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

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...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2014-01, Vol.111 (1), p.343-348
Hauptverfasser: Ionita-Laza, Iuliana, Xu, Bin, Makarov, Vlad, Buxbaum, Joseph D., Roos, J. Louw, Gogos, Joseph A., Karayiorgou, Maria
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Sprache:eng
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Zusammenfassung: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 whole-exome 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1309475110