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Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk.

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 - PLoS ONE (2015)

Bottom Line: 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 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]).

View Article: PubMed Central - PubMed

Affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

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 x 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.

No MeSH data available.


Related in: MedlinePlus

Minor Allele Frequency Differences in EU and AA.Results of polymorphisms identified by NGS are mapped to the reference human genome used by the 1000 Genomes project (hg18). Vertical lines indicate the Δ MAF (difference between the minor allele frequency in cases versus controls) for each base pair of the genome region investigated. Higher peaks indicate a greater difference in prevalence of that variation between cases and controls, and thus a higher potential for association with schizophrenia risk. The red graph indicates data for Whites and the Blue graph indicates data for African Americans. (A) Δ MAF map for the EGR3 locus, hg18 coordinates chr8:22,591,791–22,612,066. (B) Δ MAF map for the ARC locus, hg18 coordinates chr8:143,682,474–143,697,026
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pone.0135076.g001: Minor Allele Frequency Differences in EU and AA.Results of polymorphisms identified by NGS are mapped to the reference human genome used by the 1000 Genomes project (hg18). Vertical lines indicate the Δ MAF (difference between the minor allele frequency in cases versus controls) for each base pair of the genome region investigated. Higher peaks indicate a greater difference in prevalence of that variation between cases and controls, and thus a higher potential for association with schizophrenia risk. The red graph indicates data for Whites and the Blue graph indicates data for African Americans. (A) Δ MAF map for the EGR3 locus, hg18 coordinates chr8:22,591,791–22,612,066. (B) Δ MAF map for the ARC locus, hg18 coordinates chr8:143,682,474–143,697,026

Mentions: The Δ MAF results for the sequenced regions of the EU (in blue) and AA (in red) populations were plotted onto the genome map in the regions of EGR3 (Fig 1A) and ARC (Fig 1B) using the UCSC genome browser. Individual variations that produced high peaks (i.e. greater Δ MAF) in both racial groups were of greatest interest.


Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk.

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 - PLoS ONE (2015)

Minor Allele Frequency Differences in EU and AA.Results of polymorphisms identified by NGS are mapped to the reference human genome used by the 1000 Genomes project (hg18). Vertical lines indicate the Δ MAF (difference between the minor allele frequency in cases versus controls) for each base pair of the genome region investigated. Higher peaks indicate a greater difference in prevalence of that variation between cases and controls, and thus a higher potential for association with schizophrenia risk. The red graph indicates data for Whites and the Blue graph indicates data for African Americans. (A) Δ MAF map for the EGR3 locus, hg18 coordinates chr8:22,591,791–22,612,066. (B) Δ MAF map for the ARC locus, hg18 coordinates chr8:143,682,474–143,697,026
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608790&req=5

pone.0135076.g001: Minor Allele Frequency Differences in EU and AA.Results of polymorphisms identified by NGS are mapped to the reference human genome used by the 1000 Genomes project (hg18). Vertical lines indicate the Δ MAF (difference between the minor allele frequency in cases versus controls) for each base pair of the genome region investigated. Higher peaks indicate a greater difference in prevalence of that variation between cases and controls, and thus a higher potential for association with schizophrenia risk. The red graph indicates data for Whites and the Blue graph indicates data for African Americans. (A) Δ MAF map for the EGR3 locus, hg18 coordinates chr8:22,591,791–22,612,066. (B) Δ MAF map for the ARC locus, hg18 coordinates chr8:143,682,474–143,697,026
Mentions: The Δ MAF results for the sequenced regions of the EU (in blue) and AA (in red) populations were plotted onto the genome map in the regions of EGR3 (Fig 1A) and ARC (Fig 1B) using the UCSC genome browser. Individual variations that produced high peaks (i.e. greater Δ MAF) in both racial groups were of greatest interest.

Bottom Line: 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 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]).

View Article: PubMed Central - PubMed

Affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

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 x 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.

No MeSH data available.


Related in: MedlinePlus