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The benefit of diagnostic whole genome sequencing in schizophrenia and other psychotic disorders

Abstract

Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N = 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6 genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families.

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Fig. 1: Demographic and clinical characteristics of participants.
Fig. 2: Detection and classification of clinically relevant variants.
Fig. 3: Case/control enrichment of qualified variants in selected gene sets.

Data availability

WGS data from consenting participants is available via the ATAV data browser (http://atavdb.org/) and will be deposited in dbGaP (44515). ATAV code is freely provided on GitHub at https://github.com/nickzren/atav.

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Acknowledgements

This paper is dedicated to the memory of Prof. Deborah L. Levy, PhD, Director of the Psychology Research Laboratory at McLean Hospital and Associate Professor of Psychiatry, Harvard Medical School, who passed away while this paper was being prepared. Research reported in this publication was funded by the National Institute of Mental Health (5U01MH105670).

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AA, LG, ARD, ELH, AEP, VA, and DBG designed the study and supervised the project. BL, AEP, SLD, and MBH enrolled and phenotyped participants EPP and JM contributed to data collection and sample preparation. DH, AM GP, and AA developed analysis tools and generated the data AA, LG, AAS, ARD, GP, AM, DH, SG, EHB, AWZ, HH, VJ, ELH, VA, and AG analyzed the data AA and LG wrote the manuscript with input from all authors. All authors reviewed the manuscript.

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Correspondence to Anna Alkelai.

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DBG reports holding equity in the publicly traded precision medicine company Praxis Precision Medicine, Apostle Inc, and Q-State Biosciences and has in the past been a paid advisor to AstraZeneca, Gilead Sciences, GoldFinch Bio, and Johnson & Johnson.

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Alkelai, A., Greenbaum, L., Docherty, A.R. et al. The benefit of diagnostic whole genome sequencing in schizophrenia and other psychotic disorders. Mol Psychiatry 27, 1435–1447 (2022). https://doi.org/10.1038/s41380-021-01383-9

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