Schizophrenia polygenic risk score predicts mnemonic hippocampal activity

Abstract

The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.

Figure 1

Association between PRS6 and hippocampus activation during memory encoding in the Lieber discovery sample (A and D), and in Bari (B and E) and DNS (C and F) replication samples. (A–C) Section views (sagittal, coronal and transversal views) of the relationship between PRS6 and functional MRI hippocampal activity during neutral encoding in Lieber sample (A), Bari sample (B), and DNS sample (C), respectively. Genetic risk for schizophrenia is associated with right hippocampal activation (P < 0.05, uncorrected for illustration). (D–F) Scatter plot of the relationship between PRS6 and right posterior hippocampal activity, showing that subjects with greater genetic risk have lower hippocampal activation. In Lieber sample (D), peak activation is at [30, −30, −18] in right posterior hippocampal-parahippocampal region with Z = 4.10, P < 0.001 uncorrected (P = 0.016, FWE corrected within AAL bilateral hippo-parahippocampal mask). In the Bari sample (E), peak of association is at [30, −40, −8], with Z = 3.47, P < 0.001 uncorrected (P = 0.033, FWE corrected within AAL right posterior hippo-parahippocampal mask). In the DNS sample (F), peak of association is at [51, −29, −13], with Z = 2.89, P = 0.002 uncorrected. PRS6 accounted for approximately 8.23% of the variability in hippocampal activity in Lieber sample, and 12.82% and 5.71% for the Bari and DNS samples, respectively.