The genetic architecture of human brainstem structures and their involvement in common brain disorders

Torbjorn Elvsashagen; Shahram Bahrami; Dennis van der Meer; Ingrid Agartz; Dag Alnaes; Deanna M. Barch; Ramona Baur-Streubel; Alessandro Bertolino; Mona K. Beyer; Giuseppe Blasi; Stefan Borgwardt; Birgitte Boye; Jan Buitelaar; Erlend Boen; Elisabeth Gulowsen Celius; Simon Cervenka; Annette Conzelmann; David Coynel; Pasquale Di Carlo; Srdjan Djurovic; Sarah Eisenacher; Thomas Espeseth; Helena Fatouros-Bergman; Lena Flyckt; Barbara Franke; Oleksandr Frei; Barbara Gelao; Hanne Flinstad Harbo; Catharina A. Hartman; Asta Haberg; Dirk Heslenfeld; Pieter J. Hoekstra; Einar A. Hogestol; Rune Jonassen; Erik G. Jonsson; Peter Kirsch; Iwona Kloszewska; Trine Vik Lagerberg; Nils Inge Landro; Stephanie Le Hellard; Klaus-Peter Lesch; Luigi A. Maglanoc; Ulrik F. Malt; Patrizia Mecocci; Ingrid Melle; Andreas Meyer-Lindenberg; Torgeir Moberget; Jan Egil Nordvik; Lars Nyberg; Kevin S. O'Connell; Karolinska Schizophrenia Project Consortium

doi:10.1038/s41467-020-17376-1

The genetic architecture of human brainstem structures and their involvement in common brain disorders

Torbjorn Elvsashagen^*, Shahram Bahrami^*, Dennis van der Meer, Ingrid Agartz, Dag Alnaes, Deanna M. Barch, Ramona Baur-Streubel, Alessandro Bertolino, Mona K. Beyer, Giuseppe Blasi, Stefan Borgwardt, Birgitte Boye, Jan Buitelaar, Erlend Boen, Elisabeth Gulowsen Celius, Simon Cervenka, Annette Conzelmann, David Coynel, Pasquale Di Carlo, Srdjan DjurovicSarah Eisenacher, Thomas Espeseth, Helena Fatouros-Bergman, Lena Flyckt, Barbara Franke, Oleksandr Frei, Barbara Gelao, Hanne Flinstad Harbo, Catharina A. Hartman, Asta Haberg, Dirk Heslenfeld, Pieter J. Hoekstra, Einar A. Hogestol, Rune Jonassen, Erik G. Jonsson, Peter Kirsch, Iwona Kloszewska, Trine Vik Lagerberg, Nils Inge Landro, Stephanie Le Hellard, Klaus-Peter Lesch, Luigi A. Maglanoc, Ulrik F. Malt, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-Lindenberg, Torgeir Moberget, Jan Egil Nordvik, Lars Nyberg, Kevin S. O'Connell, Karolinska Schizophrenia Project Consortium

^*Corresponding author for this work

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

Abstract

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders. The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.

Original language	English
Article number	4016
Number of pages	14
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17376-1
Publication status	Published - 11 Aug 2020

Keywords

GENOME-WIDE ASSOCIATION
CHROMATIN-STATE DISCOVERY
PARKINSONS-DISEASE
SCHIZOPHRENIA
RISK
LOCI
SEGMENTATION
METAANALYSIS
SUSCEPTIBILITY
INDIVIDUALS

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Elvsashagen, T., Bahrami, S., van der Meer, D., Agartz, I., Alnaes, D., Barch, D. M., Baur-Streubel, R., Bertolino, A., Beyer, M. K., Blasi, G., Borgwardt, S., Boye, B., Buitelaar, J., Boen, E., Celius, E. G., Cervenka, S., Conzelmann, A., Coynel, D., Di Carlo, P., ... Karolinska Schizophrenia Project Consortium (2020). The genetic architecture of human brainstem structures and their involvement in common brain disorders. Nature Communications, 11(1), Article 4016. https://doi.org/10.1038/s41467-020-17376-1

@article{cddff2d9cb9d46ea859e00b8020c44c3,

title = "The genetic architecture of human brainstem structures and their involvement in common brain disorders",

abstract = "Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders. The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.",

keywords = "GENOME-WIDE ASSOCIATION, CHROMATIN-STATE DISCOVERY, PARKINSONS-DISEASE, SCHIZOPHRENIA, RISK, LOCI, SEGMENTATION, METAANALYSIS, SUSCEPTIBILITY, INDIVIDUALS",

author = "Torbjorn Elvsashagen and Shahram Bahrami and {van der Meer}, Dennis and Ingrid Agartz and Dag Alnaes and Barch, {Deanna M.} and Ramona Baur-Streubel and Alessandro Bertolino and Beyer, {Mona K.} and Giuseppe Blasi and Stefan Borgwardt and Birgitte Boye and Jan Buitelaar and Erlend Boen and Celius, {Elisabeth Gulowsen} and Simon Cervenka and Annette Conzelmann and David Coynel and {Di Carlo}, Pasquale and Srdjan Djurovic and Sarah Eisenacher and Thomas Espeseth and Helena Fatouros-Bergman and Lena Flyckt and Barbara Franke and Oleksandr Frei and Barbara Gelao and Harbo, {Hanne Flinstad} and Hartman, {Catharina A.} and Asta Haberg and Dirk Heslenfeld and Hoekstra, {Pieter J.} and Hogestol, {Einar A.} and Rune Jonassen and Jonsson, {Erik G.} and Peter Kirsch and Iwona Kloszewska and Lagerberg, {Trine Vik} and Landro, {Nils Inge} and {Le Hellard}, Stephanie and Klaus-Peter Lesch and Maglanoc, {Luigi A.} and Malt, {Ulrik F.} and Patrizia Mecocci and Ingrid Melle and Andreas Meyer-Lindenberg and Torgeir Moberget and Nordvik, {Jan Egil} and Lars Nyberg and O'Connell, {Kevin S.} and {Karolinska Schizophrenia Project Consortium}",

note = "Funding Information: Some authors received speaker{\textquoteright}s honoraria from Lundbeck (T.E., G.B., and O.A.A.), Janssen Cilag (T.E.), Merck (E.H.), Sanofi Genzyme (E.H.), and Synovion (O.A.A). A.B. received speaker{\textquoteright}s honoraria from Lundbeck, Otsuka, and Janssen Cilag and consultation fees from Biogen and Roche. J.B. has been a consultant to, member of advisory board of, and/or speaker for Shire, Roche, Medice, and Servier. E.G.C. has received personal fees from Almirall, Biogen, Merck, Roche and Teva, and grants and personal fees from Novartis and Sanofi. S.C. has received grant support from AstraZeneca as a coinvestigator and has served as a speaker for Otsuka. H.F.H. has received travel support, honoraria for advice or lecturing from Biogen Idec, Sanofi Genzyme, Merck, Novartis, Roche, and Teva and an unrestricted research grant from Novartis. N.I.L. has received consultation fees and travel support from Lundbeck. H.S. has received fees for advisory boards from ACImmune, Merck, and Novo Nordisk. P.S. has received honoraria for lecturing and travel support from Merck. M.T. has been member of advisory boards for Merck, IASIS Healthcare, ELPEN and FarmaSyn. M.Z. has received speaker fees for lectures, travel support and membership in advisory boards from Janssen Cilag, Lund-beck, Otsuka, Ferrer Pharma, Trommsdorff, Servier, and Roche. None of these external parties had any role in the analysis, writing or decision to publish this work. All other authors declare no competing interests. Funding Information: The author list between I.A. and M.Z. is in alphabetic order. The authors were funded by` the South-Eastern Norway Regional Health Authority 2015-078 (T.E.), 2013-123 (O.A.A.), 2014-097 (L.T.W.), 2015-073 (L.T.W.) and 2016-083 (L.T.W.), by the Research Council of Norway (276082 LifespanHealth (T.K.), 213837 (O.A.A), 223273 NORMENT (O.A.A.), 204966 (L.T.W.), 229129 (O.A.A.), 249795 (L.T.W.), 273345 (L.T.W.) and 283798 SYNSCHIZ (O.A.A.)), Stiftelsen Kristian Gerhard Jebsen, the European Research Council (ERCStG 802998 BRAINMINT (L.T.W.)), NVIDIA Corporation GPU Grant (T.K.), the Ebbe Fr{\o}land foundation, and a research grant from Mrs. Throne-Holst. The investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. This publication is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health investigators. Complete listings of participating sites and study investigators can be found at [http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf]. The AddNeuroMed consortium was led by Simon Lovestone, Bruno Vellas, Patrizia Mecocci, Magda Tsolaki, Iwona K{\l}oszewska, and Hilkka Soininen. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = aug,

day = "11",

doi = "10.1038/s41467-020-17376-1",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Elvsashagen, T, Bahrami, S, van der Meer, D, Agartz, I, Alnaes, D, Barch, DM, Baur-Streubel, R, Bertolino, A, Beyer, MK, Blasi, G, Borgwardt, S, Boye, B, Buitelaar, J, Boen, E, Celius, EG, Cervenka, S, Conzelmann, A, Coynel, D, Di Carlo, P, Djurovic, S, Eisenacher, S, Espeseth, T, Fatouros-Bergman, H, Flyckt, L, Franke, B, Frei, O, Gelao, B, Harbo, HF, Hartman, CA, Haberg, A, Heslenfeld, D, Hoekstra, PJ, Hogestol, EA, Jonassen, R, Jonsson, EG, Kirsch, P, Kloszewska, I, Lagerberg, TV, Landro, NI, Le Hellard, S, Lesch, K-P, Maglanoc, LA, Malt, UF, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Moberget, T, Nordvik, JE, Nyberg, L, O'Connell, KS & Karolinska Schizophrenia Project Consortium 2020, 'The genetic architecture of human brainstem structures and their involvement in common brain disorders', Nature Communications, vol. 11, no. 1, 4016. https://doi.org/10.1038/s41467-020-17376-1

TY - JOUR

T1 - The genetic architecture of human brainstem structures and their involvement in common brain disorders

AU - Elvsashagen, Torbjorn

AU - Bahrami, Shahram

AU - van der Meer, Dennis

AU - Agartz, Ingrid

AU - Alnaes, Dag

AU - Barch, Deanna M.

AU - Baur-Streubel, Ramona

AU - Bertolino, Alessandro

AU - Beyer, Mona K.

AU - Blasi, Giuseppe

AU - Borgwardt, Stefan

AU - Boye, Birgitte

AU - Buitelaar, Jan

AU - Boen, Erlend

AU - Celius, Elisabeth Gulowsen

AU - Cervenka, Simon

AU - Conzelmann, Annette

AU - Coynel, David

AU - Di Carlo, Pasquale

AU - Djurovic, Srdjan

AU - Eisenacher, Sarah

AU - Espeseth, Thomas

AU - Fatouros-Bergman, Helena

AU - Flyckt, Lena

AU - Franke, Barbara

AU - Frei, Oleksandr

AU - Gelao, Barbara

AU - Harbo, Hanne Flinstad

AU - Hartman, Catharina A.

AU - Haberg, Asta

AU - Heslenfeld, Dirk

AU - Hoekstra, Pieter J.

AU - Hogestol, Einar A.

AU - Jonassen, Rune

AU - Jonsson, Erik G.

AU - Kirsch, Peter

AU - Kloszewska, Iwona

AU - Lagerberg, Trine Vik

AU - Landro, Nils Inge

AU - Le Hellard, Stephanie

AU - Lesch, Klaus-Peter

AU - Maglanoc, Luigi A.

AU - Malt, Ulrik F.

AU - Mecocci, Patrizia

AU - Melle, Ingrid

AU - Meyer-Lindenberg, Andreas

AU - Moberget, Torgeir

AU - Nordvik, Jan Egil

AU - Nyberg, Lars

AU - O'Connell, Kevin S.

AU - Karolinska Schizophrenia Project Consortium

N1 - Funding Information: Some authors received speaker’s honoraria from Lundbeck (T.E., G.B., and O.A.A.), Janssen Cilag (T.E.), Merck (E.H.), Sanofi Genzyme (E.H.), and Synovion (O.A.A). A.B. received speaker’s honoraria from Lundbeck, Otsuka, and Janssen Cilag and consultation fees from Biogen and Roche. J.B. has been a consultant to, member of advisory board of, and/or speaker for Shire, Roche, Medice, and Servier. E.G.C. has received personal fees from Almirall, Biogen, Merck, Roche and Teva, and grants and personal fees from Novartis and Sanofi. S.C. has received grant support from AstraZeneca as a coinvestigator and has served as a speaker for Otsuka. H.F.H. has received travel support, honoraria for advice or lecturing from Biogen Idec, Sanofi Genzyme, Merck, Novartis, Roche, and Teva and an unrestricted research grant from Novartis. N.I.L. has received consultation fees and travel support from Lundbeck. H.S. has received fees for advisory boards from ACImmune, Merck, and Novo Nordisk. P.S. has received honoraria for lecturing and travel support from Merck. M.T. has been member of advisory boards for Merck, IASIS Healthcare, ELPEN and FarmaSyn. M.Z. has received speaker fees for lectures, travel support and membership in advisory boards from Janssen Cilag, Lund-beck, Otsuka, Ferrer Pharma, Trommsdorff, Servier, and Roche. None of these external parties had any role in the analysis, writing or decision to publish this work. All other authors declare no competing interests. Funding Information: The author list between I.A. and M.Z. is in alphabetic order. The authors were funded by` the South-Eastern Norway Regional Health Authority 2015-078 (T.E.), 2013-123 (O.A.A.), 2014-097 (L.T.W.), 2015-073 (L.T.W.) and 2016-083 (L.T.W.), by the Research Council of Norway (276082 LifespanHealth (T.K.), 213837 (O.A.A), 223273 NORMENT (O.A.A.), 204966 (L.T.W.), 229129 (O.A.A.), 249795 (L.T.W.), 273345 (L.T.W.) and 283798 SYNSCHIZ (O.A.A.)), Stiftelsen Kristian Gerhard Jebsen, the European Research Council (ERCStG 802998 BRAINMINT (L.T.W.)), NVIDIA Corporation GPU Grant (T.K.), the Ebbe Frøland foundation, and a research grant from Mrs. Throne-Holst. The investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. This publication is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health investigators. Complete listings of participating sites and study investigators can be found at [http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf]. The AddNeuroMed consortium was led by Simon Lovestone, Bruno Vellas, Patrizia Mecocci, Magda Tsolaki, Iwona Kłoszewska, and Hilkka Soininen. Publisher Copyright: © 2020, The Author(s).

PY - 2020/8/11

Y1 - 2020/8/11

N2 - Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders. The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.

AB - Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders. The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.

KW - GENOME-WIDE ASSOCIATION

KW - CHROMATIN-STATE DISCOVERY

KW - PARKINSONS-DISEASE

KW - SCHIZOPHRENIA

KW - RISK

KW - LOCI

KW - SEGMENTATION

KW - METAANALYSIS

KW - SUSCEPTIBILITY

KW - INDIVIDUALS

U2 - 10.1038/s41467-020-17376-1

DO - 10.1038/s41467-020-17376-1

M3 - Article

C2 - 32782260

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4016

ER -

The genetic architecture of human brainstem structures and their involvement in common brain disorders

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Keywords

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