High loading of polygenic risk in cases with chronic schizophrenia.
Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R(2) and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R(2) values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (Ptarget=0.017, Preplication=0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvementtarget= 50%; improvementreplication= 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness.
National Centre for Register-Based Research, Aarhus University, Aarhus C, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
S M
SM
Meier
National Centre for Register-Based Research, Aarhus University, Aarhus C, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Centre for Integrated Register-based Research, Aarhus University, Aarhus C, Denmark.
E
0000-0002-2849-524X
E
Agerbo
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
R
R
Maier
National Centre for Register-Based Research, Aarhus University, Aarhus C, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Centre for Integrated Register-based Research, Aarhus University, Aarhus C, Denmark.
C B
CB
Pedersen
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
M
M
Lang
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.|Bioinformatics Research Centre, Aarhus University, Aarhus C, Denmark.|Centre for integrative Sequencing (iSEQ), Aarhus University, Aarhus C, Denmark.
J
J
Grove
Danish Centre for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
M V
MV
Hollegaard
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.|Centre for integrative Sequencing (iSEQ), Aarhus University, Aarhus C, Denmark.
D
D
Demontis
National Centre for Register-Based Research, Aarhus University, Aarhus C, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
B B
BB
Trabjerg
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.|Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
C
C
Hjorthøj
Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
S
0000-0003-3622-835X
S
Ripke
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
F
F
Degenhardt
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
M M
MM
Nöthen
Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
D
D
Rujescu
Department of Psychiatry, University of Bonn, Bonn, Germany.
W
W
Maier
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
T
T
Werge
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
O
O
Mors
Danish Centre for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
D M
DM
Hougaard
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.|Centre for integrative Sequencing (iSEQ), Aarhus University, Aarhus C, Denmark.|Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
A D
AD
Børglum
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
N R
NR
Wray
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
M
M
Rietschel
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.|Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
M
M
Nordentoft
National Centre for Register-Based Research, Aarhus University, Aarhus C, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Centre for Integrated Register-based Research, Aarhus University, Aarhus C, Denmark.|Centre for integrative Sequencing (iSEQ), Aarhus University, Aarhus C, Denmark.
P B
PB
Mortensen
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.|Centre for integrative Sequencing (iSEQ), Aarhus University, Aarhus C, Denmark.|Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
M
M
Mattheisen
D000328:Adult; D016022:Case-Control Studies; D003718:Denmark; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005858:Germany; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D012680:Sensitivity and Specificity