Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Justine Y. Hansen; Golia Shafiei; Jacob W. Vogel; Kelly Smart; Carrie E. Bearden; Martine Hoogman; Barbara Franke; Daan van Rooij; Jan Buitelaar; Carrie R. McDonald; Sanjay M. Sisodiya; Lianne Schmaal; Dick J. Veltman; Odile A. van den Heuvel; Dan J. Stein; Theo G. M. van Erp; Christopher R. K. Ching; Ole A. Andreassen; Tomas Hajek; Nils Opel; Gemma Modinos; André Aleman; Ysbrand van der Werf; Neda Jahanshad; Sophia I. Thomopoulos; Paul M. Thompson; Richard E. Carson; Alain Dagher; Bratislav Misic

doi:10.1038/s41467-022-32420-y

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Justine Y. Hansen, Golia Shafiei, Jacob W. Vogel, Kelly Smart, Carrie E. Bearden, Martine Hoogman, Barbara Franke, Daan van Rooij, Jan Buitelaar, Carrie R. McDonald, Sanjay M. Sisodiya, Lianne Schmaal, Dick J. Veltman, Odile A. van den Heuvel, Dan J. Stein, Theo G. M. van Erp, Christopher R. K. Ching, Ole A. Andreassen, Tomas Hajek, Nils OpelGemma Modinos, André Aleman, Ysbrand van der Werf, Neda Jahanshad, Sophia I. Thomopoulos, Paul M. Thompson, Richard E. Carson, Alain Dagher, Bratislav Misic

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

Abstract

Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

Original language	English
Article number	4682
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32420-y
Publication status	Published - 1 Dec 2022
Externally published	Yes

Funding

C.R.K.C., N.J., P.M.T. received partial research support from Biogen, Inc., for research unrelated to this manuscript. J.B. has been in the past 3 years a consultant to/member of advisory board of/and/or speaker for Takeda/Shire, Roche, Medice, Angelini, Janssen, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. B.F. has received educational speaking fees from Medice GmbH. D.J.S. has received research grants and/or consultancy honoraria from Lundbeck and Sun. The remaining authors declare no competing interests. This research was undertaken thanks in part to funding from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives initiative. B.M. acknowledges support from the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant RGPIN #017-04265), the Canada Research Chairs Programme, the Brain Canada Future Leaders Fund and the Healthy Brains for Healthy Lives initiative. J.Y.H. acknowledges support from the Helmholtz International BigBrain Analytics & Learning Laboratory, the Natural Sciences and Engineering Research Council of Canada, and the Fonds de reserches de Québec. The research studies produced by the ENIGMA Working Groups would not be possible without the contributions of many researchers across the globe and the authors of this work thank all scientists who contribute to making this work possible. A full list of ENIGMA Consortium current and past members can be found here http://enigma.ini.usc.edu/ongoing/members/ . The authors acknowledge the NIH Big Data to Knowledge (BD2K) award for foundational support and consortium development (U54 EB020403 to P.M.T.) and support from NIMH R01MH116147 (P.M.T.), NIMH R01MH116147 (T.G.M.v.E.), NIMH R01 MH117601 (N.J., L.S.), NIMH R01MH085953 (C.E.B.), NIMH R21MH116473 (C.E.B.), NIMH 1U01MH119736 (C.E.B.). For a complete list of ENIGMA-related grant support please see here: http://enigma.ini.usc.edu/about-2/funding . J.B. has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes, which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; and by the Horizon2020 supported programme CANDY Grant No. 847818). B.F. is supported by the European Community’s Horizon 2020 Programme (H2020/2014-2020) under grant agreements no. 667302 (CoCA), no. 728018 (Eat2beNICE), and no. 847879 (PRIME). This work was supported by a personal Veni grant to M.H. from the Netherlands Organisation for Scientific Research (NWO, grant number 91619115). C.R.M. is supported by NIH R01 NS065838; R21 NS107739. D.J.S. is supported by South African Medical Research Council. G.M. is funded by a Wellcome Trust & The Royal Society Sir Henry Dale Fellowship [202397/Z/16/Z]. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funders	Funder number
Biogen, Inc.
Brain Canada Future Leaders Fund
EU-AIMS	AIMS-2-TRIALS
European Community’s Horizon 2020 Programme	H2020/2014-2020, 667302
European Union’s FP7
Fonds de reserches de Québec
Helmholtz International BigBrain Analytics & Learning Laboratory
Royal Society Sir Henry Dale Fellowship	202397/Z/16/Z
National Institutes of Health	U54 EB020403
National Institute of Mental Health	R01 MH117601, R21MH116473, 1U01MH119736, R01MH116147, R01MH085953
McGill University
Wellcome Trust
Horizon 2020 Framework Programme
Chiropractic and Osteopathic College of Australasia	847879, 728018
European Federation of Pharmaceutical Industries and Associations
Simons Foundation Autism Research Initiative	847818
Natural Sciences and Engineering Research Council of Canada	RGPIN #017-04265
South African Medical Research Council
Canada Research Chairs
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	R01 NS065838, R21 NS107739, 91619115
Innovative Medicines Initiative	115300, 777394
Canada First Research Excellence Fund

Access to Document

10.1038/s41467-022-32420-y

Persistent URL (handle)

Copy link address

Cite this

Hansen, J. Y., Shafiei, G., Vogel, J. W., Smart, K., Bearden, C. E., Hoogman, M., Franke, B., van Rooij, D., Buitelaar, J., McDonald, C. R., Sisodiya, S. M., Schmaal, L., Veltman, D. J., van den Heuvel, O. A., Stein, D. J., van Erp, T. G. M., Ching, C. R. K., Andreassen, O. A., Hajek, T., ... Misic, B. (2022). Local molecular and global connectomic contributions to cross-disorder cortical abnormalities. Nature Communications, 13(1), Article 4682. https://doi.org/10.1038/s41467-022-32420-y

@article{722d6e1d93bc45298c3032f3315aa63c,

title = "Local molecular and global connectomic contributions to cross-disorder cortical abnormalities",

abstract = "Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.",

author = "Hansen, {Justine Y.} and Golia Shafiei and Vogel, {Jacob W.} and Kelly Smart and Bearden, {Carrie E.} and Martine Hoogman and Barbara Franke and {van Rooij}, Daan and Jan Buitelaar and McDonald, {Carrie R.} and Sisodiya, {Sanjay M.} and Lianne Schmaal and Veltman, {Dick J.} and {van den Heuvel}, {Odile A.} and Stein, {Dan J.} and {van Erp}, {Theo G. M.} and Ching, {Christopher R. K.} and Andreassen, {Ole A.} and Tomas Hajek and Nils Opel and Gemma Modinos and Andr{\'e} Aleman and {van der Werf}, Ysbrand and Neda Jahanshad and Thomopoulos, {Sophia I.} and Thompson, {Paul M.} and Carson, {Richard E.} and Alain Dagher and Bratislav Misic",

year = "2022",

month = dec,

day = "1",

doi = "10.1038/s41467-022-32420-y",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Hansen, JY, Shafiei, G, Vogel, JW, Smart, K, Bearden, CE, Hoogman, M, Franke, B, van Rooij, D, Buitelaar, J, McDonald, CR, Sisodiya, SM, Schmaal, L, Veltman, DJ, van den Heuvel, OA, Stein, DJ, van Erp, TGM, Ching, CRK, Andreassen, OA, Hajek, T, Opel, N, Modinos, G, Aleman, A, van der Werf, Y, Jahanshad, N, Thomopoulos, SI, Thompson, PM, Carson, RE, Dagher, A & Misic, B 2022, 'Local molecular and global connectomic contributions to cross-disorder cortical abnormalities', Nature Communications, vol. 13, no. 1, 4682. https://doi.org/10.1038/s41467-022-32420-y

TY - JOUR

T1 - Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

AU - Hansen, Justine Y.

AU - Shafiei, Golia

AU - Vogel, Jacob W.

AU - Smart, Kelly

AU - Bearden, Carrie E.

AU - Hoogman, Martine

AU - Franke, Barbara

AU - van Rooij, Daan

AU - Buitelaar, Jan

AU - McDonald, Carrie R.

AU - Sisodiya, Sanjay M.

AU - Schmaal, Lianne

AU - Veltman, Dick J.

AU - van den Heuvel, Odile A.

AU - Stein, Dan J.

AU - van Erp, Theo G. M.

AU - Ching, Christopher R. K.

AU - Andreassen, Ole A.

AU - Hajek, Tomas

AU - Opel, Nils

AU - Modinos, Gemma

AU - Aleman, André

AU - van der Werf, Ysbrand

AU - Jahanshad, Neda

AU - Thomopoulos, Sophia I.

AU - Thompson, Paul M.

AU - Carson, Richard E.

AU - Dagher, Alain

AU - Misic, Bratislav

PY - 2022/12/1

Y1 - 2022/12/1

N2 - Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

AB - Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

UR - http://www.scopus.com/inward/record.url?scp=85135806141&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-32420-y

DO - 10.1038/s41467-022-32420-y

M3 - Article

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4682

ER -

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Abstract

Funding

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this