Abstract
Genotype-first and within-family studies can elucidate factors that contribute to psychiatric illness. Combining these approaches, we investigated the patterns of influence of parental scores, a high-impact variant, and schizophrenia on dimensional neurobehavioral phenotypes implicated in major psychiatric disorders. We quantitatively assessed cognitive (FSIQ, VIQ, PIQ), social, and motor functioning in 82 adult individuals with a de novo 22q11.2 deletion (22 with schizophrenia), and 148 of their unaffected parents. We calculated within-family correlations and effect sizes of the 22q11.2 deletion and schizophrenia, and used linear regressions to assess contributions to neurobehavioral measures. Proband-parent intra-class correlations (ICC) were significant for cognitive measures (e.g. FSIQ ICC = 0.549, p < 0.0001), but not for social or motor measures. Compared to biparental scores, the 22q11.2 deletion conferred significant impairments for all phenotypes assessed (effect sizes -1.39 to -2.07 s.d.), strongest for PIQ. There were further decrements in those with schizophrenia. Regression models explained up to 37.7% of the variance in IQ and indicated that for proband IQ, parental IQ had larger effects than schizophrenia. This study, for the first time, disentangles the impact of a high-impact variant from the modifying effects of parental scores and schizophrenia on relevant neurobehavioral phenotypes. The robust proband-parent correlations for cognitive measures, independent of the impact of the 22q11.2 deletion and of schizophrenia, suggest that, for certain phenotypes, shared genetic variation plays a significant role in expression. Molecular genetic and predictor studies are needed to elucidate shared factors and their contribution to psychiatric illness in this and other high-risk groups.
Highlights
The dimensional study of clinical and behavioral phenotypes can further our understanding of the etiologies of major neuropsychiatric disorders (Nelson, McGorry, Wichers, Wigman, & Hartmann, 2017; Sonuga-Barke, 2014)
Examining the dimensional trait results within these main subgroups allowed us to estimate the relative effect sizes of the de novo 22q11.2 deletion and of expression of schizophrenia, anchored by expected results based on parental scores
For those with no psychotic illness, the differences between proband and parental mean scores indicated that the 22q11.2 deletion exerts a deleterious impact of −1.93 S.D. (FSIQ), −1.47 S.D. (VIQ), −2.07 S.D. (PIQ), −1.39 S.D. (SRS), and −1.39 S.D. (Purdue), i.e., substantial for all phenotypes and with the largest effect size for performance IQ (PIQ) (Fig. 1)
Summary
The dimensional study of clinical and behavioral phenotypes can further our understanding of the etiologies of major neuropsychiatric disorders (Nelson, McGorry, Wichers, Wigman, & Hartmann, 2017; Sonuga-Barke, 2014). Genotype-first and within-family studies can elucidate factors that contribute to psychiatric illness. Combining these approaches, we investigated the patterns of influence of parental scores, a high-impact variant, and schizophrenia on dimensional neurobehavioral phenotypes implicated in major psychiatric disorders. We calculated within-family correlations and effect sizes of the 22q11.2 deletion and schizophrenia, and used linear regressions to assess contributions to neurobehavioral measures. This study, for the first time, disentangles the impact of a high-impact variant from the modifying effects of parental scores and schizophrenia on relevant neurobehavioral phenotypes. The robust proband-parent correlations for cognitive measures, independent of the impact of the 22q11.2 deletion and of schizophrenia, suggest that, for certain phenotypes, shared genetic variation plays a significant role in expression. Molecular genetic and predictor studies are needed to elucidate shared factors and their contribution to psychiatric illness in this and other high-risk groups
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