Genetic schizophrenia risk variants jointly modulate total brain and white matter volume

Psychiatric Genome-Wide Association Study (GWAS) Consortium

doi:10.1016/j.biopsych.2012.08.017

Genetic schizophrenia risk variants jointly modulate total brain and white matter volume

Psychiatric Genome-Wide Association Study (GWAS) Consortium

School of Medicine, Dentistry and Biomedical Sciences

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

92 Citations (Scopus)

Abstract

Background: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. Methods: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. Results: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R²=.048, p=1.6×10^-4) and white matter volume (R²=.051, p=8.6×10^-5) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n=2020) was much smaller than the entire set of SNPs that modulated disease status (n=14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. Conclusions: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.

Original language	English
Pages (from-to)	525-531
Number of pages	7
Journal	Biological Psychiatry
Volume	73
Issue number	6
DOIs	https://doi.org/10.1016/j.biopsych.2012.08.017
Publication status	Published - 15 Mar 2013

Bibliographical note

Funding Information:
This work was supported by a Veni grant from Zorg Onderzoek Nederland, Medische Wetenschappen to SCB (the Dutch organization for health research and development, project number: 91686137), by a grant from the Dutch Brain Foundation to SCB [Grant 14F06(2)-34], and by Top Institute Pharma (project T5-203). The Genetic Risk and Outcome of Psychosis project was supported by a Grant from Zorg Onderzoek Nederland, Medische Wetenschappen, within the Mental Health program (project number: 10.000.1001). Genome-wide association study of this sample was funded by the National Institute of Mental Health (Grant RO1 MG078075 to RAO).

Funding Information:
All individual authors on this paper declare no biomedical financial interests or potential conflicts of interest. The following are financial disclosures for the Psychiatric Genomics Consortium: Eli Lilly funded portions of the genotyping for the Clinical Antipsychotic Trials of Intervention Effectiveness Study and TOP. PFS received research funding from Eli Lilly in connection with the Clinical Antipsychotic Trials of Intervention Effectiveness Study. TSS received research funding from Eli Lilly and consulting fees from Janssen Pharmaceutica, GlaxoSmithKline, and Bristol-Myers Squibb. JAL received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer, and Solvay. DStC received research funding from GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. FA received funds from Pfizer, Organon, and the Foundation for the National Institutes of Health. DWB has received research support from Shire and Forest, has been on the speakers' bureau for Pfizer, and has received consulting honoraria from Forest and Jazz. TW has received consulting and lecture fees from H. Lundbeck A/S. OAA has received Speaker's honorarium from AstraZeneca, Janssen, Bristol-Myers Squibb, and GlaxoSmithKline. IM has received a Speaker's honorarium from Janssen and AstraZeneca. AKM has received consulting fees or honoraria from Eli Lilly & Company, Janssen Pharmaceutica, Merck, Bristol-Meyers Squibb, Pfizer, PGxHealth (a division of Clinical Data, Inc.), Roche Diagnostics, and Vanda Pharmaceuticals and has received research support from Eli Lilly & Company. TL has received consulting fees or honoraria from Merck, Eli Lilly & Company, Golden Helix, Inc., InforMed Insights, and PGxHealth (a division of Clinical Data, Inc.). IB has been an advisory board member, consultant, and lecturer for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EGIS, Janssen, H. Lundbeck A/S, Novartis, Pfizer, Richter, and Schering-Plough and received a grant for an investigator-initiated study from H. Lundbeck A/S. JJM has received consulting and speaker's fees from Johnson & Johnson, Schering-Plough and Eli Lilly. CP has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne), and AstraZeneca; provided consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer, and Schering-Plough; and has undertaken investigator-initiated studies supported by Eli Lilly, Hospira, Janssen Cilag, and AstraZeneca. The Denmark-Aarhus group (The GEMSStud [Genetic and Phenotypic Architecture of Metabolic Syndrome-Associated Components in Dyslipidemic and Normolipidemic Subjects Study] with principal investigators ADB, OM, and PBM) received research funding from H. Lundbeck A/S. EGJ has served as an unpaid consultant for Eli Lilly.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

Endophenotype
genome-wide
imaging
psychiatric
SNPs
structural MRI

ASJC Scopus subject areas

Biological Psychiatry

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10.1016/j.biopsych.2012.08.017

Cite this

@article{4dff224871064bda994fe5efa335b2e4,

title = "Genetic schizophrenia risk variants jointly modulate total brain and white matter volume",

abstract = "Background: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. Methods: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. Results: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2=.048, p=1.6×10-4) and white matter volume (R2=.051, p=8.6×10-5) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n=2020) was much smaller than the entire set of SNPs that modulated disease status (n=14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. Conclusions: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.",

keywords = "Endophenotype, genome-wide, imaging, psychiatric, SNPs, structural MRI",

author = "{Terwisscha Van Scheltinga}, {Afke F.} and Bakker, {Steven C.} and {Van Haren}, {Neeltje E.M.} and Derks, {Eske M.} and Buizer-Voskamp, {Jacobine E.} and Boos, {Heleen B.M.} and Wiepke Cahn and {Hulshoff Pol}, {Hilleke E.} and Stephan Ripke and Ophoff, {Roel A.} and Kahn, {Ren{\'e} S.} and Stephan Ripke and Sanders, {Alan R.} and Kendler, {Kenneth S.} and Levinson, {Douglas F.} and Pamela Sklar and Holmans, {Peter A.} and Lin, {Dan Yu} and Jubao Duan and Ophoff, {Roel A.} and Andreassen, {Ole A.} and Edward Scolnick and Sven Cichon and {St. Clair}, David and Aiden Corvin and Hugh Gurling and Thomas Werge and Dan Rujescu and Blackwood, {Douglas H.R.} and Pato, {Carlos N.} and Malhotra, {Anil K.} and Shaun Purcell and Frank Dudbridge and Neale, {Benjamin M.} and Lizzy Rossin and Visscher, {Peter M.} and Danielle Posthuma and Ruderfer, {Douglas M.} and Ayman Fanous and Hreinn Stefansson and Stacy Steinberg and Mowry, {Bryan J.} and Vera Golimbet and {De Hert}, Marc and J{\"o}nsson, {Erik G.} and Istv{\'a}n Bitter and Pietil{\"a}inen, {Olli P.H.} and Collier, {David A.} and Sarah Tosato and O{\textquoteright}Neill, {F. Anthony} and {Psychiatric Genome-Wide Association Study (GWAS) Consortium}",

note = "Funding Information: This work was supported by a Veni grant from Zorg Onderzoek Nederland, Medische Wetenschappen to SCB (the Dutch organization for health research and development, project number: 91686137), by a grant from the Dutch Brain Foundation to SCB [Grant 14F06(2)-34], and by Top Institute Pharma (project T5-203). The Genetic Risk and Outcome of Psychosis project was supported by a Grant from Zorg Onderzoek Nederland, Medische Wetenschappen, within the Mental Health program (project number: 10.000.1001). Genome-wide association study of this sample was funded by the National Institute of Mental Health (Grant RO1 MG078075 to RAO). Funding Information: All individual authors on this paper declare no biomedical financial interests or potential conflicts of interest. The following are financial disclosures for the Psychiatric Genomics Consortium: Eli Lilly funded portions of the genotyping for the Clinical Antipsychotic Trials of Intervention Effectiveness Study and TOP. PFS received research funding from Eli Lilly in connection with the Clinical Antipsychotic Trials of Intervention Effectiveness Study. TSS received research funding from Eli Lilly and consulting fees from Janssen Pharmaceutica, GlaxoSmithKline, and Bristol-Myers Squibb. JAL received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer, and Solvay. DStC received research funding from GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. FA received funds from Pfizer, Organon, and the Foundation for the National Institutes of Health. DWB has received research support from Shire and Forest, has been on the speakers' bureau for Pfizer, and has received consulting honoraria from Forest and Jazz. TW has received consulting and lecture fees from H. Lundbeck A/S. OAA has received Speaker's honorarium from AstraZeneca, Janssen, Bristol-Myers Squibb, and GlaxoSmithKline. IM has received a Speaker's honorarium from Janssen and AstraZeneca. AKM has received consulting fees or honoraria from Eli Lilly & Company, Janssen Pharmaceutica, Merck, Bristol-Meyers Squibb, Pfizer, PGxHealth (a division of Clinical Data, Inc.), Roche Diagnostics, and Vanda Pharmaceuticals and has received research support from Eli Lilly & Company. TL has received consulting fees or honoraria from Merck, Eli Lilly & Company, Golden Helix, Inc., InforMed Insights, and PGxHealth (a division of Clinical Data, Inc.). IB has been an advisory board member, consultant, and lecturer for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EGIS, Janssen, H. Lundbeck A/S, Novartis, Pfizer, Richter, and Schering-Plough and received a grant for an investigator-initiated study from H. Lundbeck A/S. JJM has received consulting and speaker's fees from Johnson & Johnson, Schering-Plough and Eli Lilly. CP has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne), and AstraZeneca; provided consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer, and Schering-Plough; and has undertaken investigator-initiated studies supported by Eli Lilly, Hospira, Janssen Cilag, and AstraZeneca. The Denmark-Aarhus group (The GEMSStud [Genetic and Phenotypic Architecture of Metabolic Syndrome-Associated Components in Dyslipidemic and Normolipidemic Subjects Study] with principal investigators ADB, OM, and PBM) received research funding from H. Lundbeck A/S. EGJ has served as an unpaid consultant for Eli Lilly. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

year = "2013",

month = mar,

day = "15",

doi = "10.1016/j.biopsych.2012.08.017",

language = "English",

volume = "73",

pages = "525--531",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Inc.",

number = "6",

}

TY - JOUR

T1 - Genetic schizophrenia risk variants jointly modulate total brain and white matter volume

AU - Terwisscha Van Scheltinga, Afke F.

AU - Bakker, Steven C.

AU - Van Haren, Neeltje E.M.

AU - Derks, Eske M.

AU - Buizer-Voskamp, Jacobine E.

AU - Boos, Heleen B.M.

AU - Cahn, Wiepke

AU - Hulshoff Pol, Hilleke E.

AU - Ripke, Stephan

AU - Ophoff, Roel A.

AU - Kahn, René S.

AU - Ripke, Stephan

AU - Sanders, Alan R.

AU - Kendler, Kenneth S.

AU - Levinson, Douglas F.

AU - Sklar, Pamela

AU - Holmans, Peter A.

AU - Lin, Dan Yu

AU - Duan, Jubao

AU - Ophoff, Roel A.

AU - Andreassen, Ole A.

AU - Scolnick, Edward

AU - Cichon, Sven

AU - St. Clair, David

AU - Corvin, Aiden

AU - Gurling, Hugh

AU - Werge, Thomas

AU - Rujescu, Dan

AU - Blackwood, Douglas H.R.

AU - Pato, Carlos N.

AU - Malhotra, Anil K.

AU - Purcell, Shaun

AU - Dudbridge, Frank

AU - Neale, Benjamin M.

AU - Rossin, Lizzy

AU - Visscher, Peter M.

AU - Posthuma, Danielle

AU - Ruderfer, Douglas M.

AU - Fanous, Ayman

AU - Stefansson, Hreinn

AU - Steinberg, Stacy

AU - Mowry, Bryan J.

AU - Golimbet, Vera

AU - De Hert, Marc

AU - Jönsson, Erik G.

AU - Bitter, István

AU - Pietiläinen, Olli P.H.

AU - Collier, David A.

AU - Tosato, Sarah

AU - O’Neill, F. Anthony

AU - Psychiatric Genome-Wide Association Study (GWAS) Consortium

N1 - Funding Information: This work was supported by a Veni grant from Zorg Onderzoek Nederland, Medische Wetenschappen to SCB (the Dutch organization for health research and development, project number: 91686137), by a grant from the Dutch Brain Foundation to SCB [Grant 14F06(2)-34], and by Top Institute Pharma (project T5-203). The Genetic Risk and Outcome of Psychosis project was supported by a Grant from Zorg Onderzoek Nederland, Medische Wetenschappen, within the Mental Health program (project number: 10.000.1001). Genome-wide association study of this sample was funded by the National Institute of Mental Health (Grant RO1 MG078075 to RAO). Funding Information: All individual authors on this paper declare no biomedical financial interests or potential conflicts of interest. The following are financial disclosures for the Psychiatric Genomics Consortium: Eli Lilly funded portions of the genotyping for the Clinical Antipsychotic Trials of Intervention Effectiveness Study and TOP. PFS received research funding from Eli Lilly in connection with the Clinical Antipsychotic Trials of Intervention Effectiveness Study. TSS received research funding from Eli Lilly and consulting fees from Janssen Pharmaceutica, GlaxoSmithKline, and Bristol-Myers Squibb. JAL received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer, and Solvay. DStC received research funding from GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. FA received funds from Pfizer, Organon, and the Foundation for the National Institutes of Health. DWB has received research support from Shire and Forest, has been on the speakers' bureau for Pfizer, and has received consulting honoraria from Forest and Jazz. TW has received consulting and lecture fees from H. Lundbeck A/S. OAA has received Speaker's honorarium from AstraZeneca, Janssen, Bristol-Myers Squibb, and GlaxoSmithKline. IM has received a Speaker's honorarium from Janssen and AstraZeneca. AKM has received consulting fees or honoraria from Eli Lilly & Company, Janssen Pharmaceutica, Merck, Bristol-Meyers Squibb, Pfizer, PGxHealth (a division of Clinical Data, Inc.), Roche Diagnostics, and Vanda Pharmaceuticals and has received research support from Eli Lilly & Company. TL has received consulting fees or honoraria from Merck, Eli Lilly & Company, Golden Helix, Inc., InforMed Insights, and PGxHealth (a division of Clinical Data, Inc.). IB has been an advisory board member, consultant, and lecturer for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EGIS, Janssen, H. Lundbeck A/S, Novartis, Pfizer, Richter, and Schering-Plough and received a grant for an investigator-initiated study from H. Lundbeck A/S. JJM has received consulting and speaker's fees from Johnson & Johnson, Schering-Plough and Eli Lilly. CP has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne), and AstraZeneca; provided consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer, and Schering-Plough; and has undertaken investigator-initiated studies supported by Eli Lilly, Hospira, Janssen Cilag, and AstraZeneca. The Denmark-Aarhus group (The GEMSStud [Genetic and Phenotypic Architecture of Metabolic Syndrome-Associated Components in Dyslipidemic and Normolipidemic Subjects Study] with principal investigators ADB, OM, and PBM) received research funding from H. Lundbeck A/S. EGJ has served as an unpaid consultant for Eli Lilly. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2013/3/15

Y1 - 2013/3/15

N2 - Background: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. Methods: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. Results: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2=.048, p=1.6×10-4) and white matter volume (R2=.051, p=8.6×10-5) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n=2020) was much smaller than the entire set of SNPs that modulated disease status (n=14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. Conclusions: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.

AB - Background: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. Methods: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. Results: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2=.048, p=1.6×10-4) and white matter volume (R2=.051, p=8.6×10-5) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n=2020) was much smaller than the entire set of SNPs that modulated disease status (n=14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. Conclusions: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.

KW - Endophenotype

KW - genome-wide

KW - imaging

KW - psychiatric

KW - SNPs

KW - structural MRI

UR - http://www.scopus.com/inward/record.url?scp=84874542049&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2012.08.017

DO - 10.1016/j.biopsych.2012.08.017

M3 - Article

AN - SCOPUS:84874542049

SN - 0006-3223

VL - 73

SP - 525

EP - 531

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 6

ER -

Genetic schizophrenia risk variants jointly modulate total brain and white matter volume

Abstract

Bibliographical note

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