title: Exome array analysis suggests an increased variant burden in families with schizophrenia.
abstract: The exome array assays rare-but-recurrent, likely deleterious, exonic variants and represents an intermediary between single nucleotide polymorphism (SNP) arrays and sequencing for genetic association studies. Multiplex families with multiple affected individuals may be enriched for disease-associated variants of this class compared to unrelated populations. We present an exome array study of schizophrenia in 99 multiplex families (n=341, including 118 cases) from the Western Australian Family Study of Schizophrenia (WAFSS). Compared to 55,726 individuals from the DIAGRAM sample not selected for schizophrenia, overall allele frequency of exome variants was higher in the WAFSS (P<2.2E-16). This was pronounced in variants nominally associated (P<0.05) with schizophrenia. Genes harbouring variants present only in WAFSS cases were enriched (FDR-corrected P=0.05) for membership of the 'extracellular matrix (ECM) - receptor interaction' biological pathway, adding to evidence that processes affecting the composition or turnover of ECM may contribute to neuropsychiatric disease. We did not find individual variants significantly associated with schizophrenia, although like previous studies, power to detect associations of small effect size was low. Cases did not exhibit a higher burden of variants compared to their unaffected relatives and the finding of previous exome chip studies of unrelated samples that 'schizophrenia gene-sets' were enriched for case-only variants was not replicated in the WAFSS. The higher frequency of moderately rare, exonic variants in these multiplex families compared to a population-based sample may account for some of their genetic liability to schizophrenia, and adds to evidence for a role of exome array variants from previous studies of unrelated samples.
authors.affiliation: Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia and Faculty of Health 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.
authors.forename: Nina S
authors.initials: NS
authors.lastname: McCarthy
authors.affiliation: Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia and Faculty of Health Sciences, Curtin University, MRF Building, 50 Murray St, Perth, WA 6000, Australia.
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Melton
authors.affiliation: Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia and Faculty of Health Sciences, Curtin University, MRF Building, 50 Murray St, Perth, WA 6000, Australia.
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Ward
authors.affiliation: Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia and Faculty of Health Sciences, Curtin University, MRF Building, 50 Murray St, Perth, WA 6000, Australia.
authors.forename: Spencer M
authors.initials: SM
authors.lastname: Allan
authors.affiliation: Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia.
authors.forename: Milan
authors.initials: M
authors.lastname: Dragovic
authors.affiliation: Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Clark
authors.affiliation: 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.
authors.forename: Bharti
authors.initials: B
authors.lastname: Morar
authors.affiliation: Department of Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, VIC 3010, Australia; The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
authors.affiliation: South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley, One West University Blvd, Brownsville, TX 78520, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: 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.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Badcock
authors.affiliation: Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia; Neuropsychiatric Epidemiology Research Unit, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia.
authors.forename: Vera A
authors.initials: VA
authors.lastname: Morgan
authors.affiliation: Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia and Faculty of Health Sciences, Curtin University, MRF Building, 50 Murray St, Perth, WA 6000, Australia.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Moses
authors.affiliation: 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.
authors.forename: Assen
authors.initials: A
authors.lastname: Jablensky
mesh_terms: D059472:Exome / Q000235:genetics*; D005109:Extracellular Matrix / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
keywords: Exome array; Family association study; Genetics