Research lines
Roel Ophoff's group works on human genetics, studying genetic variation in the context of a phenotype (causality). They focus on 2 lines for studying neurogenetic disorders.
(1) Genetic Architecture of Disease:
• common vs rare alleles
• relative risk (odds ratio)
(2) Approaches of Genetic Studies:
• candidate genes (e.g. functional insights)
• genome-wide (with or without prior selection of specific genes)
Study design variables are allele frequency and effect size, which lead to: pedigree studies, trio designs, and case/control designs
There are 3 molecular levels for study:
- DNA: “blueprint” of genetic variation
- RNA: gene expression - molecular phenotype, primary & secondary effects, tissue-specific
- DNA methylation: epigenetic profile of DNA - environmental effects (incl. smoking, drugs, age), parental effects, molecular phenotype, tissue-specific, primary & secondary effects
Alternatively, there is a clinical approach: refining the phenotype to decrease genetic heterogeneity
The group is studying two neurogenetic traits:
• Schizophrenia, in collaboration with Prof René Kahn, Dept. of Psychiatry, UMC Utrecht
• Amyotrophic Lateral Sclerosis (ALS), in collaboration with Prof Leonard vd Berg, Dept. of Neurology, UMC Utrecht
Highlights of 2008/2009
• Identification of rare genomic copy number variants associated with schizophrenia
Ingason et al (2009) Mol Psychiatry. 2009 Sep 29.
Rujescu et al (2009) Hum Mol Genet. 2009 Mar 1;18(5):988-96.
Stefansson et al (2008) Nature. 2008 Sep 11;455(7210):232-6.
Vrijenhoek et al (2008) Am J Hum Genet. 2008 Oct;83(4):504-10
• Identification of common variants associated with schizophrenia
Stefansson et al (2009) Nature. 2009 Aug 6;460(7256):744-7
• Identification of common variants associated with ALS
Van Es et al (2009) Nat Genet. 2009 Oct;41(10):1083-7
Van Es et al (2008) Nat Genet. 2008 Jan;40(1):29-31
• Gene expression profiles and disease
Saris et al (2009) BMC Genomics. 2009 Aug 27;10:405
Rietkerk et al (2009) Mol Psychiatry. 2009 Apr;14(4):353-5
• DNA methylation profiles in healthy twins and singletons
Boks et al (2009) PLoS One. 2009 Aug 26;4(8):e6767
Future directions (ongoing):
• Psychiatric GWAS Consortium (PGC) for meta-analysis
• Refinement of disease phenotypes for genetic studies
• Further study of gene expression profiles and disease (incl endophenotypes)
• DNA methylation study of schizophrenia (blood & brain)
• Cerebrospinal Spinal Fluid (CSF) metabolites and exosomes
• In-depth study of brain tissue of SCZ patients (vs controls)
• Molecular analysis of mouse models (for SCZ)
• Switch from case/control back to pedigree-based studies
• Switch from targeted array-based analyses to nextgen sequencing technologies
• Expanding to study of manic depressive illness (bipolar disorder)
• Bioinformatic approaches for analyses (merge genetic, gene expression and epigenetic data)
Collaborations
Dept of Medical Genetics, DBG
• Bobby Koeleman, Edwin Cuppen (shared lab, discussions)
• Ploos van Amstel, Poot, Hochstenbach, Brilstra, vd Zwaag (autism)
Utrecht University
• Willem Stoorvogel
Rudolf Magnus Institute (UMC Utrecht)
• René Kahn, Steven Bakker, Marco Boks, Iris Sommer
• Wouter Staal, Jacob Vorstman, Peter Burbach
• Leonard van den Berg
• Martien Kas
University of California, Los Angeles (UCLA)
• Nelson Freimer, Rita Cantor, Chiara Sabatti
• Steve Horvath, Jake Lusis
• Eleazar Eskin, Guoping Fan
International
• SGENE: European Schizophrenia Consortium
• PGC: International Psychiatric meta analyses
• NIH Roadmap Initiative of Epigenomics
People in group
Marijke Laarakker, postdoc, generating mouse models for SCZ
Eric Strengman, lab manager, technician
Esther Janson, technician
Simone de Jong, PhD student, gene expression
Kristel van Eijk, PhD student, DNA methylation
Jacobine Buizer, PhD student, schizophrenia and genomic variation (CNVs)
vacancy: PhD student, molecular genetics of SCZ brains
Jacqueline de Winkel Secretary, administrative assistant