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Tandem repeat expansions (TREs) can cause neurological diseases but their impact in schizophrenia is unclear. Here we analyzed genome sequences of adults with schizophrenia and found that they have a higher burden of TREs that are near exons and rare in the general population, compared with non-psychiatric controls. These TREs are disproportionately found at loci known to be associated with schizophrenia from genome-wide association studies, in individuals with clinically-relevant genetic variants at other schizophrenia loci, and in families where multiple individuals have schizophrenia. Our findings support the involvement of genome-wide rare TREs in the polygenic nature of schizophrenia.

SummaryFAN1 nuclease is a modifier of repeat expansion diseases, including Huntington’s disease (HD), fragile X syndrome, and autism. The age of HD onset correlates with ongoing ‘inchworm-like’ repeat expansions (1-3 CAG units/event) in HD brains, and is regulated by three modifiers: The first two, repeat tract length and purity exert their effects by enhancing and slowing CAG expansions, respectively, by affecting the formation of slipped-DNAs — mutagenic intermediates of instability; which are processed to expansions by the third modifiers, DNA repair proteins. FAN1 protects against hyper-expansions of repeats, by unknown mechanisms. We show FAN1, through iterative cycles bound, dimerized and cleaved slipped-DNAs, yielding striking patterns of distinct exo-nuclease pauses along slip-outs; 5′-C↓A↓GC↓A↓G-3′ and 5′-C↓T↓G↓C↓T↓G-3′. The transcriptionally-displaced CAG strand was excised slower than its complementary CTG strand, required A•A and T•T mismatches, as fully-paired hairpins arrested excision progression, while disease-delaying CAA interruptions further slowed FAN1 excision. In contrast, endo-nucleolytic cleavage was insensitive to slip-outs. Rare FAN1 variants were found in autism individuals with CGG/CCG repeat expansions. Excision of CGG/CCG slip-outs were similarly excised, with CGG being slower than CCG. The slip-out specific ligand, Naphthyridine-Azaquinolone, shown to induce contractions of expanded repeats in cells, required FAN1 for its effect, and protected slip-outs from FAN1’s exo- but not endo-nucleolytic digestion. FAN1’s ‘inchworm’ pausing of slip-out excision is suited to minimize incremental expansions and modulating disease onset.