Expert group Psychiatric Genetics
WHAT
Psychiatric genetics is a subfield of behavioral neurogenetics and studies the role of genetics in psychopathology and psychiatric conditions such as schizophrenia, Alzheimer’s disease and depression. The basic principle behind psychiatric genetics is that genetic variations play a role in the etiology, severity and course of psychiatric disorders as well as in the distribution of psychological traits in the general population. Most psychiatric disorders and psychological traits are highly heritable; the estimated heritability for bipolar disorder, schizophrenia, and autism is for example much higher than that of diseases like breast cancer and Parkinson disease. However, linkage analysis and genome-wide association studies have found few reproducible risk factors associated with these psychiatric disorders. For schizophrenia, attempts to discover common alleles that relate directly to the disorder have only very recently been productive and point to very small odds ratios (O'Donovan et al., 2008a) at least when main effects alone are sought. The application of novel genetic technology to schizophrenia has also established that rare fairly high penetrance copy number variants (CNVs) may account for a small proportion of the genetic liability of schizophrenia (International Schizophrenia Consortium, 2008). However, unpublished analyses of the International Schizophrenia Consortium (ISC) SNP data along with other datasets suggest that at least half of the genetic variance results from alleles of small effect (Purcell, presented on behalf of the ISC, ISPG, 2008, Osaka).
The field of psychiatric genetics is continuously and rapidly developing through several routes:
• Substantially increased sample sizes
• Availability of high throughput genetic technologies allowing for > 500,000 SNPs to be analyzed per sample
• Improved characterization of phenotypes and the use of intermediary phenotypes, endophenotypes, symptom clusters, and quantitative trait loci
• Translational approach to elucidate molecular and cellular mechanisms underlying psychopathology
• Emphasis on gene-environment interactions
These rapid developments have already resulted in large piles of new data, with concomitant challenges in statistical analyses of these large sets of data.
The Expert Group Psychiatric Genetics:
• coordinates the design of genetic studies in the field of psychiatry conducted at MUMC
• coordinates the choice of various genetic methodologies, and choice of SNPs and genes of interest for the different research lines at MUMC
• offers a platform for the interpretation and analyses of genetic data at MUMC
• offers a platform for bringing together several disciplines in order to conduct adequately designed, multi-disciplinary and translational research to establish the role of genetic variances and gene-environment interactions in the etiology, severity and course of psychopathology and dimensions of psychological and psychiatric traits
• is involved in the coordination of large-scale national and European consortia on the study of gene-environment interactions in psychiatry
PROJECTS
A. Genetic epidemiology of psychopathology in the general population
B. Genetic variations involved in the etiology, severity and course of schizophrenia and intermediary phenotypes of schizophrenia
C. Gene-environment interactions involved in the etiology, severity and course of schizophrenia and intermediary phenotypes of schizophrenia
D. Gene-environment interactions involved in the etiology, severity and course of depression and intermediary phenotypes of depression
E. Gene-environment interactions involved in aberrant salience attribution, neurocognition and aberrant prediction error signaling
F. Role of epigenetic modulation of gene expression in psychopathology and psychiatric disorders such as depression, schizophrenia and Alzheimer’s disease
Odette Peerbooms (PhD student), Bart Rutten (supervisor)
The general aim of this research line is to dissect the role of epigenetic mechanisms on the onset and remission of psychopathology. As a first step, one PhD project aims to scrutinize the effects of variations in a particular gene relevant for epigenetic mechanisms on psychopathologic outcome measures such as stress reactivity, affect regulation and psychotic symptoms. These aspects will be studied in large populations of affected and unaffected persons. Additionally, gene-environmental interactions will be tested, again with a focus on genes relevant for epigenetic mechanisms. Further PhD projects will extend the number of investigated genes and environmental exposures on the one hand, and focus on the other hand on longitudinal studies enabling thereby the investigation of putative associations between epigenetic profiles and changes in psychopathology and/or intermediary phenotypes.
G. Role of epigenetic modulation of gene expression in psychopathology as studied in animals models of depression, schizophrenia and Alzheimer’s disease
H. Role of genetic variations and gene-environment interactions in ‘depression as a prodromal stage of dementia’, studied in large samples of the general population
I. Genetic and environmental factors modulating aging of the brain and underlying the pathophysiology of Alzheimer’s disease
J. Genetic variations involved in CO2-reactivity and panic disorder
OUTPUT
Selected references from our group in this field
Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. van Os J, Rutten BP, Poulton R. Schizophr Bull. 2008 Nov;34(6):1066-82.
Schizophrenia aetiology: do gene-environment interactions hold the key?
European Network of Schizophrenia Networks for the Study of Gene-Environment Interactions. Schizophr Res. 2008 Jul;102(1-3):21-6.
Evidence that the COMT Val158Met polymorphism moderates sensitivity to stress in psychosis: an experience-sampling study. van Winkel R, Henquet C, Rosa A, Papiol S, Fananas L, De Hert M, Peuskens J, van Os J, Myin-Germeys I. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2008;147:10-17
Mechanisms of gene-environment interactions in depression: evidence that genes potentiate multiple sources of adversity. Wichers M, Schrijvers D, Geschwind N, Jacobs N, Myin-Germeys I, Thiery E, Derom C, Sabbe B, Peeters F, Delespaul P, van Os J. Psychol Med. 2008 Oct 6:1-10.
The psychology of psychiatric genetics: evidence that positive emotions in females moderate genetic sensitivity to social stress associated with the BDNF Val-sup-6-sup-6Met polymorphism. Wichers M, Kenis G, Jacobs N, Myin-Germeys I, Schruers K, Mengelers R, Delespaul P, Derom C, Vlietinck R, van Os J. J Abnorm Psychol. 2008 Aug;117(3):699-704.
Subtle Gene-environment Interactions Driving Paranoia in Daily life. Simons C, Wichers M, Derom C, Thiery E, Myin-Germeys I, Krabbendam L, van Os J. Genes Brain Behav. 2008 Aug 21.
Susceptibility to depression expressed as alterations in cortisol day curve: a cross-twin, cross-trait study. Wichers MC, Myin-Germeys I, Jacobs N, Kenis G, Derom C, Vlietinck R, Delespaul P, Mengelers R, Peeters F, Nicolson N, Van Os J. Psychosom Med. 2008 Apr;70(3):314-8.
The catechol-O-methyl transferase Val158Met polymorphism and experience of reward in the flow of daily life. Wichers M, Aguilera M, Kenis G, Krabbendam L, Myin-Germeys I, Jacobs N, Peeters F, Derom C, Vlietinck R, Mengelers R, Delespaul P, van Os J. Neuropsychopharmacology. 2008 Dec;33(13):3030-6.
Evidence that the COMT Val158Met polymorphism moderates subclinical psychotic and affective symptoms in unaffected first-degree relatives of patients with schizophrenia. van Winkel R, Isusi P, Galdos P, Echevarria E, Bilbao JR, Martin-Pagola A, Papiol S, Castaño L, Krabbendam L, van Os J, Myin-Germeys I. European Psychiatry 2008;23(3):219-222
The BDNF Val(66)Met x 5-HTTLPR x child adversity interaction and depressive symptoms: An attempt at replication. Wichers M, Kenis G, Jacobs N, Mengelers R, Derom C, Vlietinck R, van Os J. Am J Med Genet B Neuropsychiatr Genet. 2008 Jan 5;147B(1):120-3.
Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. van Winkel R, Stefanis N, Myin-Germeys I. Schizophrenia Bulletin 2008;34(6):1095-1105.
Evidence that moment-to-moment variation in positive emotions buffer genetic risk for depression: a momentary assessment twin study. Wichers MC, Myin-Germeys I, Jacobs N, Peeters F, Kenis G, Derom C, Vlietinck R, Delespaul P, van Os J. Acta Psychiatr Scand. 2007 Jun;115(6):451-7.
Genetic risk of depression and stress-induced negative affect in daily life. Wichers M, Myin-Germeys I, Jacobs N, Peeters F, Kenis G, Derom C, Vlietinck R, Delespaul P, Van Os J. Br J Psychiatry. 2007 Sep;191:218-23.
Dimensions and the psychosis phenotype. Allardyce J, Suppes T, Van Os J. Int J Methods Psychiatr Res. 2007;16 Suppl 1 2007:S34-40.
Do symptom dimensions or categorical diagnoses best discriminate between known risk factors for psychosis? Allardyce J, McCreadie RG, Morrison G, van Os J. Soc Psychiatry Psychiatr Epidemiol. 2007 Jun;42(6):429-37.
Review: the wider social environment and schizophrenia. Allardyce J, Boydell J. Schizophr Bull. 2006 Oct;32(4):592-8..
Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression. Jacobs N, Kenis G, Peeters F, Derom C, Vlietinck R, van Os J. Arch Gen Psychiatry. 2006 Sep;63(9):989-96.
Age-related loss of synaptophysin immunoreactive presynaptic boutons within the hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L transgenic mice.
Rutten BP, Van der Kolk NM, Schafer S, van Zandvoort MA, Bayer TA, Steinbusch HW, Schmitz C. Am J Pathol. 2005 Jul;167(1):161-73.
Social fragmentation, deprivation and urbanicity: relation to first-admission rates for psychoses. Allardyce J, Gilmour H, Atkinson J, Rapson T, Bishop J, McCreadie RG. Br J Psychiatry. 2005 Nov;187:401-6.
Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. Schmitz C, Rutten BP, Pielen A, Schäfer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch HW, Pradier L, Bayer TA. Am J Pathol. 2004 Apr;164(4):1495-502.
No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the beta-cleaved C-terminal APP fragment. Rutten BP, Wirths O, Van de Berg WD, Lichtenthaler SF, Vehoff J, Steinbusch HW, Korr H, Beyreuther K, Multhaup G, Bayer TA, Schmitz C. Neurobiol Dis. 2003 Mar;12(2):110-20.
Prenatal life and post-natal psychopathology: evidence for negative gene-birth weight interaction. Wichers MC, Purcell S, Danckaerts M, Derom C, Derom R, Vlietinck R, Van Os J. Psychol Med. 2002 Oct;32(7):1165-74.