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

Afke F. Terwisscha Van Scheltinga, Steven C. Bakker, Neeltje E.M. Van Haren, Eske M. Derks, Jacobine E. Buizer-Voskamp, Heleen B.M. Boos, Wiepke Cahn, Hilleke E. Hulshoff Pol, Stephan Ripke, Roel A. Ophoff, René S. Kahn, Psychiatric Genome-wide association study (GWAS) Consortium

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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 languageEnglish
Pages (from-to)525-531
Number of pages7
JournalBiological Psychiatry
Volume73
Issue number6
DOIs
Publication statusPublished - 15 Mar 2013
Externally publishedYes

Keywords

  • Endophenotype
  • genome-wide
  • imaging
  • psychiatric
  • SNPs
  • structural MRI

Cite this

Terwisscha Van Scheltinga, A. F., Bakker, S. C., Van Haren, N. E. M., Derks, E. M., Buizer-Voskamp, J. E., Boos, H. B. M., ... Psychiatric Genome-wide association study (GWAS) Consortium (2013). Genetic schizophrenia risk variants jointly modulate total brain and white matter volume. Biological Psychiatry, 73(6), 525-531. https://doi.org/10.1016/j.biopsych.2012.08.017
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 ; Hulshoff Pol, Hilleke E. ; Ripke, Stephan ; Ophoff, Roel A. ; Kahn, René S. ; Psychiatric Genome-wide association study (GWAS) Consortium. / Genetic schizophrenia risk variants jointly modulate total brain and white matter volume. In: Biological Psychiatry. 2013 ; Vol. 73, No. 6. pp. 525-531.
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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.",
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Terwisscha Van Scheltinga, AF, Bakker, SC, Van Haren, NEM, Derks, EM, Buizer-Voskamp, JE, Boos, HBM, Cahn, W, Hulshoff Pol, HE, Ripke, S, Ophoff, RA, Kahn, RS & Psychiatric Genome-wide association study (GWAS) Consortium 2013, 'Genetic schizophrenia risk variants jointly modulate total brain and white matter volume', Biological Psychiatry, vol. 73, no. 6, pp. 525-531. https://doi.org/10.1016/j.biopsych.2012.08.017

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; Hulshoff Pol, Hilleke E.; Ripke, Stephan; Ophoff, Roel A.; Kahn, René S.; Psychiatric Genome-wide association study (GWAS) Consortium.

In: Biological Psychiatry, Vol. 73, No. 6, 15.03.2013, p. 525-531.

Research output: Contribution to journalArticleResearchpeer-review

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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 - Psychiatric Genome-wide association study (GWAS) Consortium

AU - Carr, Vaughan J.

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.

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Terwisscha Van Scheltinga AF, Bakker SC, Van Haren NEM, Derks EM, Buizer-Voskamp JE, Boos HBM et al. Genetic schizophrenia risk variants jointly modulate total brain and white matter volume. Biological Psychiatry. 2013 Mar 15;73(6):525-531. https://doi.org/10.1016/j.biopsych.2012.08.017