Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Abstract
Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.
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References and Notes
1
P. J. Harrison, D. R. Weinberger, Mol. Psychiatry10, 40 (2005).
2
K. E. Lohmueller, C. L. Pearce, M. Pike, E. S. Lander, J. N. Hirschhorn, Nat. Genet.33, 177 (2003).
3
J. M. McClellan, E. Susser, M.-C. King, Br. J. Psychiatry190, 194 (2007).
4
J. A. Lee, J. R. Lupski, Neuron52, 103 (2006).
5
J. Sebatet al., Science316, 445 (2007).
6
D. J. MacIntyre, D. H. R. Blackwood, D. J. Porteous, B. S. Pickard, W. J. Muir, Mol. Psychiatry8, 275 (2003).
7
J. E. Chubb, H. J. Bradshaw, D. C. Soares, D. J. Porteous, J. K. Millar, Mol. Psychiatry13, 36 (2008).
8
D. Kamnasaran, W. J. Muir, M. A. Ferguson-Smith, D. W. Cox, J. Med. Genet.40, 325 (2003).
9
H. Liuet al., Proc. Natl. Acad. Sci. U.S.A.99, 16859 (2002).
10
G. Kirovet al., Hum. Mol. Genet.17, 458 (2008).
11
J. I. Friedmanet al., Mol. Psychiatry13, 261 (2008).
12
Materials and methods are available as supporting material on Science Online.
13
A. J. Iafrateet al., Nat. Genet.36, 949 (2004).
14
J. L. Rapoport, G. Inoff-Germain, Curr. Psychiatry Rep.2, 410 (2000).
15
A. Spornet al., Mol. Psychiatry9, 225 (2004).
16
J. R. Idol, A. M. Addington, R. T. Long, J. L. Rapoport, E. D. Green, J. Autism Dev. Disord.38, 668 (2008).
17
J. L. Sealet al., J. Med. Genet.43, 887 (2006).
18
A. J. Sharpet al., Am. J. Hum. Genet.77, 78 (2005).
19
J. M. Friedmanet al., Am. J. Hum. Genet.79, 500 (2006).
20
The Autism Genome Project Consortium, Nat. Genet.39, 319 (2007).
21
R. A. Kumaret al., Hum. Mol. Genet.17, 628 (2007).
22
L. A. Weisset al., N. Engl. J. Med.358, 667 (2008).
23
J. R. Lupski, P. Stankiewicz, PLoS Genet.1, e49 (2005).
24
H. Mi, N. Guo, A. Kejariwal, P. D. Thomas, Nucleic Acids Res.35, D247 (2007).
25
Ingenuity Systems, www.ingenuity.com.
26
National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD, www.ncbi.nlm.nih.gov.
27
C. Rio, H. I. Rieff, P. Qi, T. S. Khurana, G. Corfas, Neuron19, 39 (1997).
28
R. S. Wooet al., Neuron54, 599 (2007).
29
B. Li, R. S. Woo, L. Mei, R. Malinow, Neuron54, 583 (2007).
30
P. M. Beart, R. D. O'Shea, Br. J. Pharmacol.150, 5 (2007).
31
R. E. Smith, V. Haroutunian, K. L. Davis, J. H. Meador-Woodruff, Am. J. Psychiatry158, 1393 (2001).
32
K. M. Giehl, Prog. Exp. Tumor Res.39, 1 (2007).
33
J. D. Buxbaumet al., Mol. Psychiatry13, 162 (2008).
34
R. A. Garcia, K. Vasudevan, A. Buonanno, Proc. Natl. Acad. Sci. U.S.A.97, 3596 (2000).
35
R. M. Esper, M. S. Pankonin, J. A. Loeb, Brain Res. Rev.51, 161 (2006).
36
A. Makoff, C. Pilling, K. Harrington, P. Emson, Brain Res. Mol. Brain Res.40, 165 (1996).
37
M. Nedergaard, T. Takano, A. J. Hansen, Nat. Rev. Neurosci.3, 748 (2002).
38
J. Q. Wang, E. E. Fibuch, L. Mao, J. Neurochem.100, 1 (2007).
39
S. Sammut, D. J. Park, A. R. West, J. Neurochem.103, 1145 (2007).
40
J. A. Bernard-Trifiloet al., J. Neurochem.93, 834 (2005).
41
J. B. Manent, A. Represa, Neuroscientist13, 268 (2007).
42
J. I. Heng, G. Moonen, L. Nguyen, Eur. J. Neurosci.26, 537 (2007).
43
C. A. Ghianiet al., Neurochem. Res.32, 363 (2007).
44
N. Nortonet al., Am. J. Med. Genet. B Neuropsychiatr. Genet.141, 96 (2006).
45
A. J. Law, J. E. Kleinman, D. R. Weinberger, C. S. Weickert, Hum. Mol. Genet.16, 129 (2007).
46
I. Benzelet al., Behav. Brain Funct.3, 31 (2007).
47
Single-letter abbreviations for the amino acid residues are asfollows:A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.
48
We thank M. Wigler, E. Susser, and J. Watson for helpful discussion. This work was supported by The Forrest C. and Frances H. Lattner Foundation; a NARSAD Young Investigator Award; The NARSAD Constance and Steven Lieber Distinguished Investigator Award; The Simons Foundation; a gift of Ted and Vada Stanley; The Stanley Medical Research Foundation; the Howard Hughes Medical Institute; NIH grants HD043569, MH061464, MH061528, MH061355, NS052108, RR025014, and RR000046; NIH intramural research programs of the National Institute on Aging and the National Institute of Mental Health; and the Mental Health Division, Washington State Department of Social and Health Services.
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Science
Volume 320 | Issue 5875
25 April 2008
25 April 2008
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American Association for the Advancement of Science.
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Received: 2 January 2008
Accepted: 14 March 2008
Published in print: 25 April 2008
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