MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume

G. A. M. Blokland; N. Maleki; J. Jovicich; R. I. Mesholam-Gately; L. E. DeLisi; J. A. Turner; M. E. Shenton; A. N. Voineskos; R. S. Kahn; J. L. Roffman; D. J. Holt; S. Ehrlich; Z. Kikinis; P. Dazzan; R. M. Murray; J. Lee; K. Sim; M. Lam; S. M. C. de Zwarte; E. Walton; S. Kelly; M. M. Picchioni; E. Bramon; N. Makris; A. S. David; V. Mondelli; A. A. T. S. Reinders; E. Oykhman; D. W. Morris; M. Gill; A. P. Corvin; W. Cahn; N. Ho; J. Liu; R. L. Gollub; D. S. Manoach; V. D. Calhoun; S. R. Sponheim; S. L. Buka; S. Cherkerzian; H. W. Thermenos; E. W. Dickie; S. Ciufolini; T. Reis Marques; N. A. Crossley; S. M. Purcell; J. W. Smoller; N. E. M. van Haren; T. Toulopoulou; G. Donohoe; J. M. Goldstein; M. S. Keshavan; T. L. Petryshen; E. C. del Re

doi:10.1016/j.ijchp.2024.100458

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume

G. A. M. Blokland^*
, N. Maleki
, J. Jovicich
, R. I. Mesholam-Gately
, L. E. DeLisi
, J. A. Turner
, M. E. Shenton
, A. N. Voineskos
, R. S. Kahn
, J. L. Roffman
, D. J. Holt
, S. Ehrlich
, Z. Kikinis
, P. Dazzan
, R. M. Murray
, J. Lee
, K. Sim
, M. Lam
, S. M. C. de Zwarte
, E. Walton

S. Kelly, M. M. Picchioni, E. Bramon, N. Makris, A. S. David, V. Mondelli, A. A. T. S. Reinders, E. Oykhman, D. W. Morris, M. Gill, A. P. Corvin, W. Cahn, N. Ho, J. Liu, R. L. Gollub, D. S. Manoach, V. D. Calhoun, S. R. Sponheim, S. L. Buka, S. Cherkerzian, H. W. Thermenos, E. W. Dickie, S. Ciufolini, T. Reis Marques, N. A. Crossley, S. M. Purcell, J. W. Smoller, N. E. M. van Haren, T. Toulopoulou, G. Donohoe, J. M. Goldstein, M. S. Keshavan, T. L. Petryshen, E. C. del Re^*

^*Corresponding author for this work

Institute for Public Health Genomics (IPHG), Department of Genetics and Cell Biology, Research Institute GROW, University of Maastricht, Maastricht, The Netherlands;
Massachusetts General Hospital
Harvard University
Broad Institute
University of Trento
Beth Israel Deaconess Medical Center
Cambridge Health Alliance
Ohio State University
Brigham and Women’s Hospital
VA Medical Center
Centre for Addiction and Mental Health
University of Toronto
University Medical Center Utrecht
Technische Universität Dresden
King's College London
South London and Maudsley NHS Foundation Trust
Singapore Institute of Mental Health
Zucker Hillside Hospital
University of Bath, Department of Psychology
University of Southern California
Trinity College Dublin
University College London
University of Galway
Agency for Science, Technology and Research, Singapore
Georgia Institute of Technology
University of Minnesota Twin Cities
Brown University
Icahn School of Medicine at Mount Sinai
Erasmus MC
Bilkent University
National and Kapodistrian University of Athens
Department of Neurology, Stroke Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

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

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Abstract

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.

Original language	English
Article number	100458
Journal	International Journal of Clinical and Health Psychology
Volume	24
Issue number	2
DOIs	https://doi.org/10.1016/j.ijchp.2024.100458
Publication status	Published - 1 Apr 2024
Externally published	Yes

Keywords

Corpus callosum
Ephrin pathway
Lateral ventricles
MIR137
Polygenic risk score
Schizophrenia

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Mir137-polygenic-risk-for-schizophrenia-and-ephrin-regulated-pathway.pdfFinal published version, 2.68 MBLicence: CC BY

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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., ... del Re, E. C. (2024). MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume. International Journal of Clinical and Health Psychology, 24(2), Article 100458. https://doi.org/10.1016/j.ijchp.2024.100458

@article{97895836fd1a40faa669f84ebba166a3,

title = "MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume",

abstract = "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{\textquoteright}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.",

keywords = "Corpus callosum, Ephrin pathway, Lateral ventricles, MIR137, Polygenic risk score, Schizophrenia",

author = "Blokland, \{G. A. M.\} and N. Maleki and J. Jovicich and Mesholam-Gately, \{R. I.\} and DeLisi, \{L. E.\} and Turner, \{J. A.\} and Shenton, \{M. E.\} and Voineskos, \{A. N.\} and Kahn, \{R. S.\} and Roffman, \{J. L.\} and Holt, \{D. J.\} and S. Ehrlich and Z. Kikinis and P. Dazzan and Murray, \{R. M.\} and J. Lee and K. Sim and M. Lam and \{de Zwarte\}, \{S. M. C.\} and E. Walton and S. Kelly and Picchioni, \{M. M.\} and E. Bramon and N. Makris and David, \{A. S.\} and V. Mondelli and Reinders, \{A. A. T. S.\} and E. Oykhman and Morris, \{D. W.\} and M. Gill and Corvin, \{A. P.\} and W. Cahn and N. Ho and J. Liu and Gollub, \{R. L.\} and Manoach, \{D. S.\} and Calhoun, \{V. D.\} and Sponheim, \{S. R.\} and Buka, \{S. L.\} and S. Cherkerzian and Thermenos, \{H. W.\} and Dickie, \{E. W.\} and S. Ciufolini and \{Reis Marques\}, T. and Crossley, \{N. A.\} and Purcell, \{S. M.\} and Smoller, \{J. W.\} and \{van Haren\}, \{N. E. M.\} and T. Toulopoulou and G. Donohoe and Goldstein, \{J. M.\} and Keshavan, \{M. S.\} and Petryshen, \{T. L.\} and \{del Re\}, \{E. C.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = apr,

day = "1",

doi = "10.1016/j.ijchp.2024.100458",

language = "English",

volume = "24",

journal = "International Journal of Clinical and Health Psychology",

issn = "1697-2600",

publisher = "Facultad de Psicologia",

number = "2",

}

Blokland, GAM, Maleki, N, Jovicich, J, Mesholam-Gately, RI, DeLisi, LE, Turner, JA, Shenton, ME, Voineskos, AN, Kahn, RS, Roffman, JL, Holt, DJ, Ehrlich, S, Kikinis, Z, Dazzan, P, Murray, RM, Lee, J, Sim, K, Lam, M, de Zwarte, SMC, Walton, E, Kelly, S, Picchioni, MM, Bramon, E, Makris, N, David, AS, Mondelli, V, Reinders, AATS, Oykhman, E, Morris, DW, Gill, M, Corvin, AP, Cahn, W, Ho, N, Liu, J, Gollub, RL, Manoach, DS, Calhoun, VD, Sponheim, SR, Buka, SL, Cherkerzian, S, Thermenos, HW, Dickie, EW, Ciufolini, S, Reis Marques, T, Crossley, NA, Purcell, SM, Smoller, JW, van Haren, NEM, Toulopoulou, T, Donohoe, G, Goldstein, JM, Keshavan, MS, Petryshen, TL & del Re, EC 2024, 'MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume', International Journal of Clinical and Health Psychology, vol. 24, no. 2, 100458. https://doi.org/10.1016/j.ijchp.2024.100458

TY - JOUR

T1 - MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway

T2 - Role in lateral ventricles and corpus callosum volume

AU - Blokland, G. A. M.

AU - Maleki, N.

AU - Jovicich, J.

AU - Mesholam-Gately, R. I.

AU - DeLisi, L. E.

AU - Turner, J. A.

AU - Shenton, M. E.

AU - Voineskos, A. N.

AU - Kahn, R. S.

AU - Roffman, J. L.

AU - Holt, D. J.

AU - Ehrlich, S.

AU - Kikinis, Z.

AU - Dazzan, P.

AU - Murray, R. M.

AU - Lee, J.

AU - Sim, K.

AU - Lam, M.

AU - de Zwarte, S. M. C.

AU - Walton, E.

AU - Kelly, S.

AU - Picchioni, M. M.

AU - Bramon, E.

AU - Makris, N.

AU - David, A. S.

AU - Mondelli, V.

AU - Reinders, A. A. T. S.

AU - Oykhman, E.

AU - Morris, D. W.

AU - Gill, M.

AU - Corvin, A. P.

AU - Cahn, W.

AU - Ho, N.

AU - Liu, J.

AU - Gollub, R. L.

AU - Manoach, D. S.

AU - Calhoun, V. D.

AU - Sponheim, S. R.

AU - Buka, S. L.

AU - Cherkerzian, S.

AU - Thermenos, H. W.

AU - Dickie, E. W.

AU - Ciufolini, S.

AU - Reis Marques, T.

AU - Crossley, N. A.

AU - Purcell, S. M.

AU - Smoller, J. W.

AU - van Haren, N. E. M.

AU - Toulopoulou, T.

AU - Donohoe, G.

AU - Goldstein, J. M.

AU - Keshavan, M. S.

AU - Petryshen, T. L.

AU - del Re, E. C.

PY - 2024/4/1

Y1 - 2024/4/1

N2 - 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.

AB - 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.

KW - Corpus callosum

KW - Ephrin pathway

KW - Lateral ventricles

KW - MIR137

KW - Polygenic risk score

KW - Schizophrenia

UR - https://www.scopus.com/pages/publications/85189910370

U2 - 10.1016/j.ijchp.2024.100458

DO - 10.1016/j.ijchp.2024.100458

M3 - Article

C2 - 38623146

SN - 1697-2600

VL - 24

JO - International Journal of Clinical and Health Psychology

JF - International Journal of Clinical and Health Psychology

IS - 2

M1 - 100458

ER -

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume

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