Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism

摘要

We used a family-based cluster detection approach designed tolocalize significant rare disease–risk variants clusters within a regionof interest to systematically search for schizophrenia (SCZ)susceptibility genes within 49 genomic loci previously implicatedby de novo copy number variants. Using two independent wholeexomesequencing family datasets and a follow-up autism spectrumdisorder (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 locatedin a region on chromosome 15q13.3 implicated by a recurrent copynumber variant, which predisposes to an array of psychiatric andneurodevelopmental phenotypes. In both SCZ and ASD datasets,rare nonsynonymous risk variants cluster significantly in affectedindividuals within a 20-kb window that spans several key functionaldomains of the gene. Our finding suggests that FAN1 is akey driver in the 15q13.3 locus for the associated psychiatric andneurodevelopmental phenotypes. FAN1 encodes a DNA repair enzyme,thus implicating abnormalities in DNA repair in the susceptibilityto SCZ or ASD.