Strong association of de novo copy number mutations with sporadic schizophrenia

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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.

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Figure 1: Procedures for CNV identification, de novo CNV detection and verification.
Figure 2: Identification and confirmation of a de novo CN mutation in a subject with schizophrenia.


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We thank all the families who participated in this research. We also thank H. Pretorius and nursing sisters R. van Wyk, C. Botha and H. van den Berg for their assistance with subject recruitment and diagnostic evaluations. We thank A. Abrams-Downey and Y. Sun for expert technical assistance and J. Merriam and R.L. Allikmets for their help. We also thank A. Hagerty, J. Mote and J. Hallock for sample processing support and B. Boone and P. Dexheimer for genotyping data generation and support. All microarray experiments were performed in the Vanderbilt Microarray Shared Resource, which is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Digestive Disease Center (P30 DK58404) and the Vanderbilt Vision Center (P30 EY08126). This work was supported in part by National Institute of Mental Health (NIMH) grants MH061399 (to M.K.) and MH077235 (to J.A.G.) and the Lieber Center for Schizophrenia Research at Columbia University Medical Center.

Author information

B.X. carried out the analysis; J.L.R. collected subjects and participated in the diagnostic evaluations; E.J.V.R. collected a subset of the control subjects; S.L. oversaw the genotyping; J.A.G. and M.K. designed the project and oversaw the analysis; M.K. directed the project; and B.X., J.A.G. and M.K. wrote the paper.

Correspondence to Joseph A Gogos or Maria Karayiorgou.

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