Evaluation of the interaction between genetic variants of GAD1 and miRNA in bipolar disorders

Yu-Chu Ella Chung, Shao-Chien Chen, Li-Chung Chuang, Wei-Liang Shih, Yi-Hang Chiu, Mong-Liang Lu, Hsi-Chung Chen, Po-Hsiu Kuo

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Abstract

BACKGROUND: Glutamic acid dehydrogenase 1 (GAD1) serves as the rate-limiting enzyme for synthesizing GABA, and is reported to be associated with several psychiatric disorders. The present study examined the effects of GAD1 genetic variants on bipolar disorder (BD) and its subtypes. Moreover, we investigated functional interactions between genetic variants and miRNAs via algorithm prediction and experimental validation.

METHODS: A case-control study was conducted with 280 BD patients and 200 healthy controls. Eight tag SNPs in GAD1 were genotyped. For associated markers, we performed in silico prediction for their potential functions through SNP-miRNA interactions by establishing a scoring system to combine information from several miRNA predictive algorithms. We then tested allelic expression differences using Dual-Glo luciferase reporter assays for the selected SNP-miRNA pair. Lastly, we examined the associations of the GAD1 gene and BD in two additional independent datasets with a few thousand samples for replication.

RESULTS: Marker rs3749034 was associated with BD, in particular the BD-II subtype. According to our scoring system, several candidate miRNAs were predicted to interact with rs3749034, and hsa-miR-504 had the highest score. Findings from an in vitro experiment revealed a non-statistically significant trend for lower gene expression level with the A allele of rs3749034 compared with the G allele. The association between rs3749034 and BD was not replicated in either of the independent datasets. Instead, other rarer genetic variants in GAD1 showed suggestive signals (e.g. rs575441409, p-value = 3.8*10(-4), D' = 1 with rs3749034) with BD in the Taiwanese dataset.

LIMITATIONS: The present study considered common genetic variants only. In addition, we only used a 293T cell-line in conducting luciferase reporter assays, as no primary cell-lines from patient samples were available to differentiate the effects between BD subtypes.

CONCLUSIONS: Our results demonstrate a weak effect of the GAD1 gene on the risk of bipolar illness, and the associated marker might represent a proxy for real signals of rare variants.

Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalJournal of Affective Disorders
Volume223
DOIs
Publication statusE-pub ahead of print - Jul 10 2017

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MicroRNAs
Bipolar Disorder
Glutamic Acid
Oxidoreductases
Single Nucleotide Polymorphism
Luciferases
Alleles
Cell Line
HEK293 Cells
Proxy
Computer Simulation
gamma-Aminobutyric Acid
Genes
Psychiatry
Case-Control Studies
Gene Expression
Enzymes
Datasets

Keywords

  • Journal Article

Cite this

Evaluation of the interaction between genetic variants of GAD1 and miRNA in bipolar disorders. / Chung, Yu-Chu Ella; Chen, Shao-Chien; Chuang, Li-Chung; Shih, Wei-Liang; Chiu, Yi-Hang; Lu, Mong-Liang; Chen, Hsi-Chung; Kuo, Po-Hsiu.

In: Journal of Affective Disorders, Vol. 223, 10.07.2017, p. 1-7.

Research output: Contribution to journalArticle

Chung, Yu-Chu Ella ; Chen, Shao-Chien ; Chuang, Li-Chung ; Shih, Wei-Liang ; Chiu, Yi-Hang ; Lu, Mong-Liang ; Chen, Hsi-Chung ; Kuo, Po-Hsiu. / Evaluation of the interaction between genetic variants of GAD1 and miRNA in bipolar disorders. In: Journal of Affective Disorders. 2017 ; Vol. 223. pp. 1-7.
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abstract = "BACKGROUND: Glutamic acid dehydrogenase 1 (GAD1) serves as the rate-limiting enzyme for synthesizing GABA, and is reported to be associated with several psychiatric disorders. The present study examined the effects of GAD1 genetic variants on bipolar disorder (BD) and its subtypes. Moreover, we investigated functional interactions between genetic variants and miRNAs via algorithm prediction and experimental validation.METHODS: A case-control study was conducted with 280 BD patients and 200 healthy controls. Eight tag SNPs in GAD1 were genotyped. For associated markers, we performed in silico prediction for their potential functions through SNP-miRNA interactions by establishing a scoring system to combine information from several miRNA predictive algorithms. We then tested allelic expression differences using Dual-Glo luciferase reporter assays for the selected SNP-miRNA pair. Lastly, we examined the associations of the GAD1 gene and BD in two additional independent datasets with a few thousand samples for replication.RESULTS: Marker rs3749034 was associated with BD, in particular the BD-II subtype. According to our scoring system, several candidate miRNAs were predicted to interact with rs3749034, and hsa-miR-504 had the highest score. Findings from an in vitro experiment revealed a non-statistically significant trend for lower gene expression level with the A allele of rs3749034 compared with the G allele. The association between rs3749034 and BD was not replicated in either of the independent datasets. Instead, other rarer genetic variants in GAD1 showed suggestive signals (e.g. rs575441409, p-value = 3.8*10(-4), D' = 1 with rs3749034) with BD in the Taiwanese dataset.LIMITATIONS: The present study considered common genetic variants only. In addition, we only used a 293T cell-line in conducting luciferase reporter assays, as no primary cell-lines from patient samples were available to differentiate the effects between BD subtypes.CONCLUSIONS: Our results demonstrate a weak effect of the GAD1 gene on the risk of bipolar illness, and the associated marker might represent a proxy for real signals of rare variants.",
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T1 - Evaluation of the interaction between genetic variants of GAD1 and miRNA in bipolar disorders

AU - Chung, Yu-Chu Ella

AU - Chen, Shao-Chien

AU - Chuang, Li-Chung

AU - Shih, Wei-Liang

AU - Chiu, Yi-Hang

AU - Lu, Mong-Liang

AU - Chen, Hsi-Chung

AU - Kuo, Po-Hsiu

N1 - Copyright © 2017 Elsevier B.V. All rights reserved.

PY - 2017/7/10

Y1 - 2017/7/10

N2 - BACKGROUND: Glutamic acid dehydrogenase 1 (GAD1) serves as the rate-limiting enzyme for synthesizing GABA, and is reported to be associated with several psychiatric disorders. The present study examined the effects of GAD1 genetic variants on bipolar disorder (BD) and its subtypes. Moreover, we investigated functional interactions between genetic variants and miRNAs via algorithm prediction and experimental validation.METHODS: A case-control study was conducted with 280 BD patients and 200 healthy controls. Eight tag SNPs in GAD1 were genotyped. For associated markers, we performed in silico prediction for their potential functions through SNP-miRNA interactions by establishing a scoring system to combine information from several miRNA predictive algorithms. We then tested allelic expression differences using Dual-Glo luciferase reporter assays for the selected SNP-miRNA pair. Lastly, we examined the associations of the GAD1 gene and BD in two additional independent datasets with a few thousand samples for replication.RESULTS: Marker rs3749034 was associated with BD, in particular the BD-II subtype. According to our scoring system, several candidate miRNAs were predicted to interact with rs3749034, and hsa-miR-504 had the highest score. Findings from an in vitro experiment revealed a non-statistically significant trend for lower gene expression level with the A allele of rs3749034 compared with the G allele. The association between rs3749034 and BD was not replicated in either of the independent datasets. Instead, other rarer genetic variants in GAD1 showed suggestive signals (e.g. rs575441409, p-value = 3.8*10(-4), D' = 1 with rs3749034) with BD in the Taiwanese dataset.LIMITATIONS: The present study considered common genetic variants only. In addition, we only used a 293T cell-line in conducting luciferase reporter assays, as no primary cell-lines from patient samples were available to differentiate the effects between BD subtypes.CONCLUSIONS: Our results demonstrate a weak effect of the GAD1 gene on the risk of bipolar illness, and the associated marker might represent a proxy for real signals of rare variants.

AB - BACKGROUND: Glutamic acid dehydrogenase 1 (GAD1) serves as the rate-limiting enzyme for synthesizing GABA, and is reported to be associated with several psychiatric disorders. The present study examined the effects of GAD1 genetic variants on bipolar disorder (BD) and its subtypes. Moreover, we investigated functional interactions between genetic variants and miRNAs via algorithm prediction and experimental validation.METHODS: A case-control study was conducted with 280 BD patients and 200 healthy controls. Eight tag SNPs in GAD1 were genotyped. For associated markers, we performed in silico prediction for their potential functions through SNP-miRNA interactions by establishing a scoring system to combine information from several miRNA predictive algorithms. We then tested allelic expression differences using Dual-Glo luciferase reporter assays for the selected SNP-miRNA pair. Lastly, we examined the associations of the GAD1 gene and BD in two additional independent datasets with a few thousand samples for replication.RESULTS: Marker rs3749034 was associated with BD, in particular the BD-II subtype. According to our scoring system, several candidate miRNAs were predicted to interact with rs3749034, and hsa-miR-504 had the highest score. Findings from an in vitro experiment revealed a non-statistically significant trend for lower gene expression level with the A allele of rs3749034 compared with the G allele. The association between rs3749034 and BD was not replicated in either of the independent datasets. Instead, other rarer genetic variants in GAD1 showed suggestive signals (e.g. rs575441409, p-value = 3.8*10(-4), D' = 1 with rs3749034) with BD in the Taiwanese dataset.LIMITATIONS: The present study considered common genetic variants only. In addition, we only used a 293T cell-line in conducting luciferase reporter assays, as no primary cell-lines from patient samples were available to differentiate the effects between BD subtypes.CONCLUSIONS: Our results demonstrate a weak effect of the GAD1 gene on the risk of bipolar illness, and the associated marker might represent a proxy for real signals of rare variants.

KW - Journal Article

U2 - 10.1016/j.jad.2017.07.024

DO - 10.1016/j.jad.2017.07.024

M3 - Article

C2 - 28710909

VL - 223

SP - 1

EP - 7

JO - Journal of Affective Disorders

JF - Journal of Affective Disorders

SN - 0165-0327

ER -