Presentation on theme: "Genetics and Neuroimaging:"— Presentation transcript:
1 Genetics and Neuroimaging: Current Findings and Future StrategiesJames L Kennedy MD, FRCPCI’Anson Professor of Psychiatry and Medical ScienceHead, Neurogenetics Section, Clarke Division,Director, Department of Neuroscience ResearchCentre for Addiction and Mental Health (CAMH),University of Toronto& SG Potkin, D Mueller, M Masellis,N Potapova, F Macciardi
4 Candidate gene selection for schizophrenia Neurotransmitter system genese.g. dopamine receptors, transporterNeurodevelopmental genesCortical development, patterningNeuronal differentiation, migrationSynaptic protein genesHuman post-mortem expression studies (Mirnics et al, 2000; Vawter et al, 2001)Animal model expression studies (Wong et al, 2002; Barrett et al, 2003)Dissect the neurotransmitter, synaptic machinery, myelin system, etc, with molecular genetics… Neuroimaging will help both hypothesis generation and validation of new genetic findings
5 Cytoarchitectural abnormalities ControlComparison of hippocampal pyramids at the CA1 and CA2 interface between control and schizophrenic.Cresyl violet stain, original magnification X250Conrad et al. (1991) Arch Gen PsychiatrySchizophrenia
7 Symptoms of TD TD is characterized by abnormal involuntary movements of the lip, jaw and tongue.Choreoathetoid movements of the extremitiesand/or trunk may occur as well.- Symptoms aremeasured usingscales such as :the AbnormalInvoluntaryMovement Scale(AIMS) and theRockland SimpsonScale (RSS).- The AIMS scaleranges fromand patients withhigher AIMS scoreshave more severesymptoms.
9 Why DRD3 ?D3 mRNA and protein have been localized to the ventral side of the striatum and the ventral putamen (motor control) (Joyce & MeadorWoodruff, 1997)D3 receptors have been shown to have an inhibitory effect on locomotor activity in rats (Kling-Peterson et al, 1995)Evidence that the Msc I polymorphism of DRD3 is functional: allelic differences display different affinities for dopamine in vitro. (Lundstrom & Turpin, 1996)
11 Mean AIMS Scores for DRD3 Msc I Polymorphism after Typical Neuroleptic Treatment 14.20CorrectedMeanAIMSscoreMean3.920Mean3.470n=34n=53n=25DRD3 GenotypeF[2,95] = 8.25, p < ( n = 112 ), Power = 0.568, r-square=0.297(Bonferroni p < ) (Basile et al, 1999)
12 Ethnically Stratified Means 91643339F[2,83]=3.85, p = 0.026(Bonferroni p = 0.078)F[1,23]=8.10, p =(Bonferroni p = 0.009)
14 CYP2D6 vs 1A2(12.7%)(Shimoda et al, 1994)- Metabolism is determined by both affinity and abundance relative to the total liver P450 content.- 2D6 has a higher affinity for most typicals, but it accounts for only 2% of total liver content. 2D6 is “high affinity-low capacity”-2D6 is not inducible; 1A2 is(1.5%)Note: CYP2D6 also expressed in brain – neuroimaging may capture some of this variance
15 Mean AIMS Scale Scores for DRD3 by CYP1A2 Genotype DRD3 GenotypeAdditive recessive model strongly supported compared to alternative models
16 Tardive Dyskinesia Summary : - Given the numerous replications of the DRD3-TD finding, and the PET neuroimaging validation, it appears that the dopamine D3 receptor is involved in TD susceptibility.- The interaction between DRD3 and CYP1A2 genes fits a recessive - recessive model with each gene interacting additively.- The DRD3 and CYP1A2 results account for ~55% of the variancein TD; other genes and environment may account for the rest.??Clinical genetic test for TD risk in the future??
21 Improvement of Symptoms D1 Receptor Blockade:D1 blockade by antipsychotics may potentiate activity in the PFC by disinhibiting NMDA receptor (Williams 1995)D1NMDACognition?Improvement of Symptoms
22 Dopamine D1 Gene (DRD1) (5q35.1) Markers in 5’ upstream region may be implicated in the regulation of D1 gene expression.(-1251)(-800)(-48)(+1403)+1+1341EREP1P2Coding Region
23 DRD1, PET FDG, & Clozapine Response Genotype 2/2BPRS = 30%ImprovementGenotype 1/2BPRS = 7%WorseningGenotype 1/2(Potkin et al, 2002)
24 Clozapine Response Prediction Algorithm? Arranz et al (2000) have reported a multi-gene (n = 10+ markers) model for clozapine response in one sample. Includes: D2, D4; 5HT1A, 2A, 2C, 4, 6; H1, H3,…Model must be replicated in a new sample to be meaningfulNeuroimaging as a augmenting phenotype in each patient may provide valuable intermediary information from the brain, allowing more biologically meaningful subtyping.
26 5HTT specific ligand in PET 5HTT specific ligand for PET [11C]DASB optimized in Toronto by radiochemist Alan WilsonN = 20 medication-free depressed patients, 20 anxiety disorder, and 20 normal controls underwent PET imaging with [11C]DASB ligand; blood for genetics5HTT gene typed for ins/del in promoter and the VNTR in intron II
27 [11C] DASB Binding to 5HTT in Depressives vs Normals by Genotype: Frontal Region nM
28 PET Ligand (DASB) 5HTT Binding Potential correlates with Dysfunctional Attitude [Meyer et al, Toronto PET Group, Arch Gen Psych, 2004]5HTTLPR genetic marker does not predict 5HTT Binding (Kennedy et al, in prep)Serotonin Transporter Ligand Binding PotentialN=20 Major Depressives P < .001Dysfunctional Attitude Scale Score
29 (GT)n repeat (function? mRNA stability) Will the Brain Derived Neurotrophic Factor (BDNF) Gene Predict Grey Matter Volume?BDNF-1 SNP BDNF BDNF-3 BDNF-4Exon 11Val-66-met(GT)n repeat (function? mRNA stability)
30 BDNF val66met: MRI functional brain imaging (Egan et al, Cell 2003) The red/yellow areas indicate brain regions (primarily hippocampus) that function differently between val/val (n=8) and val/met (n=5) subjects while performing a working memory task. Subjects with the met allele had more abnormal function.
31 Haplotype TDT: BDNF (GT)n repeat & val66met in schizophrenia ** HTDT for 170-val66c2 = 7.11; 1 df;p = 0.007Muglia et al, (2002)
32 Neurotrophic Mechanisms in Depression Nestler et al, 2002
33 Bipolar Disorder: TDT studies show robust effect of BDNF gene Combined Toronto sample (Neves-Pereira et al, 2002; N=300) plus MIT (Sklar et al, 2003) (N= NIMH) for val66met yields p =Phenotype dissection of our Toronto bipolar sample shows association with rapid cycling, non-suicidal, non-psychotic, earlier age at onset subjects (Mueller et al, in preparation)
34 BDNF polymorphisms in Childhood Onset Depression: Pittsburgh Sample N=104 pairs; 2=4.7;df=1; p=0.03Haplotype p = 0.001N=104 pairs; 2= 17.8; df=5; p=172 bp allele: OR = bp allele: OR = 3.94GT repeat alleles
35 Hippocampal shape as a phenotype for genetic studies Figure 1d: Principal deformation for the right hippocampus for normal controls (top) and schizophrenia patients (bottom). Four views (front, lateral, back, medial) of each shape are shown. The color indicates the direction and the magnitude of the deformation, changing from blue (inwards) to green (no deformation) to red (outwards).
36 Will MOG gene variants predict white matter abnormalities?
37 Prefrontal fMRI activity and myelin reduced in schizophrenia Figure 3:1-4: Statistical parametric maps of the fractional anisotropy (FA) (left) and Magnetic Transfer Ratio (MTR) (myelin) (right) group comparison. Similar areas in yellow on both maps correspond to the location of both the internal capsule and prefrontal white matter, and indicate smaller values of FA and myelin in schizophrenia patients (n=14) compared with controls (n=15).
38 UNC Fractional Anisotropy clusteringBundle selectionMeasurement along tractHypothesis: MOG, MAG, MBP genes will predict quantity or distribution of myelinated tracts
39 DTI New MRI Imaging Technique Reveals Brain Circuits CingulumCorpus callosumDorsalstreamFrontal striatialprojectionsFornixActual white matter tracks inschizophrenic patient revealedby DTI (colors and location by J. Fallon)
40 Complexities in Genetics & Neuroimaging Genetic variants express themselves in many ways – singularly, or combined (haplotypes, epistasis, partial penetrance…)What are the appropriate phenotypes to use from brain imaging data?How to control massive multiple testing of genome scan x brain voxels (millions x millions)?
41 National Alliance for Medical Imaging and Computing: SummaryD3 gene link to tardive dyskinesia validated by PET imagingD1 role in schizophrenia and clozapine response supported by genetic variants and PET activity pre/post clozapineBDNF gene candidate for grey matter measures?MOG gene candidate for white matter?Vast expanses of quality data await us: we only need to develop our informatics sophistication…National Alliance for Medical Imaging and Computing:NAMIC