“High-Impact Rare Genetic Variants in Severe Schizophrenia”, 2021-12-21 (; similar):
In this study, we found that selecting individuals with extremely severe forms of schizophrenia led to a substantially improved ability to detect disease-associated rare variants. The high prevalence of rare variant risk factors in individuals with severe, extremely treatment-resistant schizophrenia suggests future clinical opportunities for risk prediction, prognostic stratification, and genetic counseling. These findings have implications for the design of future genetic studies in schizophrenia and highlight a strategy to reduce phenotypic heterogeneity and improve gene discovery efforts in other neuropsychiatric disorders.
Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia.
We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes.
Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; p = 7.8 × 10−5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; p = 3.2 × 10−9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; p = 1.6 × 10−3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; p = 2.9 × 10−7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; p = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; p = 2.6 × 10−8).
These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.
[Keywords: schizophrenia, genomics, rare variants, treatment-resistant schizophrenia]