1. The biology of the brain and its implications for health care Barbara Franke, PhD Departments of Human Genetics & Psychiatry Donders Institute for Brain, Cognition and Behavior Radboud University Medical Center Nijmegen, The Netherlands barbara.franke@radboudumc.nl

3. BrainFacts.org Disorders of the brain pose one of the greatest threats to human health Global disease burden in 2010: Mental and behavioral disorders: 7.4% Neurological disorders: 3.0% Stroke: 4.1% (not taken into account: (a) other cardiovascular disorders, (b) communicable diseases like meningitis, encephalitis, or HIV / AIDS, (c) chronic pain, (d) head and spinal cord injury) Burden in “disability adjusted life years” (DALYs)* in 2010: the mental and behavioral disorders accounted for 2,669 out of every 100,000 DALYs, the neurological disorders made up 1,071 out of every 100,000 DALYs Global cost in 2010 in Europe: cost of all brain disorders was estimated at € 798 billion, projected to grow to > € 1.9 trillion in 2030 Global Burden of Disease study conducted by the WHO, the World Bank, and Harvard School of Public Health since 1993 *one DALY is equivalent to one lost year of healthy life

4. Deep brain stimulation treats symptoms of neurological disorders and severe forms of obsessive compulsive disorder and depression

5. Diagnosis of (different forms of) dementia now involves routine MRI Patient with dementia with Lewy Bodies

6. Adult neurogenesis is important for learning and memory and mental health

7. An adapted diet prevents/reduces symptoms of dementia, ADHD, depression, …..

8. Exome sequencing in diagnostic routine of highly heterogeneous brain disorders

9. Pharmacogenetic testing (PGT) enables personalized treatment Determination of optimal drug and optimal dose for an individual patient

10. An area of research with great potential: psychiatry One of the last disciplines of medicine that cannot benefit from use of biological tests for diagnosing patients Available medication reduces symptoms, but does not cure No medication is available for many disorders Global disease burden from mental and behavioral disorders: 7.4% The mental and behavioral disorders account for 2,669 out of every 100,000 DALYs Estimated yearly cost of mental disorders in Europe is € 461 billion (excluding dementia and neurological disorders)

11.  ADHD76%  Autistic spectrum disorders 50-90%  Schizophrenia 80%  Bipolar disorder77%  Intellectual disability, genetic cause50%  Late onset Alzheimer’s disease60-80% Heritability of most neurodevelopmental disorders is high

12. The variable genome The genome of two humans varies substantially 15 million variants with frequency >1% over 30 million low frequency variants We now have the tools to explore genome variance: genome-wide genotyping & next generation sequencing

13. New ADHD meta-analysis 18,284 cases and 33,836 controls 10 genome-wide significant loci! Slide courtesy of Borglum, Neale, Faraone Gene-finding is only the first step

14. Bioinformatics Induced neurons Animal models CACNA1C rs7959938 alters brainstem volume patient and (engineered) wild type cells

15. Steroid hormone synthesis Neurite outgrowth Neuronal/synaptic signalling Poelmans et al., Translational Psychiatry 2013 Gene-networks/-pathways in autism etiology These approaches can uncover new leads for treatment development

16. patient and (engineered) wild type cells Bioinformatics Induced neurons Animal models CACNA1C rs7959938 alters brainstem volume Epigenetics

17. Bioinformatics Induced neurons Animal models CACNA1C rs7959938 alters brainstem volume patient and (engineered) wild type cells

19. Bioinformatics Induced neurons Animal models CACNA1C rs7959938 alters brainstem volume patient and (engineered) wild type cells

20. Phenotype can be rescued with methylphenidate (model lends itself for drug screening) Animal model Drosophila DAT1 homologue knock-down Activity monitoring in the fruit fly Van der Voet et al., Mol Psychiatry 2015 more boutons: p=6E-07

21. Bioinformatics Induced neurons Animal models CACNA1C rs7959938 alters brainstem volume patient and (engineered) wild type cells

22. Nijmegen: world-class centre for biological research of the (healthy) brain