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

Genetic Predisposition to Disease / genetics Humans Multifactorial Inheritance / genetics Psychotic Disorders / genetics Schizophrenia / diagnosis Whole Genome Sequencing

Journal

Molecular psychiatry

ISSN: 1476-5578

Titre abrégé: Mol Psychiatry

Pays: England

ID NLM: 9607835

Informations de publication

Date de publication:
03 2022

Historique:

received: 21 04 2021

accepted: 27 10 2021

revised: 25 10 2021

pubmed: 21 11 2021

medline: 18 5 2022

entrez: 20 11 2021

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41380-021-01383-9 PMID: 34799694

pubmed: 34799694

doi: 10.1038/s41380-021-01383-9

pii: 10.1038/s41380-021-01383-9

doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

Pagination

1435-1447

Subventions

Organisme : NIMH NIH HHS

ID : K23 MH121669

Pays : United States

Organisme : NIMH NIH HHS

ID : U01 MH105670

Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

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