Abstract:
Loss-of-function (LOF) (i.e., nonsense, splice site,
and frameshift) variants that lead to disruption of
gene function are likely to contribute to the etiology
of neuropsychiatric disorders. Here, we perform a
systematic investigation of the role of both de novo
and inherited LOF variants in schizophrenia using
exome sequencing data from 231 case and 34 control
trios. We identify two de novo LOF variants in
the SETD1A gene, which encodes a subunit of histone
methyltransferase, a finding unlikely to have
occurred by chance, and provide evidence for a
more general role of chromatin regulators in schizophrenia
risk. Transmission pattern analyses reveal
that LOF variants are more likely to be transmitted
to affected individuals than controls. This is especially
true for private LOF variants in genes intolerant
to functional genetic variation. These findings highlight
the contribution of LOF mutations to the genetic
architecture of schizophrenia and provide important
insights into disease pathogenesis.
