Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk

Matthew J. Huentelman, Leela Muppana, Jason J. Corneveaux, Valentin Dinu, Jeremy J. Pruzin, Rebecca Reiman, Cassie N. Borish, Matt De Both, Amber Ahmed, Alexandre Todorov, C. Robert Cloninger, Rui Zhang, Jie Ma, Amelia L. Gallitano

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 × 10-7; OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.

Original languageEnglish (US)
Article numbere0135076
JournalPLoS One
Volume10
Issue number10
DOIs
StatePublished - Oct 16 2015

Fingerprint

AIDS-Related Complex
Single Nucleotide Polymorphism
Schizophrenia
Genes
Plasticity
Neuronal Plasticity
genes
Immediate-Early Genes
schizophrenia
Genome-Wide Association Study
Proteins
Population

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Huentelman, M. J., Muppana, L., Corneveaux, J. J., Dinu, V., Pruzin, J. J., Reiman, R., ... Gallitano, A. L. (2015). Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk. PLoS One, 10(10), [e0135076]. https://doi.org/10.1371/journal.pone.0135076

Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk. / Huentelman, Matthew J.; Muppana, Leela; Corneveaux, Jason J.; Dinu, Valentin; Pruzin, Jeremy J.; Reiman, Rebecca; Borish, Cassie N.; De Both, Matt; Ahmed, Amber; Todorov, Alexandre; Cloninger, C. Robert; Zhang, Rui; Ma, Jie; Gallitano, Amelia L.

In: PLoS One, Vol. 10, No. 10, e0135076, 16.10.2015.

Research output: Contribution to journalArticle

Huentelman, MJ, Muppana, L, Corneveaux, JJ, Dinu, V, Pruzin, JJ, Reiman, R, Borish, CN, De Both, M, Ahmed, A, Todorov, A, Cloninger, CR, Zhang, R, Ma, J & Gallitano, AL 2015, 'Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk', PLoS One, vol. 10, no. 10, e0135076. https://doi.org/10.1371/journal.pone.0135076
Huentelman, Matthew J. ; Muppana, Leela ; Corneveaux, Jason J. ; Dinu, Valentin ; Pruzin, Jeremy J. ; Reiman, Rebecca ; Borish, Cassie N. ; De Both, Matt ; Ahmed, Amber ; Todorov, Alexandre ; Cloninger, C. Robert ; Zhang, Rui ; Ma, Jie ; Gallitano, Amelia L. / Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk. In: PLoS One. 2015 ; Vol. 10, No. 10.
@article{1b402162debd41c29ece0208c8638046,
title = "Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk",
abstract = "We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 × 10-7; OR [95{\%} CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.",
author = "Huentelman, {Matthew J.} and Leela Muppana and Corneveaux, {Jason J.} and Valentin Dinu and Pruzin, {Jeremy J.} and Rebecca Reiman and Borish, {Cassie N.} and {De Both}, Matt and Amber Ahmed and Alexandre Todorov and Cloninger, {C. Robert} and Rui Zhang and Jie Ma and Gallitano, {Amelia L.}",
year = "2015",
month = "10",
day = "16",
doi = "10.1371/journal.pone.0135076",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk

AU - Huentelman, Matthew J.

AU - Muppana, Leela

AU - Corneveaux, Jason J.

AU - Dinu, Valentin

AU - Pruzin, Jeremy J.

AU - Reiman, Rebecca

AU - Borish, Cassie N.

AU - De Both, Matt

AU - Ahmed, Amber

AU - Todorov, Alexandre

AU - Cloninger, C. Robert

AU - Zhang, Rui

AU - Ma, Jie

AU - Gallitano, Amelia L.

PY - 2015/10/16

Y1 - 2015/10/16

N2 - We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 × 10-7; OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.

AB - We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 × 10-7; OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.

UR - http://www.scopus.com/inward/record.url?scp=84949238528&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949238528&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0135076

DO - 10.1371/journal.pone.0135076

M3 - Article

C2 - 26474411

AN - SCOPUS:84949238528

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e0135076

ER -