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

Terwisscha van Scheltinga, Afke F., Bakker, Steven C., van Haren, Neeltje E. M., Derks, Eske M., Buizer-Voskamp, Jacobine E., Boos, Heleen B. M., Cahn, Wiepke, Pol, Hilleke E. Hulshoff, Ripke, Stephan, Ophoff, Roel A., Kahn, Rene S., Psychiatric Genome-wide Association Study Consortium, Mowry, Bryan J., McGrath, John J ., Nertney, Deborah A ., Brown, Matthew A., Danoy, Patrick A. and Catts, Stanley V. (2013) Genetic schizophrenia risk variants jointly modulate total brain and white matter volume. Biological Psychiatry, 73 6: 525-531. doi:10.1016/j.biopsych.2012.08.017


Author Terwisscha van Scheltinga, Afke F.
Bakker, Steven C.
van Haren, Neeltje E. M.
Derks, Eske M.
Buizer-Voskamp, Jacobine E.
Boos, Heleen B. M.
Cahn, Wiepke
Pol, Hilleke E. Hulshoff
Ripke, Stephan
Ophoff, Roel A.
Kahn, Rene S.
Psychiatric Genome-wide Association Study Consortium
Mowry, Bryan J.
McGrath, John J .
Nertney, Deborah A .
Brown, Matthew A.
Danoy, Patrick A.
Catts, Stanley V.
Title Genetic schizophrenia risk variants jointly modulate total brain and white matter volume
Journal name Biological Psychiatry   Check publisher's open access policy
ISSN 0006-3223
1873-2402
Publication date 2013-03-15
Sub-type Article (original research)
DOI 10.1016/j.biopsych.2012.08.017
Open Access Status DOI
Volume 73
Issue 6
Start page 525
End page 531
Total pages 7
Place of publication Philadelphia, United States
Publisher Elsevier
Language eng
Abstract Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.
Formatted 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.
Keyword Endophenotype
Genome-wide
Iimaging
Psychiatric
SNPs
Structural MRI
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 090532/Z/09/Z
RC2 MH089951
R01 MH061675
K23 MH001760
P41 EB015922
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104036
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NIMH R01 MH078075
085475/Z/08/Z
U01 MH081928
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072894/Z/03/Z
R01 MH060879
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WT0618S8
K99MH102357
MC_UU_12013/2
MH081802
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2014 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
 
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Created: Thu, 11 Apr 2013, 22:04:41 EST by Sheila Cleary on behalf of Scholarly Communication and Digitisation Service