Replicated evidence that endophenotypic expression of schizophrenia polygenic risk is greater in healthy siblings of patients compared to controls, suggesting gene–environment interaction. The EUGEI study

Abstract

Background First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes. Methods We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS. Results In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group. Conclusions The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.

Polygenic Risk Scores Shed Light on the Relationship between Schizophrenia and Cognitive Functioning: Review and Meta-Analysis

“…The genetic study by [54] reveal that current SZ diagnoses aggregate over at least two disease subtypes: one part resembles high intelligence and bipolar disorder, while the other part is a cognitive disorder (independent of bipolar disorder). SZ PRS would then predict lower cognitive functioning in patients of the latter group (conflation between diagnosis and prognosis, as suggested by [72]).…”

“…A recent study with a replication sample failed to show intermediate neurocognitive phenotypes in control samples with high PRS [72]. Interestingly, an intermediate phenotype was observed in sibling with high PRS (subthreshold psychotic phenotype, jumping to conclusion bias), while no cognitive dysfunction was observed nor in the sibling nor in the control sample, showing that in the absence of a sibling with psychotic disorder, expression of polygenic risk may even be protective against expression of psychosis proneness, as also reported by others [61] or constitute an advantage (e.g., for creativity, as reported by [52]).…”

“…They thus hypothesize that higher rates of expression of psychosis intermediate phenotypes in sibling is not because of higher levels of genetic risk, but because of genetic risk interacting with higher rates of exposure to environmental risks in this group (shared environmental exposure with their affected relatives, for example urbanicity, childhood trauma, cannabis). Concerning the lack of association between neurocognition and SZ PRS in controls and siblings, authors suggest that variation in cognition as observed in schizophrenia may represent a 'prognostic' rather than a 'disease' factor [72]. Schizophrenia would represent the poorer outcome of a much broader psychotic phenotype, associated with cognitive alterations comorbidity.…”

Interaction between polygenic liability for schizophrenia and childhood adversity influences daily-life emotional dysregulation and psychosis proneness

“…These studies in healthy participants have shown inconsistent results (61)(62)(63)(64)(65)(66). Some reported no association between PRS-S and several symptoms dimensions (63,67), while others reported negative associations between polygenic risk and schizotypy (64,67). In addition, in the rare instances where it has been examined, PRS-S appear to contribute to abilities required for a creative profession (68).…”

Study investigating executive function in schizophrenia patients and their unaffected siblings

“…Although evidence suggests that executive impairment is consistent with disease progression, the current damaging mechanism is still unclear. Decades of family, twin, and adoption studies have shown that the effects of substantial genetic components on risk have a certain contribution to environmental impact, but how schizophrenia is transmitted is complex, and convergence evidence supports highly polygenic structures [10,11].Both patients and their unaffected siblings exhibit cognitive function impairments, such as social cognition, working memory, and attention [12,13]. Since early intervention can help prevent and delay the onset of psychosis, it is necessary to identify a biomarker that can identify individuals at a higher risk of developing schizophrenia early [14].…”