TY - JOUR
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 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/12/1
Y1 - 2017/12/1
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 293 T 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 293 T 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 - Bipolar disorder subtypes
KW - miRNA prediction
KW - rs3749034
KW - SNP-miRNA interaction
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U2 - 10.1016/j.jad.2017.07.024
DO - 10.1016/j.jad.2017.07.024
M3 - Article
C2 - 28710909
AN - SCOPUS:85022321357
SN - 0165-0327
VL - 223
SP - 1
EP - 7
JO - Journal of Affective Disorders
JF - Journal of Affective Disorders
ER -
