Dentate gyrus volume deficit in schizophrenia

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

doi:10.1017/S0033291719001144

Dentate gyrus volume deficit in schizophrenia

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

Psychiatry & Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1267-1277
Number of pages	11
Journal	Psychological medicine
Volume	50
Issue number	8
DOIs	https://doi.org/10.1017/S0033291719001144
State	Published - Jun 1 2020

Bibliographical note

Funding Information:
Conflict of interest. Dr Soichiro Nakahara’s effort was supported by Astellas Pharma Inc. while he was a visiting scholar in the University of California, Irvine. Dr Bustillo consulted with Novartis and Otsuka Pharmaceuticals. Dr Mathalon consulted for Boerhinger Ingelheim and Takeda. Dr Preda consulted for Boehringer-Ingelheim. Dr Potkin has financial interests in Bristol-Myers Squibb, Eisai, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Lundbeck, Merck, Novartis, Organon, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, Novartis, Lundbeck, Merck, Sunovion and has received grant funding from Amgen, Baxter, Bristol-Myers Squibb, Cephalon, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Merck, Otsuka, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, NIAAA, NIBIB, NIH/ NCRR, University of Southern California, UCSF, UCSD, Baylor College of Medicine. Dr Van Erp has had a contract with Otsuka Pharmaceuticals. The remaining authors declare no potential conflict of interest.

Funding Information:
Financial support. This work was supported by the National Center for Research Resources at the National Institutes of Health [grant numbers: NIH 1 U24 RR021992 (Function Biomedical Informatics Research Network), NIH 1 U24 RR025736-01 (Biomedical Informatics Research Network Coordinating Center)], the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153, and the National Institutes of Health through 5R01MH094524, P20GM103472, and R21MH097196. The funding sources had no role in the study design, conduct of the study, data collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Publisher Copyright:
Copyright © Cambridge University Press 2019.

Keywords

genetics
genome-wide association analysis
hippocampus
imaging
subfield

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1017/S0033291719001144

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Nakahara, S., Nakahara, S., Turner, J. A., Turner, J. A., Turner, J. A., Calhoun, V. D., Calhoun, V. D., Calhoun, V. D., Calhoun, V. D., Lim, K. O., Mueller, B., Bustillo, J. R., O'Leary, D. S., McEwen, S., Voyvodic, J., Belger, A., Mathalon, D. H., Mathalon, D. H., Ford, J. M., ... Van Erp, T. G. M. (2020). Dentate gyrus volume deficit in schizophrenia. Psychological medicine, 50(8), 1267-1277. https://doi.org/10.1017/S0033291719001144

Nakahara, S, Nakahara, S, Turner, JA, Turner, JA, Turner, JA, Calhoun, VD, Calhoun, VD, Calhoun, VD, Calhoun, VD, Lim, KO , Mueller, B, Bustillo, JR, O'Leary, DS, McEwen, S, Voyvodic, J, Belger, A, Mathalon, DH, Mathalon, DH, Ford, JM, Ford, JM, MacCiardi, F, Matsumoto, M, Potkin, SG, Van Erp, TGM & Van Erp, TGM 2020, 'Dentate gyrus volume deficit in schizophrenia', Psychological medicine, vol. 50, no. 8, pp. 1267-1277. https://doi.org/10.1017/S0033291719001144

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title = "Dentate gyrus volume deficit in schizophrenia",

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.",

keywords = "genetics, genome-wide association analysis, hippocampus, imaging, subfield",

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

note = "Funding Information: Conflict of interest. Dr Soichiro Nakahara{\textquoteright}s effort was supported by Astellas Pharma Inc. while he was a visiting scholar in the University of California, Irvine. Dr Bustillo consulted with Novartis and Otsuka Pharmaceuticals. Dr Mathalon consulted for Boerhinger Ingelheim and Takeda. Dr Preda consulted for Boehringer-Ingelheim. Dr Potkin has financial interests in Bristol-Myers Squibb, Eisai, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Lundbeck, Merck, Novartis, Organon, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, Novartis, Lundbeck, Merck, Sunovion and has received grant funding from Amgen, Baxter, Bristol-Myers Squibb, Cephalon, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Merck, Otsuka, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, NIAAA, NIBIB, NIH/ NCRR, University of Southern California, UCSF, UCSD, Baylor College of Medicine. Dr Van Erp has had a contract with Otsuka Pharmaceuticals. The remaining authors declare no potential conflict of interest. Funding Information: Financial support. This work was supported by the National Center for Research Resources at the National Institutes of Health [grant numbers: NIH 1 U24 RR021992 (Function Biomedical Informatics Research Network), NIH 1 U24 RR025736-01 (Biomedical Informatics Research Network Coordinating Center)], the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153, and the National Institutes of Health through 5R01MH094524, P20GM103472, and R21MH097196. The funding sources had no role in the study design, conduct of the study, data collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Publisher Copyright: Copyright {\textcopyright} Cambridge University Press 2019.",

year = "2020",

month = jun,

day = "1",

doi = "10.1017/S0033291719001144",

language = "English (US)",

volume = "50",

pages = "1267--1277",

journal = "Psychological Medicine",

issn = "0033-2917",

publisher = "Cambridge University Press",

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TY - JOUR

T1 - Dentate gyrus volume deficit in schizophrenia

AU - Nakahara, Soichiro

AU - Turner, Jessica A.

AU - Calhoun, Vince D.

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.

N1 - Funding Information: Conflict of interest. Dr Soichiro Nakahara’s effort was supported by Astellas Pharma Inc. while he was a visiting scholar in the University of California, Irvine. Dr Bustillo consulted with Novartis and Otsuka Pharmaceuticals. Dr Mathalon consulted for Boerhinger Ingelheim and Takeda. Dr Preda consulted for Boehringer-Ingelheim. Dr Potkin has financial interests in Bristol-Myers Squibb, Eisai, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Lundbeck, Merck, Novartis, Organon, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, Novartis, Lundbeck, Merck, Sunovion and has received grant funding from Amgen, Baxter, Bristol-Myers Squibb, Cephalon, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Merck, Otsuka, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, NIAAA, NIBIB, NIH/ NCRR, University of Southern California, UCSF, UCSD, Baylor College of Medicine. Dr Van Erp has had a contract with Otsuka Pharmaceuticals. The remaining authors declare no potential conflict of interest. Funding Information: Financial support. This work was supported by the National Center for Research Resources at the National Institutes of Health [grant numbers: NIH 1 U24 RR021992 (Function Biomedical Informatics Research Network), NIH 1 U24 RR025736-01 (Biomedical Informatics Research Network Coordinating Center)], the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153, and the National Institutes of Health through 5R01MH094524, P20GM103472, and R21MH097196. The funding sources had no role in the study design, conduct of the study, data collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Publisher Copyright: Copyright © Cambridge University Press 2019.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - 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.

AB - 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.

KW - genetics

KW - genome-wide association analysis

KW - hippocampus

KW - imaging

KW - subfield

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JF - Psychological Medicine

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ER -

Dentate gyrus volume deficit in schizophrenia

Abstract

Bibliographical note

Keywords

UN SDGs

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