title: Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism.
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 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.
authors.affiliation: Departments of Biostatistics, Psychiatry, Neuroscience, Physiology, and Cellular Biophysics, Columbia University, New York, NY 10032.
authors.forename: Iuliana
authors.initials: I
authors.lastname: Ionita-Laza
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Vlad
authors.initials: V
authors.lastname: Makarov
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: J Louw
authors.initials: JL
authors.lastname: Roos
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
mesh_terms: D000595:Amino Acid Sequence; D001321:Autistic Disorder / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D016000:Cluster Analysis; D003198:Computer Simulation; D004260:DNA Repair; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases / Q000235:genetics*; D059472:Exome; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes; D009711:Nucleotides / Q000235:genetics; D010641:Phenotype; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013019:South Africa; D014481:United States
chemical_list: D005819:Genetic Markers; D064251:Multifunctional Enzymes; D009711:Nucleotides; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human