Impact of polygenic schizophrenia-related risk and hippocampal volumes on the onset of psychosis.

F Harrisberger,A E Simon,C Lenz,A Riecher-Rössler,R Smieskova,C Vogler,T Egli,S Borgwardt,A Papassotiropoulos,A Schmidt

doi:10.1038/tp.2016.143

Abstract

Alterations in hippocampal volume are a known marker for first-episode psychosis (FEP) as well as for the clinical high-risk state. The Polygenic Schizophrenia-related Risk Score (PSRS), derived from a large case–control study, indicates the polygenic predisposition for schizophrenia in our clinical sample. A total of 65 at-risk mental state (ARMS) and FEP patients underwent structural magnetic resonance imaging. We used automatic segmentation of hippocampal volumes using the FSL-FIRST software and an odds-ratio-weighted PSRS based on the publicly available top single-nucleotide polymorphisms from the Psychiatric Genomics Consortium genome-wide association study (GWAS). We observed a negative association between the PSRS and hippocampal volumes (β=−0.42, P=0.01, 95% confidence interval (CI)=(−0.72 to −0.12)) across FEP and ARMS patients. Moreover, a higher PSRS was significantly associated with a higher probability of an individual being assigned to the FEP group relative to the ARMS group (β=0.64, P=0.03, 95% CI=(0.08–1.29)). These findings provide evidence that a subset of schizophrenia risk variants is negatively associated with hippocampal volumes, and higher values of this PSRS are significantly associated with FEP compared with the ARMS. This implies that FEP patients have a higher genetic risk for schizophrenia than the total cohort of ARMS patients. The identification of associations between genetic risk variants and structural brain alterations will increase our understanding of the neurobiology underlying the transition to psychosis.

Highlights

Schizophrenia can be a severe mental disorder, affecting ~ 1% of the population.[1]
On the basis of findings supporting a role for hippocampal alterations in first-episode psychosis (FEP) and even in the at-risk mental state (ARMS),[10,11,12,13,14] we aimed to explore the association between the Polygenic Schizophrenia-related Risk Score (PSRS), hippocampal volume and the onset of psychosis
Linear regression analysis revealed a significant relationship between the PSRS and hippocampal volumes (β = − 0.42, P = 0.01, 95% confidence interval (CI) = (−0.72 to − 0.12), Table 2) in our total sample and the subgroup of ARMS individuals (β = − 0.51, P = 0.02, 95% CI = (−0.94 to − 0.08), Figure 1, Table 2) and FEP patients separately (β = − 0.41, P = 0.05, 95% CI = (−0.83 to 0.01), Figure 1, Table 2)

Summary

Introduction

Schizophrenia can be a severe mental disorder, affecting ~ 1% of the population.[1]. the pathophysiological mechanisms underlying schizophrenia are still poorly understood, it is known that genetic factors and combinations thereof (that is, singlenucleotide polymorphisms (SNP), copy-number variations or mutations) are involved in disease aetiology, as is indicated by the substantial heritability estimates for schizophrenia.[2]. Results are inconsistent in the differences in hippocampal volume between first-episode psychosis (FEP) patients and ARMS individuals, regardless of future transition to psychosis.[10,11,17] hippocampal volumes were shown to be highly heritable in twin studies of healthy individuals;[18,19] twin studies where one of the twins was affected by schizophrenia revealed substantial modulation of hippocampal volumes by environmental factors.[20,21,22,23] In addition, moderate genetic heritability of the hippocampal volumes was shown in large extended families affected with schizophrenia.[24]

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Methods

Results

Conclusion