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Exome array analysis suggests an increased variant burden in families with schizophrenia

McCarthy, NS, Melton, PE ORCID: 0000-0003-4026-2964, Ward, SV, Allan, SM, Dragovic, M, Clark, ML, Morar, B, Rubio, JP, Blangero, J, Badcock, JC, Morgan, VA, Moses, EK and Jablensky, A 2017 , 'Exome array analysis suggests an increased variant burden in families with schizophrenia' , Schizophrenia Research, vol. 185 , pp. 9-16 , doi: 10.1016/j.schres.2016.12.007.

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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. Multiplexfamilies with multiple affected individuals may be enriched for disease-associated variants of this class comparedto 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 b 2.2E-16). This was pronounced in variants nominally associated (P b 0.05) with schizophrenia.Genes harbouring variants present only inWAFSS cases were enriched (FDR-corrected P = 0.05) for membershipof the ‘extracellular matrix (ECM) - receptor interaction’ biological pathway, adding to evidence that processesaffecting 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 ofexome array variants from previous studies of unrelated samples.

Item Type: Article
Authors/Creators:McCarthy, NS and Melton, PE and Ward, SV and Allan, SM and Dragovic, M and Clark, ML and Morar, B and Rubio, JP and Blangero, J and Badcock, JC and Morgan, VA and Moses, EK and Jablensky, A
Keywords: exome array, family association study, genetics, schizophrenia, Australia
Journal or Publication Title: Schizophrenia Research
Publisher: Elsevier Science Bv
ISSN: 0920-9964
DOI / ID Number: 10.1016/j.schres.2016.12.007
Copyright Information:

© 2016 Elsevier B.V. All rights reserved

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