The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

Sonja M C de Zwarte; Rachel M Brouwer; Ingrid Agartz; Martin Alda; André Aleman; Kathryn I Alpert; Carrie E Bearden; Alessandro Bertolino; Catherine Bois; Aurora Bonvino; Elvira Bramon; Elizabeth E L Buimer; Wiepke Cahn; Dara M Cannon; Tyrone D Cannon; Xavier Caseras; Josefina Castro-Fornieles; Qiang Chen; Yoonho Chung; Elena De la Serna; Annabella Di Giorgio; Gaelle E Doucet; Mehmet Cagdas Eker; Susanne Erk; Scott C Fears; Sonya F Foley; Sophia Frangou; Andrew Frankland; Janice M Fullerton; David C Glahn; Vina M Goghari; Aaron L Goldman; Ali Saffet Gonul; Oliver Gruber; Lieuwe de Haan; Tomas Hajek; Emma L Hawkins; Andreas Heinz; Manon H J Hillegers; Hilleke E Hulshoff Pol; Christina M Hultman; Martin Ingvar; Viktoria Johansson; Erik G Jönsson; Fergus Kane; Matthew J Kempton; Marinka M G Koenis; Miloslav Kopecek; Lydia Krabbendam; Bernd Krämer; Stephen M Lawrie; Rhoshel K Lenroot; Machteld Marcelis; Jan-Bernard C Marsman; Venkata S Mattay; Colm McDonald; Andreas Meyer-Lindenberg; Stijn Michielse; Philip B Mitchell; Dolores Moreno; Robin M Murray; Benson Mwangi; Pablo Najt; Emma Neilson; Jason Newport; Jim van Os; Bronwyn Overs; Aysegul Ozerdem; Marco M Picchioni; Anja Richter; Gloria Roberts; Aybala Saricicek Aydogan; Peter R Schofield; Fatma Simsek; Jair C Soares; Gisela Sugranyes; Timothea Toulopoulou; Giulia Tronchin; Henrik Walter; Lei Wang; Daniel R Weinberger; Heather C Whalley; Nefize Yalin; Ole A Andreassen; Christopher R K Ching; Theo G M van Erp; Jessica A Turner; Neda Jahanshad; Paul M Thompson; René S Kahn; Neeltje E M van Haren

doi:10.1016/j.biopsych.2019.03.985

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

Sonja M C de Zwarte, Rachel M Brouwer, Ingrid Agartz, Martin Alda, André Aleman, Kathryn I Alpert, Carrie E Bearden, Alessandro Bertolino, Catherine Bois, Aurora Bonvino, Elvira Bramon, Elizabeth E L Buimer, Wiepke Cahn, Dara M Cannon, Tyrone D Cannon, Xavier Caseras, Josefina Castro-Fornieles, Qiang Chen, Yoonho Chung, Elena De la SernaAnnabella Di Giorgio, Gaelle E Doucet, Mehmet Cagdas Eker, Susanne Erk, Scott C Fears, Sonya F Foley, Sophia Frangou, Andrew Frankland, Janice M Fullerton, David C Glahn, Vina M Goghari, Aaron L Goldman, Ali Saffet Gonul, Oliver Gruber, Lieuwe de Haan, Tomas Hajek, Emma L Hawkins, Andreas Heinz, Manon H J Hillegers, Hilleke E Hulshoff Pol, Christina M Hultman, Martin Ingvar, Viktoria Johansson, Erik G Jönsson, Fergus Kane, Matthew J Kempton, Marinka M G Koenis, Miloslav Kopecek, Lydia Krabbendam, Bernd Krämer, Stephen M Lawrie, Rhoshel K Lenroot, Machteld Marcelis, Jan-Bernard C Marsman, Venkata S Mattay, Colm McDonald, Andreas Meyer-Lindenberg, Stijn Michielse, Philip B Mitchell, Dolores Moreno, Robin M Murray, Benson Mwangi, Pablo Najt, Emma Neilson, Jason Newport, Jim van Os, Bronwyn Overs, Aysegul Ozerdem, Marco M Picchioni, Anja Richter, Gloria Roberts, Aybala Saricicek Aydogan, Peter R Schofield, Fatma Simsek, Jair C Soares, Gisela Sugranyes, Timothea Toulopoulou, Giulia Tronchin, Henrik Walter, Lei Wang, Daniel R Weinberger, Heather C Whalley, Nefize Yalin, Ole A Andreassen, Christopher R K Ching, Theo G M van Erp, Jessica A Turner, Neda Jahanshad, Paul M Thompson, René S Kahn, Neeltje E M van Haren

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

Abstract

BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.

METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.

RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.

CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

Original language	English
Pages (from-to)	545-556
Number of pages	12
Journal	Biological Psychiatry
Volume	86
Issue number	7
DOIs	https://doi.org/10.1016/j.biopsych.2019.03.985
Publication status	Published - 1 Oct 2019
Externally published	Yes

Keywords

Adult
Bipolar Disorder/genetics
Brain/pathology
Cohort Studies
Female
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Schizophrenia/genetics
Young Adult

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de Zwarte, S. M. C., Brouwer, R. M., Agartz, I., Alda, M., Aleman, A., Alpert, K. I., Bearden, C. E., Bertolino, A., Bois, C., Bonvino, A., Bramon, E., Buimer, E. E. L., Cahn, W., Cannon, D. M., Cannon, T. D., Caseras, X., Castro-Fornieles, J., Chen, Q., Chung, Y., ... van Haren, N. E. M. (2019). The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder. Biological Psychiatry, 86(7), 545-556. https://doi.org/10.1016/j.biopsych.2019.03.985

@article{01fcc53a993c45028b612a4d545ebeaf,

title = "The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder",

abstract = "BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.",

keywords = "Adult, Bipolar Disorder/genetics, Brain/pathology, Cohort Studies, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Schizophrenia/genetics, Young Adult",

author = "{de Zwarte}, {Sonja M C} and Brouwer, {Rachel M} and Ingrid Agartz and Martin Alda and Andr{\'e} Aleman and Alpert, {Kathryn I} and Bearden, {Carrie E} and Alessandro Bertolino and Catherine Bois and Aurora Bonvino and Elvira Bramon and Buimer, {Elizabeth E L} and Wiepke Cahn and Cannon, {Dara M} and Cannon, {Tyrone D} and Xavier Caseras and Josefina Castro-Fornieles and Qiang Chen and Yoonho Chung and {De la Serna}, Elena and {Di Giorgio}, Annabella and Doucet, {Gaelle E} and Eker, {Mehmet Cagdas} and Susanne Erk and Fears, {Scott C} and Foley, {Sonya F} and Sophia Frangou and Andrew Frankland and Fullerton, {Janice M} and Glahn, {David C} and Goghari, {Vina M} and Goldman, {Aaron L} and Gonul, {Ali Saffet} and Oliver Gruber and {de Haan}, Lieuwe and Tomas Hajek and Hawkins, {Emma L} and Andreas Heinz and Hillegers, {Manon H J} and {Hulshoff Pol}, {Hilleke E} and Hultman, {Christina M} and Martin Ingvar and Viktoria Johansson and J{\"o}nsson, {Erik G} and Fergus Kane and Kempton, {Matthew J} and Koenis, {Marinka M G} and Miloslav Kopecek and Lydia Krabbendam and Bernd Kr{\"a}mer and Lawrie, {Stephen M} and Lenroot, {Rhoshel K} and Machteld Marcelis and Marsman, {Jan-Bernard C} and Mattay, {Venkata S} and Colm McDonald and Andreas Meyer-Lindenberg and Stijn Michielse and Mitchell, {Philip B} and Dolores Moreno and Murray, {Robin M} and Benson Mwangi and Pablo Najt and Emma Neilson and Jason Newport and {van Os}, Jim and Bronwyn Overs and Aysegul Ozerdem and Picchioni, {Marco M} and Anja Richter and Gloria Roberts and Aydogan, {Aybala Saricicek} and Schofield, {Peter R} and Fatma Simsek and Soares, {Jair C} and Gisela Sugranyes and Timothea Toulopoulou and Giulia Tronchin and Henrik Walter and Lei Wang and Weinberger, {Daniel R} and Whalley, {Heather C} and Nefize Yalin and Andreassen, {Ole A} and Ching, {Christopher R K} and {van Erp}, {Theo G M} and Turner, {Jessica A} and Neda Jahanshad and Thompson, {Paul M} and Kahn, {Ren{\'e} S} and {van Haren}, {Neeltje E M}",

year = "2019",

month = oct,

day = "1",

doi = "10.1016/j.biopsych.2019.03.985",

language = "English",

volume = "86",

pages = "545--556",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "7",

}

de Zwarte, SMC, Brouwer, RM, Agartz, I, Alda, M, Aleman, A, Alpert, KI, Bearden, CE, Bertolino, A, Bois, C, Bonvino, A, Bramon, E, Buimer, EEL, Cahn, W, Cannon, DM, Cannon, TD, Caseras, X, Castro-Fornieles, J, Chen, Q, Chung, Y, De la Serna, E, Di Giorgio, A, Doucet, GE, Eker, MC, Erk, S, Fears, SC, Foley, SF, Frangou, S, Frankland, A, Fullerton, JM, Glahn, DC, Goghari, VM, Goldman, AL, Gonul, AS, Gruber, O, de Haan, L, Hajek, T, Hawkins, EL, Heinz, A, Hillegers, MHJ, Hulshoff Pol, HE, Hultman, CM, Ingvar, M, Johansson, V, Jönsson, EG, Kane, F, Kempton, MJ, Koenis, MMG, Kopecek, M, Krabbendam, L, Krämer, B, Lawrie, SM, Lenroot, RK, Marcelis, M, Marsman, J-BC, Mattay, VS, McDonald, C, Meyer-Lindenberg, A, Michielse, S, Mitchell, PB, Moreno, D, Murray, RM, Mwangi, B, Najt, P, Neilson, E, Newport, J, van Os, J, Overs, B, Ozerdem, A, Picchioni, MM, Richter, A, Roberts, G, Aydogan, AS, Schofield, PR, Simsek, F, Soares, JC, Sugranyes, G, Toulopoulou, T, Tronchin, G, Walter, H, Wang, L, Weinberger, DR, Whalley, HC, Yalin, N, Andreassen, OA, Ching, CRK, van Erp, TGM, Turner, JA, Jahanshad, N, Thompson, PM, Kahn, RS & van Haren, NEM 2019, 'The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder', Biological Psychiatry, vol. 86, no. 7, pp. 545-556. https://doi.org/10.1016/j.biopsych.2019.03.985

TY - JOUR

T1 - The Association Between Familial Risk and Brain Abnormalities Is Disease Specific

T2 - An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

AU - de Zwarte, Sonja M C

AU - Brouwer, Rachel M

AU - Agartz, Ingrid

AU - Alda, Martin

AU - Aleman, André

AU - Alpert, Kathryn I

AU - Bearden, Carrie E

AU - Bertolino, Alessandro

AU - Bois, Catherine

AU - Bonvino, Aurora

AU - Bramon, Elvira

AU - Buimer, Elizabeth E L

AU - Cahn, Wiepke

AU - Cannon, Dara M

AU - Cannon, Tyrone D

AU - Caseras, Xavier

AU - Castro-Fornieles, Josefina

AU - Chen, Qiang

AU - Chung, Yoonho

AU - De la Serna, Elena

AU - Di Giorgio, Annabella

AU - Doucet, Gaelle E

AU - Eker, Mehmet Cagdas

AU - Erk, Susanne

AU - Fears, Scott C

AU - Foley, Sonya F

AU - Frangou, Sophia

AU - Frankland, Andrew

AU - Fullerton, Janice M

AU - Glahn, David C

AU - Goghari, Vina M

AU - Goldman, Aaron L

AU - Gonul, Ali Saffet

AU - Gruber, Oliver

AU - de Haan, Lieuwe

AU - Hajek, Tomas

AU - Hawkins, Emma L

AU - Heinz, Andreas

AU - Hillegers, Manon H J

AU - Hulshoff Pol, Hilleke E

AU - Hultman, Christina M

AU - Ingvar, Martin

AU - Johansson, Viktoria

AU - Jönsson, Erik G

AU - Kane, Fergus

AU - Kempton, Matthew J

AU - Koenis, Marinka M G

AU - Kopecek, Miloslav

AU - Krabbendam, Lydia

AU - Krämer, Bernd

AU - Lawrie, Stephen M

AU - Lenroot, Rhoshel K

AU - Marcelis, Machteld

AU - Marsman, Jan-Bernard C

AU - Mattay, Venkata S

AU - McDonald, Colm

AU - Meyer-Lindenberg, Andreas

AU - Michielse, Stijn

AU - Mitchell, Philip B

AU - Moreno, Dolores

AU - Murray, Robin M

AU - Mwangi, Benson

AU - Najt, Pablo

AU - Neilson, Emma

AU - Newport, Jason

AU - van Os, Jim

AU - Overs, Bronwyn

AU - Ozerdem, Aysegul

AU - Picchioni, Marco M

AU - Richter, Anja

AU - Roberts, Gloria

AU - Aydogan, Aybala Saricicek

AU - Schofield, Peter R

AU - Simsek, Fatma

AU - Soares, Jair C

AU - Sugranyes, Gisela

AU - Toulopoulou, Timothea

AU - Tronchin, Giulia

AU - Walter, Henrik

AU - Wang, Lei

AU - Weinberger, Daniel R

AU - Whalley, Heather C

AU - Yalin, Nefize

AU - Andreassen, Ole A

AU - Ching, Christopher R K

AU - van Erp, Theo G M

AU - Turner, Jessica A

AU - Jahanshad, Neda

AU - Thompson, Paul M

AU - Kahn, René S

AU - van Haren, Neeltje E M

PY - 2019/10/1

Y1 - 2019/10/1

N2 - BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

AB - BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

KW - Adult

KW - Bipolar Disorder/genetics

KW - Brain/pathology

KW - Cohort Studies

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Middle Aged

KW - Schizophrenia/genetics

KW - Young Adult

U2 - 10.1016/j.biopsych.2019.03.985

DO - 10.1016/j.biopsych.2019.03.985

M3 - Article

C2 - 31443932

SN - 0006-3223

VL - 86

SP - 545

EP - 556

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 7

ER -

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

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Keywords

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