Abstract
Genetic risk for schizophrenia has a negative impact on memory and other cognitive abilities in unaffected individuals, and it was recently shown that this effect is specific to males. Using functional MRI, we investigated the effect of a polygenic risk score (PRS) for schizophrenia on brain activation during working memory and episodic memory in 351 unaffected participants (167 males and 184 females, 25–95 years), and specifically tested if any effect of PRS on brain activation is sex-specific. Schizophrenia PRS was significantly associated with decreased brain activation in the left dorsolateral prefrontal cortex (DLPFC) during working-memory manipulation and in the bilateral superior parietal lobule (SPL) during episodic-memory encoding and retrieval. A significant interaction effect between sex and PRS was seen in the bilateral SPL during episodic-memory encoding and retrieval, and sex-stratified analyses showed that the effect of PRS on SPL activation was male-specific. These results confirm previous findings of DLPFC inefficiency in schizophrenia, and highlight the SPL as another important genetic intermediate phenotype of the disease. The observed sex differences suggest that the previously shown male-specific effect of schizophrenia PRS on cognition translates into an additional corresponding effect on brain functioning.
Highlights
Schizophrenia is a severe neuropsychiatric disorder that affects about 1% of the population [1]
Using Nagelkerke’s pseudo-R2, we have previously shown that a schizophrenia polygenic risk score (PRS) with the p-value threshold of p ≤ 1 explained the largest amount of variance in cognitive performance [16], and to avoid multiple testing, we used p ≤ 1 for the main functional magnetic resonance imaging (fMRI) analyses including all clumped single-nucleotide polymorphism (SNP) (N = 102,088) from the genome-wide association study (GWAS) summary statistics, and used three PRSs with lower p-value thresholds as described above as sensitivity analyses
Genetic risk for schizophrenia was associated with lower performance on the working memory (WM) and episodic memory (EM) scanner-task as well as longer response time during EM retrieval in males only (Table 2)
Summary
Schizophrenia is a severe neuropsychiatric disorder that affects about 1% of the population [1]. Functional brain activity constitutes an intermediate phenotype that allows disease genetics to be mapped onto related brain processes that are typically altered in schizophrenia patients [32]. Studies on healthy individuals have shown hypoactivation of temporal, prefrontal, and parietal regions during various EM tasks to be associated with high schizophrenia PRS [42]. One fMRI study showed that sex differences in cerebral activations during mental rotation in schizophrenia patients deviated from sex differences observed in healthy volunteers [43], but whether sex differences in brain activation in schizophrenia are related to underlying disease genetics in schizophrenia or in healthy unaffected individuals is not known
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