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The copy number of DUF1220, a protein domain implicated in human brain evolution, has been linearly associated with autism severity. Given the possibility that autism and schizophrenia are related disorders, the present study examined DUF1220 copy number variation in schizophrenia severity. There are notable similarities between autism symptoms and schizophrenia negative symptoms, and divergence between autism symptoms and schizophrenia positive symptoms. We therefore also examined DUF1220 copy number in schizophrenia subgroups defined by negative and positive symptom features, versus autistic individuals and controls. In the schizophrenic population ( N =609), decreased DUF1220 copy number was linearly associated with increasing positive symptom severity (CON1  P =0.013, HLS1  P =0.0227), an association greatest in adult-onset schizophrenia (CON1  P =0.00155, HLS1  P =0.00361). In schizophrenic males, DUF1220 CON1 subtype copy number increase was associated with increased negative symptom severity ( P =0.0327), a finding similar to that seen in autistic populations. Subgroup analyses demonstrated that schizophrenic individuals with predominantly positive symptoms exhibited reduced CON1 copy number compared with both controls ( P =0.0237) and schizophrenic individuals with predominantly negative symptoms ( P =0.0068). These findings support the view that (1) autism and schizophrenia exhibit both opposing and partially overlapping phenotypes and may represent a disease continuum, (2) variation in DUF1220 copy number contributes to schizophrenia disease risk and to the severity of both disorders, and (3) schizophrenia and autism may be, in part, a harmful by-product of the rapid and extreme evolutionary increase in DUF1220 copy number in the human species.

DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases