ripke S. et al Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010; 49: 884-897 http://www.ncbi.nlm.nih.gov/pubmed/20732625
• 21 Fagerberg L, Hallström BM, Oksvold P. et al Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics. Mol Cell Proteomics 2014; 13: 397-406
• 22 Takeuchi T, Misaki A, Liang S Ben. et al Expression of T-cadherin (CDH13, H-cadherin) in human brain and its characteristics as a negative growth regulator of epidermal growth factor in neuroblastoma cells. J Neurochem 2000; 74: 1489-1497
• 23 Arcos-Burgos M, Jain M, Acosta MT. et al A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry 2010; 15: 1053-1066
• 24 Bruxel EM, Salatino-Oliveira A. et al LPHN3 and attention-deficit/hyperactivity disorder: A susceptibility and pharmacogenetic study. Genes, Brain Behav 2015; 14: 419-427 doi.org/10.1111/gbb.12224
• 25 Ribasés M, Ramos-Quiroga JA, Sánchez-Mora C. et al Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: A replication study. Genes, Brain Behav 2011; 10: 149-157
• 26 Lange M, Norton W, Coolen M. et al The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development. Mol Psychiatry 2012; 17: 946-954
• 27 Orsini CA, Setlow B, DeJesus M. et al Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction. Mol Genet Genomic Med 2016; 4: 322-343
• 28 Mortimer N, Ganster T, O’Leary A. et al Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation. Neuropharmacology 2019 https://www.sciencedirect.com/science/article/pii/S0028390819300784?via%3Dihub
• 29 Middeldorp CM, Hammerschlag AR, Ouwens KG. et al A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts. J Am Acad Child Adolesc Psychiatry 2016; 55
• 30 Groen-Blokhuis MM, Middeldorp CM, Kan K-J. et al Attention-Deficit/Hyperactivity Disorder Polygenic Risk Scores Predict Attention Problems in a Population-Based Sample of Children. J Am Acad Child Adolesc Psychiatry 2014; 53: 1123-1129.e6
• 31 Rovira P, Demontis D, Sánchez-Mora C. et al Shared genetic background between children and adults with attention deficit/hyperactivity disorder. bioRxiv 2019; 589614 https://www.biorxiv.org/content/10.1101/589614v2
• 32 Martin J, O’Donovan MC, Thapar A. et al The relative contribution of common and rare genetic variants to ADHD. Transl Psychiatry 2015; 5: e506
• 33 Merker S, Reif A, Ziegler GC. et al SLC2A3 single-nucleotide polymorphism and duplication influence cognitive processing and population-specific risk for attention-deficit/hyperactivity disorder. J Child Psychol Psychiatry Allied Discip 2017; 58: 798-809
• 34 Hoeffding LK, Trabjerg BB, Olsen L. et al Risk of Psychiatric Disorders Among Individuals With the 22q11.2 Deletion or Duplication. JAMA Psychiatry 2017; 74: 282
• 35 Williams NM, Franke B, Mick E. et al Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3. Am J Psychiatry 2012; 169: 195-204
• 36 Williams NM, Zaharieva I, Martin A. et al Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: A genome-wide analysis. Lancet 2010; 376: 1401-1408
• 37 Lionel AC, Crosbie J, Barbosa N. et al Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci Transl Med 2011; 3: 95ra75
• 38 Sánchez-Mora C, Ramos-Quiroga JA, Bosch R. et al Case-control genome-wide association study of persistent attention-deficit hyperactivity disorder identifies FBXO33 as a novel susceptibility gene for the disorder. Neuropsychopharmacology 2015; 40: 915-926
• 39 Elia J, Glessner JT, Wang K, Takahashi N. 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
• 40 de Araújo Lima L, Feio-dos-Santos AC, Belangero SI. et al An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder. Sci Rep 2016; 6: 22851
• 41 Lesch K-P, Selch S, Renner TJ. 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 2011; 16: 491-503
• 42 Demontis D, Lescai F, Børglum A. et al Whole-Exome Sequencing Reveals Increased Burden of Rare Functional and Disruptive Variants in Candidate Risk Genes in Individuals With Persistent Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry 2016; 55: 521-523 https://www.sciencedirect.com/science/article/pii/S0890856716300971?via%3Dihub
• 43 Satterstrom FK, Walters RK, Singh T. et al ASD and ADHD have a similar burden of rare protein-truncating variants. bioRxiv 2018: 277707 https://www.biorxiv.org/content/10.1101/277707v1
• 44 Elia J, Gai X, Xie HM. et al Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 2010; 15: 637-646
• 45 Alemany S, Ribasés M, Vilor-Tejedor N. et al New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2015; 168: 459-470
• 46 Boyle EA, Li YI, Pritchard JK, at et. An Expanded View of Complex Traits: From Polygenic to Omnigenic. Cell 2017; 169: 1177-1186
• 47 Kambeitz J, Romanos M, Ettinger U. Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD. Pharmacogenomics J 2014; 14: 77-84
• 48 Myer NM, Boland JR, Faraone S V. Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD. Mol Psychiatry 2017; 23: 1929-1936 doi.org/10.1038/mp.2017.234
• 49 da Silva BS, Cupertino RB, Rovaris DL. et al Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD. Mol Psychiatry 2018; 23: 1446-1452
• 50 Khera A V, Chaffin M, Aragam KG. et al Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet 2018; 50: 1219-1224
• 51 Mega JL, Stitziel NO, Smith JG. et al Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet 2015; 385: 2264-2271
• 52 van der Maas HLJ, Dolan C V, Grasman RPPP. et al A dynamical model of general intelligence: the positive manifold of intelligence by mutualism. Psychol Rev 2006; 113: 842-861
• 53 Lebowitz MS. Stigmatization of ADHD: A Developmental Review. J Atten Disord 2016; 20: 199-205 doi.org/10.1177/1087054712475211