Browsing by Author "Breier, A."

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    Convergent Functional Genomics of Schizophrenia: From Comprehensive Understanding to Genetic Risk Prediction
    (Office of the Vice Chancellor for Research, 2012-04-13) Ayalew, M.; Le-Niculescu, H.; Levey, D.F.; Jain, N.; Changala, B.; Patel, S.D.; Winiger, E.; Breier, A.; Shekhar, A.; Amdur, R.; Koller, D.; Nurnberger, J.I.; Corvin, A.; Geyer, M.; Tsuang, M.T.; Salomon, D.; Schork, N.; Fanous, A.H.; O’ Donovan, M.C.; Niculescu, A.B.
    We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study (GWAS) data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein coupled receptor signaling and cAMP- mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data is consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European-American (EA) and one African-American (AA), increasing overlap, reproducibility and consistency of findings from SNPs to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Lastly, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics, and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
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    The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis
    (Springer Nature, 2023) Levitt, J. J.; Zhang, F.; Vangel, M.; Nestor, P. G.; Rathi, Y.; Cetin-Karayumak, S.; Kubicki, M.; Coleman, M. J.; Lewandowski, K. E.; Holt, D. J.; Keshavan, M.; Bouix, S.; Öngür, D.; Breier, A.; Shenton, M. E.; O’Donnell, L. J.; Psychiatry, School of Medicine
    Background: Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography. Methods: Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively. Results: We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right (p = 0.03), but not left (p = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p = .00023; p = .00023) originating in selective PFC subregions. Conclusions: In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.