A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains

Wellcome Trust Case Control Consortium 2 (WTCCC2), PEIC, GROUP investigators, Siri Ranlund*, Stella Calafato, Johan H. Thygesen, Kuang Lin, Wiepke Cahn, Benedicto Crespo-Facorro, Sonja M.C. de Zwarte, Álvaro Díez, Marta Di Forti, Conrad Iyegbe, Assen Jablensky, Rebecca Jones, Mei Hua Hall, Rene Kahn, Luba Kalaydjieva, Eugenia Kravariti, Colm McDonaldAndrew M. McIntosh, Andrew McQuillin, Marco Picchioni, Diana P. Prata, Dan Rujescu, Katja Schulze, Madiha Shaikh, Timothea Toulopoulou, Neeltje van Haren, Jim van Os, Evangelos Vassos, Muriel Walshe, Cathryn Lewis, Robin M. Murray, John Powell, Elvira Bramon

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

54 Citations (Scopus)

Abstract

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

Original languageEnglish
Pages (from-to)21-34
Number of pages14
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume177
Issue number1
DOIs
Publication statusPublished - Jan 2018
Externally publishedYes

Bibliographical note

Funding Information:
Wellcome Trust, Grant numbers: 085475/B/ 08/Z, 085475/Z/08/Z; Medical Research Council, Grant number: G0901310; Dutch Health Research Council (ZON-MW), Grant number: 10-000-1001; Instituto de Salud Carlos III, Grant numbers: PI020499, PI050427, PI060507; SENY Fundació, Grant number: CI 2005-0308007; Fundacion Ramón Areces and Fundacion Marqués de Valdecilla, Grant numbers: API07/011, API10/ 13; NIHR Biomedical Research Centre at University College London; The British Medical Association (BMA) Margaret Temple grants 2016 and 2006; The Medical Research Council (MRC)-Korean Health Industry Development Institute Partnering Award, Grant number: MC_PC_16014; National Institute of Health Research UK Post-Doctoral Fellowship; Psychiatry Research Trust; Schizophrenia Research Fund; Wellcome Trust Research Training Fellowship; NIHR Biomedical Research Centre for Mental Health at the South London; Maudsley NHS Foundation Trust and Institute of Psychiatry Kings College London; Brain and Behaviour Research Foundation's (NARSAD's) Young Investigator Award, Grant number: 22604; European Research Council Marie Curie Award

Funding Information:
We would like to thank all the patients, relatives and controls who took part in this research, as well as the clinical staff who facilitated their involvement. This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). We thank the UCL Computer Science Cluster team. This study was supported by the NIHR Biomedical Research Centre at University College London (mental health theme). Further support to E. Bramon: BMA Margaret Temple grants 2016 and 2006, MRC-Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK postdoctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation's NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry Kings College London. Further support: The Brain and Behaviour Research foundation's (NARSAD's) Young Investigator Award (Grant 22604, awarded to C. Iyegbe). The BMA Margaret Temple grant 2016 to Johan Thygesen. European Research Council Marie Curie award to A Díez-Revuelta. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en de kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan Zorggroep, Prins Clauscentrum Sittard, RIAGG Roermond, Universitair Centrum Sint-Jozef Kortenberg, CAPRI

Funding Information:
We would like to thank all the patients, relatives and controls who took part in this research, as well as the clinical staff who facilitated their involvement. This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). We thank the UCL Computer Science Cluster team. This study was supported by the NIHR Biomedical Research Centre at University College London (mental health theme). Further support to E. Bramon: BMA Margaret Temple grants 2016 and 2006, MRC- Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation's NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry Kings College London. Further support: The Brain and Behaviour Research foundation's (NARSAD's) Young Investigator Award (Grant 22604, awarded to C. Iyegbe). The BMA Margaret Temple grant 2016 to Johan Thygesen. European Research Council Marie Curie award to A D?ez-Revuelta. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en de kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan Zorggroep, Prins Clauscentrum Sittard, RIAGG Roermond, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia Psycho-Medical Center [The Hague]. Utrecht: University Medical Center Utrecht and the Mental Health Institutions Altrecht, GGZ Centraal, Riagg Amersfoort and Delta.) The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundaci? (CI 2005-0308007), Fundacion Ram?n Areces and Fundacion Marqu?s de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data.

Funding Information:
University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia Psycho-Medical Center [The Hague]. Utrecht: University Medical Center Utrecht and the Mental Health Institutions Altrecht, GGZ Centraal, Riagg Amersfoort and Delta.) The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data.

Publisher Copyright:
© 2017 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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