69. Exploring Polygenic Risk in Cognitive Subgroups of Schizophrenia: Associations Between Risk Profile Scores and Measures of Cognition

摘要

>Background: The purpose of this study was to evaluate associations between cognition and risk profile scores (RPS), at varying levels of specificity, for schizophrenia patients divided into three subgroups previously determined by premorbid and fluid intelligence. >Methods: 550 people with schizophrenia, 432 of their unaffected siblings, and 1127 community controls provided demographic and clinical information, completed cognitive and symptom assessments and provided blood for genetics analyses, as part of the NIMH Study of Schizophrenia Genetics. We performed cluster analyses (SPSS) in the schizophrenia cases to identify cognitive subgroups, using only “premorbid” (WRAT) and “current” (WAIS) IQ as clustering indicators, with the hypothesis that different patterns of performance identify subgroups with different trajectories of cognitive development. Schizophrenia RPS for all individuals were calculated at different thresholds based on illness-associated genetic variants identified by the multi-national Psychiatric Genetics Consortium. Across RPS thresholds, we used planned hierarchical regression to test the association of RPS with general cognitive ability (“g”) in the derived cognitive subgroups, controlling for age, sex, and population stratification. >Results: Based on 1000 runs, three cluster solutions were, by far, the most frequent and parsimonious result for the cluster analyses, suggesting one subgroup with high scores on both WRAT and IQ (HH), one with low scores on both WRAT and IQ (LL), and one with high scores on the WRAT and low IQ (HL). Cognitive performance was significantly impaired and RPS scores were significantly elevated in all schizophrenia groups relative to controls. The HH subgroup showed significant associations between RPS and “g” at six of 10 RPS thresholds (e.g., at RPS_0.05 P = .002; R² = .047). The LL subgroup showed a pattern of similar but non-significant associations. However, the HL subgroup showed no evidence of association of schizophrenia RPS with “g” at any threshold. >Conclusion: Cognitive impairment is recognized as a core feature of schizophrenia. These analyses suggest, further, that for some individuals with schizophrenia (HH), common genetic risk for the condition is also predictive of cognitive impairment. It is striking, however, that for another subgroup (HL), polygenic risk for schizophrenia is entirely “decoupled” from cognition. These differences in cognitive profile and in the association of cognitive performance with common genetic risk for schizophrenia may point to important distinctions in etiology.