Update on the genetics of ADHD
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1 UKAAN Body and Mind conference, September 11, 2014 Update on the genetics of ADHD Barbara Franke, PhD Departments of Human Genetics & Psychiatry Donders Institute for Brain, Cognition and Behavior Radboud university medical center Nijmegen, The Netherlands
2 Ulitmate goals of research: Improving diagnosis of ADHD Common genetic variants Rare genetic variants Improving treatment and outcome of ADHD Bioinformatics Animal models
3 Heritability estimates ADHD 76% Autistic spectrum disorders 60-90% Schizophrenia 80% Bipolar disorder 77% Substance abuse disorders 40-80% Major depressive disorder 40% Late onset Alzheimer s disease 60-80%
4 ADHD has a multifactorial etiology Involvement of many genes simultaneously polygenic heterogeneous Involvement of environmental factors Contributing genetic variants = polymorphisms Common in population, individually small effect In unknown percentage of patients rare, large-effect mutations involved
5 Collaboration is essential to find genes for complex disorders
6 PGC meta-analysis of GWAS in schizophrenia identifies 128 risk variants in 108 independent loci Manhattan plot showing schizophrenia associations. Genome-wide association meta-analysis of 49 case control samples (34,241 cases and 45,604 controls) and 3 family-based association studies (1,235 parent affected-offspring trios). S Ripke et al. Nature 000, 1-7 (2014) doi: /nature13595
7 PGC mega-analysis of GWAS in ADHD September 2012: 5,621 cases, 13,589 controls Intergenic locus, p-value 8.178E-08 PGC ADHD working group; unpublished result GWAS = genome-wide association study
8 IMpACT, the International Multicenter persistent ADHD CollaboraTion Nijmegen, NL: Barbara Franke, Jan Buitelaar Barcelona, Spain: Toni Ramos-Quiroga, Bru Cormand Würzburg, Germany: Peter Lesch Frankfurt, Germany: Andreas Reif Bergen, Norway: Jan Haavik, Stefan Johansson London, UK: Philip Asherson, Jonna Kuntsi Stockholm, Sweden: Henrik Larsson Boston/Syracuse, USA: Steve Faraone, Alysa Doyle Porto Alegre, Brazil: Claiton Bau, Eugenio Grevet
9 A genome-wide association study of adult ADHD Discovery: 607 adult cases, 584 controls Replication: 2104 adult cases, 1901 controls Sanchez-Mora et al., Neuropsychopharmacol., in press
10 PGC mega-analysis of GWAS in ADHD September 2012: 5,621 cases, 13,589 controls Intergenic locus, p-value 8.178E-08 Addition of 25,000 genotyped cases expected in 2015 PGC ADHD working group; unpublished result GWAS = genome-wide association study
11 Family provided by K.P. Lesch, Würzburg University, Germany
12 Older fathers children have more ADHD
13 Gene-finding in multifactorial diseases Adapted from Manolio et al., Nature 2009
14 Rare copy number variants in ADHD Am. J. Psychiatry 2012
15 An example of a family from our clinic Microduplication ~400 Mb RPL23AP5 ZNF596 FBXO25 TDRP
16 Next generation sequencing - whole exome sequencing - whole genome sequencing
17 Family provided by K.P. Lesch, Würzburg University, Germany
18 Exome sequencing in autism spectrum disorders about 10% of autism spectrum disorders explained by de novo mutations
19 IMpACT-NL: demographic characteristics ADHD HC p value N Gender (m/f) 56/77 53/79 n.s. Average age 35,6 36,3 n.s. IQ estimated 108 ± ± 15 n.s. No additional ADHD cases in family 34 (26,4%) Inattentive sympt 7,4 ± 1,6 0,4 ± 0,8 <.001 Hyperactivity sympt 5,8 ± 2,3 0,5 ± 1,0 <.001 Total sympt 13,1 ± 2,8 0,9 ± 1,4 <.001
20 Ulitmate goals of research: Improving diagnosis of ADHD Common genetic variants Rare genetic variants Improving treatment and outcome of ADHD Bioinformatics Animal models
21 PGC meta-analysis of GWAS in schizophrenia identifies 128 risk variants in 108 independent loci Odds ratio by risk score profile Manhattan plot showing schizophrenia associations. Genome-wide association meta-analysis of 49 case control samples (34,241 cases and 45,604 controls) and 3 family-based association studies (1,235 parent affected-offspring trios). S Ripke et al. Nature 000, 1-7 (2014) doi: /nature13595
22 Cross-disorder GWAS 33,332 cases and 27,888 controls Alzheimer s disease: APOE, CLU, CR1, BIN1, PICALM, ABCA7 CD33, MS4A4/MS4A6, CD2AP, EPHA1 Schizophrenia: ZNF804A, CACNA1C, ANK3, MIR137, ITIH3/ITIH4 schizophrenia + bipolar disorder + major depression + ADHD + autism Psychiatric Genomics Consortium, Lancet 2013
23 Ulitmate goals of research: Improving diagnosis of ADHD Common genetic variants Rare genetic variants Improving treatment and outcome of ADHD Bioinformatics Animal models
24 How bioinformatics can help us improve ADHD treatment Gene(-products) interact in pathways and networks that support biological processes. ADHD: Poelmans et al., Am J Psychiatry 2011 Dyslexia: Poelmans et al., Mol Psychiatry 2011 Developmental coordination disorder: Fliers et al., World J Biol Psychiatry 2012 Autism: Poelmans et al., Translational Psychiatry 2013
25 Convergence of findings: Do the different GWASs point to specific biological processes involved in ADHD? 5 GWAS for ADHD: 85 genes selected (study-specific p-value < 10E-05) Software for enrichment of biological processes Systematic literature review 44 out of 85 genes (52%) involved in neurite outgrowth
26 Neurite outgrowth genes from 5 GWAS in ADHD Of 85 genes with association p<10e-05, 44 (52%) are related to neurite outgrowth Poelmans et al., Am J Psychiatry, 2011
27 Gene-landscapes involved in autism Steroid hormone synthesis Neuronal/synaptic signalling These approaches can uncover new leads for treatment development Neurite outgrowth Poelmans et al., Translational Psychiatry 2013
28 Ulitmate goals of research: Improving diagnosis of ADHD Common genetic variants Rare genetic variants Improving treatment and outcome of ADHD Bioinformatics Animal models
29 Human ADHD genes make flies hyperactive! DAT1 homologue knock-down Night hyperactivity light regulates dopamine signaling Hyperactivity can be rescued by methylfenidate
30 Ulitmate goals of research: Improving diagnosis of ADHD Common genetic variants Rare genetic variants? Improving treatment and outcome of ADHD Bioinformatics Animal models
31 Acknowledgements IMpACT Netherlands IMpACT Germany IMpACT Spain IMpACT Norway IMpACT UK IMpACT Brazil IMpACT USA Barbara Franke (chair) Jan K. Buitelaar Martine Hoogman Alejandro Arias Vasquez Kimm van Hulzen Monique van der Voet Angelien Heister Janneke Dammers Andreas Reif (vice-chair) Klaus-Peter Lesch Florian Freudenberg Lena Weissflog Miriam Schiele Sarah Kittel- Schneider Silke Groß-Lesch J. Antoni Ramos Bru Cormand Marta Ribasés Iris Garcia Rosa Bosch Cristina Sánchez- Mora Raquel Vidal Vanesa Richarte Mariana Nogueira Jan Haavik Stefan Johansson Anne Halmøy Helene Halleland Ingeborg Winge Jeffrey McKinney M. Dramsdahl Kaya K. Jacobsen Elisabeth Landaas Philip Asherson Jonna Kuntsi IMpACT Sweden Henrik Larsson Ylva Ginsberg Claiton Bau Eugenio Grevet Luis Rohde Nina Roth-Mota Veronica Contini Paulo Silva Belmonte de-abreu Stephen Faraone Alysa Doyle Joseph Biederman Cees C. Kan Marten Onnink Jeanette Mostert Marieke Klein Marjolein van Donkelaar Thomas Wolfers Marlies Naber Remco Makkinje Montserrat Corrales Noelia Fernández Castillo Per M. Knappskog Ole B. Fasmer Astri Lundervold K. von Plessen T. Mavroconstanti Sidsel E. Riise We also thank the NIMH (grant: 7R13MH ) for funding the conferences of the ADHD Molecular Genetics Network that fostered this collaboration
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