Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms¹. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively 8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.

1. Department of Physiology and Cellular Biophysics, Columbia University, 630 West 168th Street, New York, New York 10032, USA.
2. Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, New York 10032, USA.
3. Weskoppies Hospital, Private Bag H113, Pretoria 0001, Republic of South Africa.
4. Vanderbilt University, Microarray Shared Resource, 465 21st Avenue South, Nashville, Tennessee 37232, USA.
5. Department of Genetics, University of Pretoria, P.O. Box 667, Pretoria 0001, Republic of South Africa.
6. Department of Neuroscience, Columbia University, 1051 Riverside Drive, New York, New York 10032, USA.

Correspondence to: Maria Karayiorgou² e-mail: mk2758@columbia.edu

Correspondence to: Joseph A Gogos^1,6 e-mail: jag90@columbia.edu

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