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 | |
State | Published - Mar 15 2013 |
Keywords
- Endophenotype
- SNPs
- genome-wide
- imaging
- psychiatric
- structural MRI
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Genetic schizophrenia risk variants jointly modulate total brain and white matter volume. / Psychiatric Genome-wide association study (GWAS) Consortium.
In: Biological Psychiatry, Vol. 73, No. 6, 15.03.2013, p. 525-531.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genetic schizophrenia risk variants jointly modulate total brain and white matter volume
AU - Psychiatric Genome-wide association study (GWAS) Consortium
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 - Agartz, Ingrid
AU - Albus, Margot
AU - Alexander, Madeline
AU - Amdur, Richard L.
AU - Amin, Farooq
AU - Bass, Nicholas
AU - Bergen, Sarah E.
AU - Black, Donald W.
AU - Børglum, Anders D.
AU - Brown, Matthew A.
AU - Bruggeman, Richard
AU - Buccola, Nancy G.
AU - Byerley, William F.
AU - Cahn, Wiepke
AU - Cantor, Rita M.
AU - Carr, Vaughan J.
AU - Catts, Stanley V.
AU - Choudhury, Khalid
AU - Cloninger, C. Robert
AU - Cormican, Paul
AU - Craddock, Nicholas
AU - Danoy, Patrick A.
AU - Datta, Susmita
AU - de Haan, Lieuwe
AU - Demontis, Ditte
AU - Dikeos, Dimitris
AU - Djurovic, Srdjan
AU - Donnelly, Peter
AU - Donohoe, Gary
AU - Duong, Linh
AU - Dwyer, Sarah
AU - Fink-Jensen, Anders
AU - Freedman, Robert
AU - Freimer, Nelson B.
AU - Friedl, Marion
AU - Georgieva, Lyudmila
AU - Giegling, Ina
AU - Gill, Michael
AU - Glenthøj, Birte
AU - Godard, Stephanie
AU - Hamshere, Marian
AU - Hansen, Mark
AU - Hansen, Thomas
AU - Hartmann, Annette M.
AU - Henskens, Frans A.
AU - Hougaard, David M.
AU - Hultman, Christina M.
AU - Ingason, Andrés
AU - Jablensky, Assen V.
AU - Jakobsen, Klaus D.
AU - Jay, Maurice
AU - Jürgens, Gesche
AU - Kahn, René S.
AU - Keller, Matthew C.
AU - Kenis, Gunter
AU - Kenny, Elaine
AU - Kim, Yunjung
AU - Kirov, George K.
AU - Konnerth, Heike
AU - Konte, Bettina
AU - Krabbendam, Lydia
AU - Krasucki, Robert
AU - Lasseter, Virginia K.
AU - Laurent, Claudine
AU - Lawrence, Jacob
AU - Lencz, Todd
AU - Lerer, F. Bernard
AU - Liang, Kung Yee
AU - Lichtenstein, Paul
AU - Lieberman, Jeffrey A.
AU - Linszen, Don H.
AU - Lönnqvist, Jouko
AU - Loughland, Carmel M.
AU - Maclean, Alan W.
AU - Maher, Brion S.
AU - Maier, Wolfgang
AU - Mallet, Jacques
AU - Malloy, Pat
AU - Mattheisen, Manuel
AU - Mattingsdal, Morten
AU - McGhee, Kevin A.
AU - McGrath, John J.
AU - McIntosh, Andrew
AU - McLean, Duncan E.
AU - McQuillin, Andrew
AU - Melle, Ingrid
AU - Michie, Patricia T.
AU - Milanova, Vihra
AU - Morris, Derek W.
AU - Mors, Ole
AU - Mortensen, Preben B.
AU - Moskvina, Valentina
AU - Muglia, Pierandrea
AU - Myin-Germeys, Inez
AU - Nertney, Deborah A.
AU - Nestadt, Gerald
AU - Nielsen, Jimmi
AU - Nikolov, Ivan
AU - Nordentoft, Merete
AU - Norton, Nadine
AU - Nöthen, Markus M.
AU - O’Dushlaine, Colm T.
AU - Olincy, Ann
AU - Olsen, Line
AU - O’Neill, F. Anthony
AU - ørntoft, Torben F.
AU - Owen, Michael J.
AU - Pantelis, Christos
AU - Papadimitriou, George
AU - Pato, Michele T.
AU - Peltonen, Leena
AU - Petursson, Hannes
AU - Pickard, Ben
AU - Pimm, Jonathan
AU - Pulver, Ann E.
AU - Puri, Vinay
AU - Quested, Digby
AU - Quinn, Emma M.
AU - Rasmussen, Henrik B.
AU - Réthelyi, János M.
AU - Ribble, Robert
AU - Rietschel, Marcella
AU - Riley, Brien P.
AU - Ruggeri, Mirella
AU - Schall, Ulrich
AU - Schulze, Thomas G.
AU - Schwab, Sibylle G.
AU - Scott, Rodney J.
AU - Shi, Jianxin
AU - Sigurdsson, Engilbert
AU - Silverman, Jeremy M.
AU - Spencer, Chris C.A.
AU - Stefansson, Kari
AU - Strange, Amy
AU - Strengman, Eric
AU - Stroup, T. Scott
AU - Suvisaari, Jaana
AU - Terenius, Lars
AU - Thirumalai, Srinivasa
AU - Thygesen, Johan H.
AU - Timm, Sally
AU - Toncheva, Draga
AU - van den Oord, Edwin
AU - van Os, Jim
AU - van Winkel, Ruud
AU - Veldink, Jan
AU - Walsh, Dermot
AU - Wang, August G.
AU - Wiersma, Durk
AU - Wildenauer, Dieter B.
AU - Williams, Hywel J.
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.
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 - SNPs
KW - genome-wide
KW - imaging
KW - psychiatric
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
C2 - 23039932
AN - SCOPUS:84874542049
VL - 73
SP - 525
EP - 531
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 6
ER -