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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)8627-8632
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number24
DOIs
StatePublished - Jun 14 2005
Externally publishedYes

Fingerprint

Schizophrenia
Hippocampus
Haplotypes
Single Nucleotide Polymorphism
Genes
Healthy Volunteers
Alleles
Magnetic Resonance Imaging
Phenotype

Keywords

  • Association
  • Hippocampus
  • Morphometry

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. / Callicott, Joseph H.; Straub, Richard E.; Pezawas, Lukas; Egan, Michael F.; Mattay, Venkata; Hariri, Ahmad R.; Verchinski, Beth A.; Meyer-Lindenberg, Andreas; Balkissoon, Rishi; Kolachana, Bhaskar; Goldberg, Terry E.; Weinberger, Daniel.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 24, 14.06.2005, p. 8627-8632.

Research output: Contribution to journalArticle

Callicott, JH, Straub, RE, Pezawas, L, Egan, MF, Mattay, V, Hariri, AR, Verchinski, BA, Meyer-Lindenberg, A, Balkissoon, R, Kolachana, B, Goldberg, TE & Weinberger, D 2005, 'Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 24, pp. 8627-8632. https://doi.org/10.1073/pnas.0500515102
Callicott, Joseph H. ; Straub, Richard E. ; Pezawas, Lukas ; Egan, Michael F. ; Mattay, Venkata ; Hariri, Ahmad R. ; Verchinski, Beth A. ; Meyer-Lindenberg, Andreas ; Balkissoon, Rishi ; Kolachana, Bhaskar ; Goldberg, Terry E. ; Weinberger, Daniel. / Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 24. pp. 8627-8632.
@article{f96d462359594f17b731222f34850e84,
title = "Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia",
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.",
keywords = "Association, Hippocampus, Morphometry",
author = "Callicott, {Joseph H.} and Straub, {Richard E.} and Lukas Pezawas and Egan, {Michael F.} and Venkata Mattay and Hariri, {Ahmad R.} and Verchinski, {Beth A.} and Andreas Meyer-Lindenberg and Rishi Balkissoon and Bhaskar Kolachana and Goldberg, {Terry E.} and Daniel Weinberger",
year = "2005",
month = "6",
day = "14",
doi = "10.1073/pnas.0500515102",
language = "English (US)",
volume = "102",
pages = "8627--8632",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "24",

}

TY - JOUR

T1 - Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia

AU - Callicott, Joseph H.

AU - Straub, Richard E.

AU - Pezawas, Lukas

AU - Egan, Michael F.

AU - Mattay, Venkata

AU - Hariri, Ahmad R.

AU - Verchinski, Beth A.

AU - Meyer-Lindenberg, Andreas

AU - Balkissoon, Rishi

AU - Kolachana, Bhaskar

AU - Goldberg, Terry E.

AU - Weinberger, Daniel

PY - 2005/6/14

Y1 - 2005/6/14

N2 - 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.

AB - 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.

KW - Association

KW - Hippocampus

KW - Morphometry

UR - http://www.scopus.com/inward/record.url?scp=20844463251&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20844463251&partnerID=8YFLogxK

U2 - 10.1073/pnas.0500515102

DO - 10.1073/pnas.0500515102

M3 - Article

C2 - 15939883

AN - SCOPUS:20844463251

VL - 102

SP - 8627

EP - 8632

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 24

ER -