Introduction
(June 4, 2015) Schizophrenia is a highly heritable disorder, the genetic
architecture of which includes a large number of alleles spanning the full
spectrum of frequencies. It has been estimated that the additive effects of
common variation, as indexed by alleles represented on the platforms used in
genome-wide association studies (GWASs), contribute around a quarter to a third
of the total population variance in schizophrenia liability. However, the 108
genome-wide-associated common variant loci reported in the largest GWAS study
to date only explain a small fraction of this contribution. An increased burden
of rare mutations has also been documented in schizophrenia, taking the form of
both large CNVs and single-nucleotide variants (SNVs), which often occur as de
novo mutations. While several CNVs have been implicated in the disorder, no
individual SNV has yet been robustly associated. The CNVs (n = 11) strongly
associated with schizophrenia in the largest systematic survey to date are in
general large in both size (> 500 kb) and effect (ORs 2–60), the latter
being in stark contrast with the small effects conferred by common alleles
(typical OR < 1.1).