Abstract:
We used a family-based cluster detection approach designed to
localize significant rare disease–risk variants clusters within a region
of interest to systematically search for schizophrenia (SCZ)
susceptibility genes within 49 genomic loci previously implicated
by de novo copy number variants. Using two independent wholeexome
sequencing family datasets and a follow-up autism spectrum
disorder (ASD) case/control whole-exome sequencing dataset,
we identified variants in one gene, Fanconi-associated nuclease 1
(FAN1), as being associated with both SCZ and ASD. FAN1 is located
in a region on chromosome 15q13.3 implicated by a recurrent copy
number variant, which predisposes to an array of psychiatric and
neurodevelopmental phenotypes. In both SCZ and ASD datasets,
rare nonsynonymous risk variants cluster significantly in affected
individuals within a 20-kb window that spans several key functional
domains of the gene. Our finding suggests that FAN1 is a
key driver in the 15q13.3 locus for the associated psychiatric and
neurodevelopmental phenotypes. FAN1 encodes a DNA repair enzyme,
thus implicating abnormalities in DNA repair in the susceptibility
to SCZ or ASD.
