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; the Psychiatric Genome-wide Association Study Consortium; Klaus Damgaard Jakobsen; Thomas Hansen; Andrés Ingason; Linh Duong; Henrik Berg Rasmussen; Line Olsen; Merete Nordentoft; Gesche Jürgens; Birte Yding Glenthøj; August Gabriel Wang; Thomas Mears Werge

doi:10.1016/j.biopsych.2012.08.017

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, the Psychiatric Genome-wide Association Study Consortium, Klaus Damgaard Jakobsen, Thomas Hansen, Andrés Ingason, Linh Duong, Henrik Berg Rasmussen, Line Olsen, Merete Nordentoft, Gesche JürgensBirte Yding Glenthøj, August Gabriel Wang, Thomas Mears Werge

74 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 (R(2)=.048, p=1.6×10(-4)) and white matter volume (R(2)=.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
Book series	Advances in Biological Psychiatry
Volume	73
Issue number	6
Pages (from-to)	525-531
ISSN	0378-7354
DOIs	https://doi.org/10.1016/j.biopsych.2012.08.017
Publication status	Published - 15 Mar 2013

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Terwisscha van Scheltinga, A. F., Bakker, S. C., van Haren, N. E. M., Derks, E. M., Buizer-Voskamp, J. E., Boos, H. B. M., Cahn, W., Hulshoff Pol, H. E., Ripke, S., Ophoff, R. A., Kahn, R. S., the Psychiatric Genome-wide Association Study Consortium, Jakobsen, K. D., Hansen, T., Ingason, A., Duong, L., Rasmussen, H. B., Olsen, L., Nordentoft, M., ... Werge, T. M. (2013). Genetic Schizophrenia Risk Variants Jointly Modulate Total Brain and White Matter Volume. Advances in Biological Psychiatry, 73(6), 525-531. https://doi.org/10.1016/j.biopsych.2012.08.017

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, the Psychiatric Genome-wide Association Study Consortium, Jakobsen, KD, Hansen, T, Ingason, A, Duong, L, Rasmussen, HB, Olsen, L, Nordentoft, M, Jürgens, G, Glenthøj, BY , Wang, AG & Werge, TM 2013, 'Genetic Schizophrenia Risk Variants Jointly Modulate Total Brain and White Matter Volume', Advances in Biological Psychiatry, vol. 73, no. 6, pp. 525-531. https://doi.org/10.1016/j.biopsych.2012.08.017

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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 (R(2)=.048, p=1.6×10(-4)) and white matter volume (R(2)=.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.",

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 Thomas Werge and Jakobsen, {Klaus Damgaard} and Thomas Hansen and Andr{\'e}s Ingason and Linh Duong and Rasmussen, {Henrik Berg} and Line Olsen and Merete Nordentoft and Gesche J{\"u}rgens and Glenth{\o}j, {Birte Yding} and Wang, {August Gabriel} and Werge, {Thomas Mears}",

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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 - the Psychiatric Genome-wide Association Study Consortium

AU - Jakobsen, Klaus Damgaard

AU - Hansen, Thomas

AU - Ingason, Andrés

AU - Duong, Linh

AU - Rasmussen, Henrik Berg

AU - Olsen, Line

AU - Nordentoft, Merete

AU - Jürgens, Gesche

AU - Glenthøj, Birte Yding

AU - Wang, August Gabriel

AU - Werge, Thomas Mears

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 (R(2)=.048, p=1.6×10(-4)) and white matter volume (R(2)=.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 (R(2)=.048, p=1.6×10(-4)) and white matter volume (R(2)=.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.

U2 - 10.1016/j.biopsych.2012.08.017

DO - 10.1016/j.biopsych.2012.08.017

M3 - Journal article

C2 - 23039932

SN - 0378-7354

VL - 73

SP - 525

EP - 531

JO - Advances in Biological Psychiatry

JF - Advances in Biological Psychiatry

IS - 6

ER -

Genetic Schizophrenia Risk Variants Jointly Modulate Total Brain and White Matter Volume

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