High loading of polygenic risk in cases with chronic schizophrenia

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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-R2 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-R2 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.

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We are indebted to all individuals who have participated in, or helped with, our research. The Danish replication samples were genotyped at the Broad Institute and funded by Stanley Center for Psychiatric Research, Broad Institute and the Lundbeck Foundation, within the context of the Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH. We acknowledge Kimberly Chambert and Christine Stevens for laboratory sample management. Dr Mortensen received further funding from the Stanley Medical Research Institute. The German SCZ GWAS sample received funding from the European Community's Seventh Framework Programme (FP7) under grant agreement n° 279227 (Crestar) and the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Programme (grant 01ZX1314A to MMN, grant 01ZX1314G to MR). Dr Wray is funded by Australian National Health and Medical Research Council grants (1078901, 1047956). We thank the Schizophrenia Working Group of the Psychiatric Genomics Consortium for kindly providing us with the summary statistics of their data.

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Correspondence to S M Meier.

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Members of the MooDS SCZ Consortium

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany—Lang M, Strohmaier J, Meier SM, Frank J, Witt SH, Rietschel M; Department of Genomics, Life and Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany—Degenhardt F, Forstner AJ, Propping P, Hoffmann P, Schumacher J, Herms S, Cichon S, Nöthen MM; Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University, Munich, Germany—Schulze TG; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany—Müller-Mhysok B; Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany—Schultz CC, Schlösser RGM, Nenadic I, Sauer H; Department of Psychiatry, University of Bonn, Bonn, Germany—Maier W; Department of Psychiatry, University of Halle-Wittenberg, Halle/Saale, Germany—Rujescu D, Giegling I.

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Meier, S., Agerbo, E., Maier, R. et al. High loading of polygenic risk in cases with chronic schizophrenia. Mol Psychiatry 21, 969–974 (2016) doi:10.1038/mp.2015.130

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