Is imaging genetics plausible? Imaging Genetics and Multimodal Approaches to Brain Imaging. Which genetic model should be used?

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1 Is imaging genetics plausible? Brain Phenotype h 2 Whole brain volume 0.78 Total gray matter volume 0.88 Total white matter volume 0.85 Glahn, Thompson, Blangero. Hum Brain Mapp 28: , 2007 Imaging Genetics and Multimodal Approaches to Brain Imaging Thickness of Cortical GM (r 2 ) Thompson et al, Nature Neuro, 4(12): , Methods for imaging genetics Cluster-wise inference preferred over voxel-wise Generally more sensitive Friston et al, NeuroImage 4: , 1996 Spatially-extended signals typical A problem in application of cluster methods to structural datasets Standard cluster methods assume stationarity, constant smoothness Assuming stationarity, false positive clusters will be found in extra-smooth regions VBM noise very non-stationary Nonstationary cluster inference Must un-warp nonstationarity Reported but not implemented Hayasaka et al, NeuroImage 22: , 2004 Now available as SPM toolbox software#ns Nonstationary noise VBM: Image of FWHM Noise Smoothness warped to stationarity Which genetic model should be used? Recessive Dominant Additive Genotypic The problem of disproportionate effects with a small population Additional nuisance effects Rare SNP can make a few subjects very influential An ever-greater problem as sample size shrinks Ad hoc solution If expected rare genotype frequency <10%, then merge genotypes If MAL > 0.31 (=!0.1) 2DF Genotypic model Additive + Nonadditive Parameterization If MAL < 0.31 Use dominant/recessive model Allele Count Age & Gender Substantial normal variation in GM w/ Age Total Gray matter Accounts for differences in head size Discounts global changes to find localized changes Scanner changes or site-differences Medication effects

2 A test case: ApoE4 in Alzheimer s disease Age-adjusted brain structural changes associated with ApoE4 allele status: additive model 229 AA polypeptide with polymorphisms in exon 4 at codons 112, 158: three isoforms Strong association with age of onset/ severity of sporadic AD Filippini et al. Neuroimage 44 (2009) 724 ApoE4 allele effect on grey matter concentration in regions showing VBM changes Age-adjusted brain structural changes associated with ApoE4 allele status: non-additive model Filippini et al. Neuroimage 44 (2009) 724 Additional effects ApoE4 allele effect on grey matter concentration: dominant model Temporal-parietal cortical regions defined with dominant model correspond with hypometabolic regions in AD MRI structuralgenetic association FDG PET hypometabolism (Alexander et al. Am J Psych 159 (2002) 738)

3 Evaluation of a novel association: GOLM1 AD patients with the rs risk GG genotype showed significantly reduced GM volume RS and RS among top 120 SNPs in Canadian WGAS (N=754 AD and N=736 matched controls) [Li, H. et al. Arch Neurol. 2008] Association found in independent Cardiff sample (N=453 AD and N=472 matched controls) In chr region previously linked in AD RS and RS intronic in GOLM1 gene: type II Golgi transmembrane protein [Lein et al. Nature 2007] Strongly expressed in mouse hippocampal dentate and CA3 sub-regions [Blacker et al. Hum Molec Gen 2003] Cluster GM concentration Association between rs genotype groups and increased cognitive decline in the Canadian AD patients (p<0.05, candidate gene approach, post-hoc) [unpublished] -15 +/ % N= 76 AD subjects The rs risk TT genotype (in high LD) also is associated with reduced GM in non-demented controls Overlap of GM variation with GOLM1 polymorphisms across demented and non-demented subjects Demented AD patients (N=76) Non-demented controls Cluster GM concentration -4 +/- 0.03% (N=278) N= 278 GSK3! as a candidate gene for depression GSK3! and brain structural variation Serotonin-related dysfunction contributes to symptoms Serotonin-receptor mediated signalling differentially modulates GSK3! activity inhibition is likely mechanism of lithium effects in bipolar disorder Fluoxetine and imipramine increase inhibitory Ser-phosphorylation of GSK3! R L 2 SNPs in strong linkage disequilibrium showed significant associations with GM differences in MDD patients: s rs Brain regions where SNP clusters show colocalization 3! Inkster et al Arch Gen Psych 66 (2009) 721

4 3! rs AA genotype group associated with decreased GM concentration in right STG Differential association of GM changes in MDD group Significant association clusters were revealed in right hippocampus and right STG ROI Mask Voxel-level P = (corrected for whole brain search and multiple SNP testing) Right hippocampus F x y z P FWE (0.0003)* Right STG (0.03)* ). rs is a putative functional SNP Inkster et al Arch Gen Psych 66 (2009) (0.057)* Left STG * Corrected for searching in 3 masks Extending the depression brain structural endophenotype Replication of amygdala anterior cingulate cortex structural covariance in MDD patients Pezawas et al. (2005) Pezawas et al. Nature Neurosci 8 (2005) 828 Cluster-based analysis Thresholded alpha = 0.01 Inkster et al., unpublished Interaction effect between GSK3" with amygdala volume structural coherence Wnt signaling pathway and TGF" signaling pathway feeds into the SMAD1 signaling pathway Inkster et al. Neuroimage (2010) Epub NOTE: PPARgC1a (MDD Candidate) significant interaction: Cont > MDD P = Analysis restricts the search space to a mask based on the FDR voxelbased analysis SMAD1 ZFHX1B TOB2 EMX2 EMX2OS BMP7 DAN SP8 COUPTF1 OTX1 BMP4 ODZ4, CXCL12 Inkster et al. unpublished

5 Selected primary association clusters Wnt signaling pathway and TGF" signaling pathway feeds into the SMAD1 signaling pathway Inkster et al. Neuroimage (2010) Epub NOTE: PPARgC1a (MDD Candidate) significant interaction: Cont > MDD EMX GSK3B WNT3A ASPM SMAD1 ZFHX1B TOB2 EMX2 EMX2OS BMP7 DAN SP8 COUPTF1 OTX1 BMP4 ODZ4, CXCL12 Inkster et al. Neuroimage (2010) Epub Primary Outcome Only Interaction Only Primary Outcome *and* Interaction Molecular imaging of neurotransmitter receptor : D3R Molecular imaging of neurotransmitter receptor : D3R Receptor pre-drug Receptor post-drug Receptor post-drug Beaver et al., CIC, unpublished Beaver et al., CIC, unpublished Defining receptor occupancy for a receptor specific antagonist Integration of molecular imaging for receptor occupancy with fmri pharmacodynamic information Open label, single oral doses of a D3 antagonist Doses and scan times varied across subjects Outcomes Plasma concentration (ng/ml) Dose Time Occupancy Activation Dosing PK HPLC/MS/MS Imaging PHNO fmri Monetary reward Baseline Single Dose 0 96 hrs post dose D3RO (%) Predicted receptor occupancy values Beaver et a., CIC, unpublished

6 Tissue PK/PD relations for a D3 antagonist Modulation of amygdala response with D3R Task-correlated BOLD activation for monetary reward Beaver et al., CIC, unpubllished Correlation of amygdala BOLD activation and D3 receptor in individual subjects T = , P < Beaver et al., CIC, unpublished Modulation of anatomically-specific network coherences by D3R An homologous OFC interaction is associated with mu opioid modulation Cole et al., CIC/Imperial, unpublished aakub et al., CIC, unpublished Summary With thanks to my many colleagues and collaborators including Genetics- even single genes- influence brain structure and genetic variation is manifest in population variation in brain size and shape Interactions between disease and genetic differences may reflect differences in influence with disease or developmental differences affecting disease susceptibility Genetics and imaging studies suggest that brain structural variation is manifest through larger developmental or structure units Brain functional changes can be related to modulation of intrinsic states of neurotransmitter release Behavioural expression is driven by their influences on interactions between regions and networks CIC, Hammersmith: Becky Inkster, Tom Nichols, John Beaver, Chris Long, Roger Gunn, Ilan Rabiner, Jan Passchier, Siitiaakub Imperial College: David Cole, Christian Beckmann Max Planck, Munich: Phillippe Saemen, Florien Holsbear, Dorothy Auer Psychiatry, Cambridge: Ed Bullmore