Soichiro Nakahara1,2, Jessica A Turner3,4,5, Vince D Calhoun3,5,6,7, Kelvin O Lim8, Bryon Mueller8, Juan R Bustillo7, Daniel S O'Leary9, Sarah McEwen10, James Voyvodic11, Aysenil Belger12, Daniel H Mathalon13,14, Judith M Ford13,14, Fabio Macciardi15, Mitsuyuki Matsumoto2, Steven G Potkin15, Theo G M van Erp1,16. 1. Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA92617, USA. 2. Virtual Venture Unit, Psychiatry, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki305-8585, Japan. 3. The Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS) {Georgia State, Georgia Tech, Emory}, Atlanta, GA30300, USA. 4. Departments of Psychology and Neuroscience, Georgia State University, Atlanta, GA30302, USA. 5. Mind Research Network, Albuquerque, NM87106, USA. 6. Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM87131, USA. 7. Departments of Psychiatry & Neuroscience, University of New Mexico, Albuquerque, NM87131, USA. 8. Department of Psychiatry, University of Minnesota, Minneapolis, MN55454, USA. 9. Department of Psychiatry, University of Iowa, Iowa City, IA52242, USA. 10. Department of Psychiatry, University of California, San Diego, La Jolla, CA92093, USA. 11. Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC27710, USA. 12. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC27599, USA. 13. Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA94143, USA. 14. Veterans Affairs San Francisco Healthcare System, San Francisco, CA94121, USA. 15. Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA92617, USA. 16. Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, CA92697, USA.
Abstract
BACKGROUND: Schizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined. METHODS: Hippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed. RESULTS: This study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = -0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = -0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (β = 10.8, p < 5 × 10-8, 95% CI 7.0-14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume. CONCLUSIONS: This study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.
BACKGROUND: Schizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined. METHODS: Hippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed. RESULTS: This study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = -0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = -0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (β = 10.8, p < 5 × 10-8, 95% CI 7.0-14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume. CONCLUSIONS: This study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.
Entities:
Keywords:
genetics; genome-wide association analysis; hippocampus; imaging; subfield
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