Dentate gyrus volume deficit in schizophrenia

Soichiro Nakahara, Jessica A. Turner, Vince Daniel Calhoun, Kelvin O. Lim, Bryon Mueller, Juan R. Bustillo, Daniel S. O'Leary, Sarah McEwen, James Voyvodic, Aysenil Belger, Daniel H. Mathalon, Judith M. Ford, Fabio Macciardi, Mitsuyuki Matsumoto, Steven G. Potkin, Theo G.M. Van Erp

Research output: Contribution to journalArticle

Abstract

BackgroundSchizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined.MethodsHippocampal 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.ResultsThis 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.ConclusionsThis 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.

Original languageEnglish (US)
JournalPsychological medicine
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Dentate Gyrus
Schizophrenia
Hippocampus
Healthy Volunteers
Functional Laterality
Chromosomes, Human, Pair 3
Genome-Wide Association Study
Linkage Disequilibrium
Cognition
Genes
Single Nucleotide Polymorphism
Phenotype

Keywords

  • genetics
  • genome-wide association analysis
  • hippocampus
  • imaging
  • subfield

ASJC Scopus subject areas

  • Applied Psychology
  • Psychiatry and Mental health

Cite this

Nakahara, S., Turner, J. A., Calhoun, V. D., Lim, K. O., Mueller, B., Bustillo, J. R., ... Van Erp, T. G. M. (2019). Dentate gyrus volume deficit in schizophrenia. Psychological medicine. https://doi.org/10.1017/S0033291719001144

Dentate gyrus volume deficit in schizophrenia. / Nakahara, Soichiro; Turner, Jessica A.; Calhoun, Vince Daniel; Lim, Kelvin O.; Mueller, Bryon; Bustillo, Juan R.; O'Leary, Daniel S.; McEwen, Sarah; Voyvodic, James; Belger, Aysenil; Mathalon, Daniel H.; Ford, Judith M.; Macciardi, Fabio; Matsumoto, Mitsuyuki; Potkin, Steven G.; Van Erp, Theo G.M.

In: Psychological medicine, 01.01.2019.

Research output: Contribution to journalArticle

Nakahara, S, Turner, JA, Calhoun, VD, Lim, KO, Mueller, B, Bustillo, JR, O'Leary, DS, McEwen, S, Voyvodic, J, Belger, A, Mathalon, DH, Ford, JM, Macciardi, F, Matsumoto, M, Potkin, SG & Van Erp, TGM 2019, 'Dentate gyrus volume deficit in schizophrenia', Psychological medicine. https://doi.org/10.1017/S0033291719001144
Nakahara, Soichiro ; Turner, Jessica A. ; Calhoun, Vince Daniel ; Lim, Kelvin O. ; Mueller, Bryon ; Bustillo, Juan R. ; O'Leary, Daniel S. ; McEwen, Sarah ; Voyvodic, James ; Belger, Aysenil ; Mathalon, Daniel H. ; Ford, Judith M. ; Macciardi, Fabio ; Matsumoto, Mitsuyuki ; Potkin, Steven G. ; Van Erp, Theo G.M. / Dentate gyrus volume deficit in schizophrenia. In: Psychological medicine. 2019.
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abstract = "BackgroundSchizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined.MethodsHippocampal 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.ResultsThis 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.ConclusionsThis 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.",
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AU - Nakahara, Soichiro

AU - Turner, Jessica A.

AU - Calhoun, Vince Daniel

AU - Lim, Kelvin O.

AU - Mueller, Bryon

AU - Bustillo, Juan R.

AU - O'Leary, Daniel S.

AU - McEwen, Sarah

AU - Voyvodic, James

AU - Belger, Aysenil

AU - Mathalon, Daniel H.

AU - Ford, Judith M.

AU - Macciardi, Fabio

AU - Matsumoto, Mitsuyuki

AU - Potkin, Steven G.

AU - Van Erp, Theo G.M.

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N2 - BackgroundSchizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined.MethodsHippocampal 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.ResultsThis 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.ConclusionsThis 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.

AB - BackgroundSchizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined.MethodsHippocampal 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.ResultsThis 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.ConclusionsThis 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.

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