Identifying genes associated with risk for schizophrenia has allowed us to generate hypotheses about molecular and neural system mechanisms related to biologic aspects of the illness. By using a convergent validation strategy of cognitive, neuroimaging and basic science offers the ability to identify new approaches to treatment based on confirmed mechanisms and may lead to potentially new therapeutic targets within molecular pathways and networks.
Our aim for biological validation of genetic association with schizophrenia is to provide biologic evidence of the effect of schizophrenia associated risk alleles on relevant measures of brain development and function assayed with cognitive and neuroimaging approaches in healthy and ill subjects. Accomplishing this will require refinement of brain functional intermediate phenotypes based on novel cognitive paradigms and analytic strategies in imaging. Phenotypes that derive from finely targeting brain information processing dynamics may result in stronger gene effects that interfere with these processes. Lemaitre et al. (Journal of Neuroscience, 2010) examined the effect of the fibroblast growth factor (FGF20) gene polymorphism associated with risk for Parkinsons disease on brain structure and function in a large sample of young and elderly male subjects. Incorporating the convergent biologic validation strategy, we used voxel-based morphometry to analyze high-resolution anatomical magnetic resonance images and FGF20 mRNA expression was measured in human postmortem brain tissue. Our results showed subjects carrying the T allele had larger hippocampal volume, reduced verbal episodic memory and demonstrated a sharp decline in hippocampal volume with normal aging. The T carriers also had greater expression of hippocampal FGF20 mRNA which is consistent with previously reported data. Individuals carrying the C allele matched the expected microRNA binding domain, whereas the T carriers disrupt the binding ability of microRNA resulting in an increase in FGF20 protein. Lastly, FGF receptor 1 is found most abundantly in the human hippocampus and is thought to mediate the strong genetic effects of FGF20 in the hippocampus. Altogether the convergent evidence in healthy subjects of Parkinsons disease risk association, mRNA expression, brain morphology, cognitive deficits and an interaction with aging confirmed the role of FGF20 in human brain structure and function during development and aging. Another aspect of our research is in imaging genetics, which plays an important role in our overall convergent validation strategy for confirming neural mechanisms implicated in neuropsychiatric disorders. Schizophrenia is complex, heritable and genetically heterogeneous. Schizophrenia susceptibility genes are associated with a myriad of symptoms by affecting the development and function of neural systems that mediate expression of behavior, cognition and executive function. This dysfunction of the human brain remains to be well understood. Imaging genetics plays a role in integrating the basic biology of putative disease mechanisms with physiological correlated traits in the living brain. Specifically, the aim of this approach is to test whether alleles that are statistically associated with clinical diagnosis predict deviations in brain structure and function that are related to findings in patients with schizophrenia and their healthy siblings. Tan et al. (Cognitive Neuropsychiatry, 2009) reviewed how imaging genetics elucidates prefrontal brain systems associated with working memory and executive function beginning with genetic variation in the dopamine system via catechol-O-methyltransferase (COMT) and modulation of prefrontal brain networks during active cognitive processing. There is also evidence of variation of dopamine-related expression downstream on AKT1 (an intracellular signaling molecule). These genetic variants are evidence of epistasis on neuroimaging measures, suggesting that a non-additive combination of multiple genes modulate active cognitive brain mechanisms. Imaging genetics has added to our knowledge of genetic mechanisms of human cognitive brain processes related to neuropsychiatric disorders. There are published reports of convergent evidence implicating the reelin gene (RELN) in neurodevelopmental deficits associated with an increased risk for schizophrenia. RELN encodes for the glycoprotein reelin, a secretory protease which plays a pivotal role in the molecular processes that subserve neuronal migration and synaptic plasticity. The convergent evidence of schizophrenia pathogenesis is from genetic association and gene expression studies showing a reduction in mRNA and protein levels in postmortem brain tissue of patients with schizophrenia. There have also been inconsistent findings regarding these measures. Tost et al. (Biological Psychiatry, 2010) evaluated brain structure using voxel-based morphometry and diffusion tensor imaging. Brain function was studied using fMRI during working memory tasks, and gene expression was measured in both prefrontal cortex and hippocampus in postmortem brain tissue. These analyses did not show evidence of a significant effect of the gene or a gene-sex interaction, which had been reported. We concluded that the tested and other related polymorphisms do not affect brain measures related to the neurobiology of schizophrenia.
| Thurin, K; Rasetti, R; Sambataro, F et al. (2013) Effects of ZNF804A on neurophysiologic measures of cognitive control. Mol Psychiatry 18:852-4 |
| Radulescu, Eugenia; Sambataro, Fabio; Mattay, Venkata S et al. (2013) Effect of Schizophrenia risk-associated alleles in SREB2 (GPR85) on functional MRI phenotypes in healthy volunteers. Neuropsychopharmacology 38:341-9 |
| Tost, Heike; Alam, Tajvar; Geramita, Matthew et al. (2013) Effects of the BDNF Val66Met polymorphism on white matter microstructure in healthy adults. Neuropsychopharmacology 38:525-32 |
| Callicott, Joseph H; Feighery, Emer L; Mattay, Venkata S et al. (2013) DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity. J Clin Invest 123:2961-4 |
| Lemaitre, Herve; Goldman, Aaron L; Sambataro, Fabio et al. (2012) Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume? Neurobiol Aging 33:617.e1-9 |
| Nichols, Lisa M; Masdeu, Joseph C; Mattay, Venkata S et al. (2012) Interactive effect of apolipoprotein e genotype and age on hippocampal activation during memory processing in healthy adults. Arch Gen Psychiatry 69:804-13 |
| Podell, Jamie E; Sambataro, Fabio; Murty, Vishnu P et al. (2012) Neurophysiological correlates of age-related changes in working memory updating. Neuroimage 62:2151-60 |
| Marenco, Stefano; Stein, Jason L; Savostyanova, Antonina A et al. (2012) Investigation of anatomical thalamo-cortical connectivity and FMRI activation in schizophrenia. Neuropsychopharmacology 37:499-507 |
| Sambataro, Fabio; Safrin, Martin; Lemaitre, Herve S et al. (2012) Normal aging modulates prefrontoparietal networks underlying multiple memory processes. Eur J Neurosci 36:3559-67 |
| Rasetti, Roberta; Weinberger, Daniel R (2011) Intermediate phenotypes in psychiatric disorders. Curr Opin Genet Dev 21:340-8 |
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