Investigation of the Genetic Association between Quantitative Measures of Psychosis and Schizophrenia: A Polygenic Risk Score Analysis

The presence of subclinical levels of psychosis in the general population may imply that schizophrenia is the extreme expression of more or less continuously distributed traits in the population. In a previous study, we identified five quantitative measures of schizophrenia (positive, negative, disorganisation, mania, and depression scores). The aim of this study is to examine the association between a direct measure of genetic risk of schizophrenia and the five quantitative measures of psychosis. Estimates of the log of the odds ratios of case/control allelic association tests were obtained from the Psychiatric GWAS Consortium (PGC) (minus our sample) which included genome-wide genotype data of 8,690 schizophrenia cases and 11,831 controls. These data were used to calculate genetic risk scores in 314 schizophrenia cases and 148 controls from the Netherlands for whom genotype data and quantitative symptom scores were available. The genetic risk score of schizophrenia was significantly associated with case-control status (p<0.0001). In the case-control sample, the five psychosis dimensions were found to be significantly associated with genetic risk scores; the correlations ranged between.15 and.27 (all p<.001). However, these correlations were not significant in schizophrenia cases or controls separately. While this study confirms the presence of a genetic risk for schizophrenia as categorical diagnostic trait, we did not find evidence for the genetic risk underlying quantitative schizophrenia symptom dimensions. This does not necessarily imply that a genetic basis is nonexistent, but does suggest that it is distinct from the polygenic risk score for schizophrenia.

[1]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[2]  G. Kirov,et al.  Polygenic dissection of the bipolar phenotype , 2011, British Journal of Psychiatry.

[3]  N C Andreasen,et al.  The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. , 1992, Archives of general psychiatry.

[4]  A. Fanous,et al.  Genetics of clinical features and subtypes of schizophrenia: A review of the recent literature , 2008, Current psychiatry reports.

[5]  Thomas W. Mühleisen,et al.  Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe , 2012, Molecular Psychiatry.

[6]  Jim van Os,et al.  Testing the psychosis continuum: differential impact of genetic and nongenetic risk factors and comorbid psychopathology across the entire spectrum of psychosis. , 2012, Schizophrenia bulletin.

[7]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[8]  R. Ophoff,et al.  Kraepelin was right: a latent class analysis of symptom dimensions in patients and controls. , 2012, Schizophrenia bulletin.

[9]  M. Owen,et al.  The genetic basis of complex human behaviors. , 1994, Science.

[10]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[11]  V. Peralta,et al.  How many and which are the psychopathological dimensions in schizophrenia? Issues influencing their ascertainment , 2001, Schizophrenia Research.

[12]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[13]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[14]  Anders D. Børglum,et al.  Genome-wide association study identifies five new schizophrenia loci , 2011, Nature Genetics.

[15]  Jim van Os,et al.  Strauss (1969) revisited: a psychosis continuum in the general population? , 2000, Schizophrenia Research.

[16]  R. Murray,et al.  Twin study of symptom dimensions in psychoses , 2001, British Journal of Psychiatry.

[17]  I. Skre,et al.  Schizotypal personality disorder inside and outside the schizophrenic spectrum , 2002, Schizophrenia Research.

[18]  R. Ophoff,et al.  The genetics of symptom dimensions of schizophrenia: Review and meta-analysis , 2008, Schizophrenia Research.

[19]  A. Fanous,et al.  Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework , 2006, Molecular Psychiatry.

[20]  J. Os,et al.  A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness–persistence–impairment model of psychotic disorder , 2008, Psychological Medicine.