PT  - JOURNAL ARTICLE
AU  - Jin P. Szatkiewicz
AU  - Menachem Fromer
AU  - Randal J. Nonneman
AU  - NaEshia Ancalade
AU  - Jessica S. Johnson
AU  - Eli A. Stahl
AU  - Elliott Rees
AU  - Sarah Bergen
AU  - Christina Hultman
AU  - George Kirov
AU  - Michael O’Donovan
AU  - Michael Owen
AU  - Peter Holmans
AU  - Pamela Sklar
AU  - Patrick F. Sullivan
AU  - Shaun M. Purcell
AU  - James J. Crowley
AU  - Douglas M. Ruderfer
TI  - Characterization of single gene copy number variants in schizophrenia
AID  - 10.1101/550863
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 550863
4099  - http://biorxiv.org/content/early/2019/02/15/550863.short
4100  - http://biorxiv.org/content/early/2019/02/15/550863.full
AB  - Genetic studies of schizophrenia (SCZ) have now implicated numerous genomic loci that contribute to risk including several copy number variants (CNV) of large effect and hundreds of associated loci of small effect. However, in only a few cases has a specific gene been clearly identified. Rare CNV that affect only a single gene offer a potential avenue to discovering specific SCZ risk genes. Here, we use CNV generated from exome-sequencing of 4,913 SCZ cases and 6,188 controls in a homogenous Swedish cohort to assess the contribution of single-gene deletions and duplications to SCZ risk. As previously seen, we found an excess of rare deletions (p = 0.0004) and duplications (p = 0.0006) in SCZ cases compared to controls. When limiting to only single-gene CNV we identified nominally significant excess of deletions (p = 0.04) and duplications (p = 0.03). In an effort to increase the number of single-gene CNV, we reduced strict filtering criteria but required support from two independent CNV calling methods to create an expanded set that showed a significant burden of deletions in 11 out of 22 gene sets previously implicated in SCZ and in the combined set of genes across those sets (p = 0.008). Finally, for the significantly enriched set of voltage-gated calcium channels, we performed an extensive validation of all deletions generated from exome-sequencing as well as any deletion with evidence from previously analyzed genotyping arrays. In total, 4 exonic, single-gene deletions validated in cases and none in controls (p = 0.039), of which all were identified by exome-sequencing. Broadly, these results point to the potential contribution of single-gene CNV to SCZ and the added value of a deeper dive into CNV calls from exome-sequencing.