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High-impact rare genetic variants in severe schizophrenia.

ABSTRACT: 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.

SUBMITTER: Zoghbi AW

PROVIDER: S-EPMC8713775 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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High-impact rare genetic variants in severe schizophrenia.

Zoghbi Anthony W AW Dhindsa Ryan S RS Goldberg Terry E TE Mehralizade Aydan A Motelow Joshua E JE Wang Xinchen X Alkelai Anna A Harms Matthew B MB Lieberman Jeffrey A JA Markx Sander S Goldstein David B DB

Proceedings of the National Academy of Sciences of the United States of America 20211201 51

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, a ...[more]

PMID: 34903660

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Project description:Abstract Schizophrenia (SZ) is a debilitating psychiatric disorder for which the complex genetic mechanisms underlying the disease state remain unclear. Whereas highly penetrant variants have proven well-suited to human induced pluripotent stem cell (hiPSC)-based models, the power of hiPSC-based studies to resolve the much smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. Overall, we consider the successes and limitations in applying human induced pluripotent stem cell (hiPSC)-based models to study the impact of rare and common variants in SZ risk. To explore the neuronal impact of rare variants, we investigated the relationship between heterozygous 2p16.3 deletions, alternative splicing of NRXN1, and perturbations in neuronal activity, finding some commonalities with idiopathic SZ. We identified ~100 NRXN1α isoforms in control hiPSC neurons; patient-derived 2p16.3 neurons show perturbed NRXN1 isoform repertoires, reduced neuronal branching and decreased neuronal activity, which unexpectedly can be partially ameliorated by overexpression of a single NRXN1 isoform. Second, we present a genetics-driven hiPSC-based CRISPR-mediated approach for the functional validation of common variants and genes associated with SZ, evaluating the impact of one putative causal SZ SNP (FURIN rs4702) and two SZ-associated genes (SNAP91 and TSNARE1) on global gene expression patterns and synaptic function. We predict a growing convergence between hiPSC and post-mortem studies as both approaches expand to larger cohort sizes. We demonstrate a systematic and scalable strategy to interpret and evaluate the growing number of SZ-associated variants and genes across neural cell types and genetic backgrounds. Altogether, our objective is to dissect the genetic origins of SZ while developing a precision medicine approach to screen for novel therapeutics with which to prevent or reverse disease course. Concurrent Symposia

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High-impact rare genetic variants in severe schizophrenia.

Publications

High-impact rare genetic variants in severe schizophrenia.

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