Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia - PubMed (original) (raw)

. 2005 Jun 14;102(24):8627-32.

doi: 10.1073/pnas.0500515102. Epub 2005 Jun 6.

Richard E Straub, Lukas Pezawas, Michael F Egan, Venkata S Mattay, Ahmad R Hariri, Beth A Verchinski, Andreas Meyer-Lindenberg, Rishi Balkissoon, Bhaskar Kolachana, Terry E Goldberg, Daniel R Weinberger

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Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia

Joseph H Callicott et al. Proc Natl Acad Sci U S A. 2005.

Abstract

Disrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.

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Figures

Fig. 1.

Fig. 1.

“Optimized” VBM and SNP10 (Ser704Cys). DISC1 SNP10 deleteriously effects hippocampal size in healthy subjects (HC) [“optimized” VBM analysis within SPM2, P < 0.05 corrected (see Methods)]. These results were displayed on the standard “MNI305 T1” canonical image within SPM2. (a) HC Ser homozygotes (n = 86) have reduced gray matter volume compared with HC Cys homozygotes (n = 10). (b) HC Ser homozygotes also showed reduced gray matter volume compared with HC Cys carriers (Ser/Cys = 62 + Cys/Cys, n = 10; total n = 72).

Fig. 2.

Fig. 2.

BOLD fMRI and SNP10 (Ser704Cys). DISC1 SNP10 affects HF activation during both working memory and declarative memory tasks in healthy subjects [SPM99, P < 0.05 corrected (see Methods)]. (a) For the N-back task, results are displayed on the “MNI305T1” canonical image within SPM99. Healthy Ser homozygotes (n = 18) showed an apparent atypical increase in HF activation during the N-back working memory task relative to Cys carriers (n = 24). (b) During the incidental episodic memory task, (encoding on the left and retrieval on the right). Healthy Ser homozygotes (n = 12) showed decreased HF engagement during both conditions relative to healthy Cys carriers (n = 16).

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References

    1. Weinberger, D. R. (1999) Biol. Psychiatry 45, 395-402. - PubMed
    1. Nelson, M. D., Saykin, A. J., Flashman, L. A. & Riordan, H. J. (1998) Arch. Gen. Psychiatry 55, 433-440. - PubMed
    1. Bertolino, A., Nawroz, S., Mattay, V. S., Barnett, A. S., Duyn, J. H., Moonen, C. T., Frank, J. A., Tedeschi, G. & Weinberger, D. R. (1996) Am. J. Psychiatry 153, 1554-1563. - PubMed
    1. Freedman, R., Waldo, M., Bickford-Wimer, P. & Nagamoto, H. (1991) Schizophr. Res. 4, 233-243. - PubMed
    1. Goldberg, T. E., Torrey, E. F., Gold, J. M., Ragland, J. D., Bigelow, L. B. & Weinberger, D. R. (1993) Psychol. Med. 23, 71-85. - PubMed

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