Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis

Martilias Farrell; Tyler E Dietterich; Matthew K Harner; Lisa M Bruno; Dawn M Filmyer; Rita A Shaughnessy; Maya L Lichtenstein; Allison M Britt; Tamara F Biondi; James J Crowley; Gabriel Lázaro-Muñoz; Annika E Forsingdal; Jacob Nielsen; Michael Didriksen; Jonathan S Berg; Jia Wen; Jin Szatkiewicz; Rose Mary Xavier; Patrick F Sullivan; Richard C Josiassen

doi:10.1093/schbul/sbac175

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Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis

Journal article

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Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis

Martilias Farrell, Tyler E Dietterich, Matthew K Harner, Lisa M Bruno, Dawn M Filmyer, Rita A Shaughnessy, Maya L Lichtenstein, Allison M Britt, Tamara F Biondi, James J Crowley, …

Schizophrenia bulletin, v 49(4), pp 881-892

04 Jul 2023

DOI: https://doi.org/10.1093/schbul/sbac175

PMID: 36454006

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Abstract

Cohort Studies

DNA Copy Number Variations - genetics

Genetic Predisposition to Disease

Humans

Prevalence

Psychotic Disorders - drug therapy

Psychotic Disorders - epidemiology

Psychotic Disorders - genetics

Schizophrenia - drug therapy

Schizophrenia - epidemiology

Schizophrenia - genetics

It remains unknown why ~30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations of treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we identified schizophrenia-associated CNVs in patients with treatment-resistant psychotic symptoms and then compared the prevalence of these CNVs to previously published schizophrenia cases not selected for treatment resistance. CNVs were identified using chromosomal microarray (CMA) and whole exome sequencing (WES) in 509 patients with treatment-resistant psychosis (a lack of clinical response to ≥3 adequate antipsychotic medication trials over at least 5 years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared to that in a previously published large schizophrenia cohort study. Integrating CMA and WES data, we identified 47 cases (9.2%) with at least one CNV of known or possible neuropsychiatric risk. 4.7% (n = 24) carried a known neurodevelopmental risk CNV. The prevalence of well-replicated schizophrenia-associated CNVs was 4.1%, with duplications of the 16p11.2 and 15q11.2-q13.1 regions, and deletions of the 22q11.2 chromosomal region as the most frequent CNVs. Pairwise loci-based analysis identified duplications of 15q11.2-q13.1 to be independently associated with treatment resistance. These findings suggest that CNVs may uniquely impact clinical phenotypes beyond increasing risk for schizophrenia and may potentially serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs.

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17 citations in Web of Science

15 citations in Scopus

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Title: Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis
Creators: Martilias Farrell - University of North Carolina at Chapel Hill
Tyler E Dietterich - Translational Neuroscience, LLC, Conshohocken, PA, USA
Matthew K Harner - Translational Neuroscience, LLC, Conshohocken, PA, USA
Lisa M Bruno - Translational Neuroscience, LLC, Conshohocken, PA, USA
Dawn M Filmyer - Translational Neuroscience, LLC, Conshohocken, PA, USA
Rita A Shaughnessy - Translational Neuroscience, LLC, Conshohocken, PA, USA
Maya L Lichtenstein - Geisinger Health System
Allison M Britt - University of North Carolina at Chapel Hill
Tamara F Biondi - University of North Carolina at Chapel Hill
James J Crowley - University of North Carolina at Chapel Hill
Gabriel Lázaro-Muñoz - Massachusetts General Hospital
Annika E Forsingdal - Lundbeck (Denmark)
Jacob Nielsen - Lundbeck (Denmark)
Michael Didriksen - Lundbeck (Denmark)
Jonathan S Berg - University of North Carolina at Chapel Hill
Jia Wen - University of North Carolina at Chapel Hill
Jin Szatkiewicz - University of North Carolina at Chapel Hill
Rose Mary Xavier - University of North Carolina at Chapel Hill
Patrick F Sullivan - University of North Carolina at Chapel Hill
Richard C Josiassen - Translational Neuroscience, LLC, Conshohocken, PA, USA
Publication Details: Schizophrenia bulletin, v 49(4), pp 881-892
Publisher: Oxford University Press
Grant note: K01 MH108894 / NIMH NIH HHS T32 ES007018 / NIEHS NIH HHS R01 MH106611 / NIMH NIH HHS K99 HG008689 / NHGRI NIH HHS R01 MH110427 / NIMH NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: Psychiatry
Web of Science ID: WOS:000892802300001
Scopus ID: 2-s2.0-85164235301
Other Identifier: 991021889913604721

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Web of Science research areas: Psychiatry

Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis

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Abstract

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Details

UN Sustainable Development Goals (SDGs)

InCites Highlights

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