High-impact rare genetic variants in severe schizophrenia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-12, Vol.118 (51), p.1-10
• Main Authors: Zoghbi, Anthony W., Dhindsa, Ryan S., Goldberg, Terry E., Mehralizade, Aydan, Motelow, Joshua E., Wang, Xinchen, Alkelai, Anna, Harms, Matthew B., Lieberman, Jeffrey A., Markx, Sander, Goldstein, David B.
• Format: Article
• Language: English
• Subjects: Aged; Autism Spectrum Disorder - genetics; Biological Sciences; Case-Control Studies; Developmental Disabilities - genetics; Female; Genes; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic variance; Genetics; Genome-Wide Association Study; Humans; Loss of Function Mutation; Male; Mendelian Randomization Analysis; Mental disorders; Middle Aged; Mutation; Mutation, Missense; Phenotypes; Risk; Schizophrenia; Schizophrenia - genetics; Schizophrenia, Treatment-Resistant - genetics; Severity of Illness Index
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2112560118

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.