Browsing by Author "Mesholam-Gately, R. I."

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Open Access
The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: a collaborative cognitive and neuroimaging genetics project
(Elsevier, 2018) Blokland, G. A. M.; Del Re, E. C.; Mesholam-Gately, R. I.; Jovicich, J.; Trampush, J. W.; Keshavan, M. S.; DeLisi, L. E.; Walters, J. T. R.; Turner, J. A.; Malhotra, A. K.; Lencz, T.; Shenton, M. E.; Voineskos, A. N.; Rujescu, D.; Giegling, I.; Kahn, R. S.; Roffman, J. L.; Holt, D. J.; Ehrlich, S.; Kikinis, Z.; Dazzan, P.; Murray, R. M.; Di Forti, M.; Lee, J.; Sim, K.; Lam, M.; Wolthusen, R. P. F.; De Zwarte, S. M. C.; Walton, E.; Cosgrove, D.; Kelly, S.; Maleki, N.; Osiecki, L.; Picchioni, M. M.; Bramon, E.; Russo, M.; David, A. S.; Mondelli, V.; Reinders, A. A. T. S.; Falcone, M. A.; Hartmann, A. M.; Konte, B.; Morris, D. W.; Gill, M.; Corvin, A. P.; Cahn, W.; Ho, N. F.; Liu, J. J.; Keefe, R. S. E.; Gollub, R. L.; Manoach, D. S.; Calhoun, V. D.; Schulz, S. C.; Sponheim, S. R.; Goff, D. C.; Buka, S. L.; Cherkerzian, S.; Thermenos, H. W.; Kubicki, M.; Nestor, P. G.; Dickie, E. W.; Vassos, E.; Ciufolini, S.; Marques, T. R.; Crossley, N. A.; Purcell, S. M.; Smoller, J. W.; Van Haren, N. E. M.; Toulopoulou, Timothea; Donohoe, G.; Goldstein, J. M.; Seidman, L. J.; McCarley, R. W.; Petryshen, T. L.
Background: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. Methods: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Results: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p < 1 × 10− 10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. Conclusions: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of > 10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.
Open Access
Heritability of neuropsychological measures in schizophrenia and nonpsychiatric populations: a systematic review and meta-analysis
(Oxford University Press, 2017) Blokland, G. A. M.; Mesholam-Gately, R. I.; Toulopoulou, T.; Del Re, E. C.; Lam, M.; Delisi, L. E.; Donohoe, G.; Walters, J. T. R.; Seidman, L. J.; Petryshen, T. L.
Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average r g = '.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population.
Open Access
MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume
(Asociacion Espanola de Psicologia Conductual, 2024-04-09) Blokland, G. A. M.; Maleki, N.; Jovicich, J.; Mesholam-Gately, R. I.; Delisi, L. E.; Turner, J. A.; Shenton, M. E.; Voineskos, A. N.; Kahn, R. S.; Roffman, J. L.; Holt, D. J.; Ehrlich, S.; Kikinis, Z.; Dazzan, P.; Murray, R. M.; Lee, J.; Sim, K.; Lam, M.; de Zwarte, S. M. C.; Walton, E.; Kelly, S.; Picchioni, M. M.; Bramon, E.; Makris, N.; David, A. S.; Mondelli, V.; Reinders, A. A. T. S.; Oykhman, E.; Morris, D. W.; Gill, M.; Corvin, A. P.; Cahn, W.; Ho, N.; Liu, J.; Gollub, R. L.; Manoach, D. S.; Calhoun, V. D.; Sponheim, S. R.; Buka, S. L.; Cherkerzian, S.; Thermenos, H. W.; Dickie, E. W.; Ciufolini, S.; Marques, T. Reis; Crossley, N. A.; Purcell, S. M.; Smoller, J. W.; Van Haren, N. E. M.; Toulopoulou, Timothea; Donohoe, G.; Goldstein, J. M.; Keshavan, M. S.; Petryshen, T. L.; del Re, E. C.
Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137 's essential role in neurodevelopment. Methods . Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid -anterior, and mid -posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP -based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.