Whole genome sequencing of 91 multiplex schizophrenia families reveals increased burden of rare, exonic copy number variation in schizophrenia probands and genetic heterogeneity

Fayeza F Khan; Phillip E Melton; Nina S McCarthy; Bharti Morar; John Blangero; Eric K Moses; Assen Jablensky

doi:10.1016/j.schres.2018.02.034

Whole genome sequencing of 91 multiplex schizophrenia families reveals increased burden of rare, exonic copy number variation in schizophrenia probands and genetic heterogeneity

Schizophr Res. 2018 Jul:197:337-345. doi: 10.1016/j.schres.2018.02.034. Epub 2018 Feb 24.

Authors

Fayeza F Khan¹, Phillip E Melton², Nina S McCarthy³, Bharti Morar⁴, John Blangero⁵, Eric K Moses⁶, Assen Jablensky⁷

Affiliations

¹ Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia and School of Biomedical Sciences, Curtin University, MRF Building, 50 Murray St., Perth, WA 6000, Australia. Electronic address: fayeza.khan@uwa.edu.au.
² Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia and School of Biomedical Sciences, Curtin University, MRF Building, 50 Murray St., Perth, WA 6000, Australia. Electronic address: phillip.melton@uwa.edu.au.
³ Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia and School of Biomedical Sciences, Curtin University, MRF Building, 50 Murray St., Perth, WA 6000, Australia; Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia; Cooperative Research Centre for Mental Health, Carlton, South Victoria, Australia. Electronic address: nina.mccarthy@uwa.edu.au.
⁴ Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia; Cooperative Research Centre for Mental Health, Carlton, South Victoria, Australia; Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, 6 Verdun Street, Nedlands, WA 6009, Australia. Electronic address: bharti.morar@perkins.uwa.edu.au.
⁵ South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley, One West University Blvd, Brownsville, TX 78520, USA. Electronic address: john.blangero@utrgv.edu.
⁶ Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia and School of Biomedical Sciences, Curtin University, MRF Building, 50 Murray St., Perth, WA 6000, Australia. Electronic address: eric.moses@uwa.edu.au.
⁷ Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia; Cooperative Research Centre for Mental Health, Carlton, South Victoria, Australia. Electronic address: assen.jablensky@uwa.edu.au.

PMID: 29486958
DOI: 10.1016/j.schres.2018.02.034

Abstract

The importance of genomic copy number variants (CNVs) has long been recognized in the etiology of neurodevelopmental diseases. We report here the results from the CNV analysis of whole-genome sequences from 91 multiplex schizophrenia families. Employing four algorithms (CNVnator, Cn.mops, DELLY and LUMPY) to identify CNVs, we find 1231 rare deletions and 287 rare duplications in 300 individuals (77 with schizophrenia (SZ), 32 with schizoaffective disorder (SAD), 82 with another neuropsychiatric diagnosis and 109 unaffected). The size of the CNVs ranges from a few hundred base-pairs to about 1.3Mb. The total burden of CNVs does not differ significantly between affected (SZ and SAD) and unaffected individuals. Parent-to-child transmission rate for rare CNVs affecting exonic regions is significantly higher for affected (SZ and SAD) probands as compared to their siblings, but rates for all CNVs is not. We observe heterogeneity between families in terms of genes involved in CNVs, and find several CNVs involving genes previously implicated in either schizophrenia or other neuropsychiatric disorders.

Keywords: Copy number variation; Family study; Schizophrenia; Whole-genome sequence.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
DNA Copy Number Variations*
Exons / genetics*
Genetic Heterogeneity*
Humans
Parents
Pedigree
Psychotic Disorders / genetics*
Schizophrenia / genetics*
Siblings
Western Australia
Whole Genome Sequencing*