Abstract
Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
Highlights
Bipolar disorder (BD) is a severe neuropsychiatric condition categorized by recurrent episodes of depression and mania
For the gene-based tests, we applied a set-based testing approach adapted from the versatile gene-based test for genome-wide association study (GWAS) (VEGAS2) [31, 32] with a minor correction for the top-0.1-test option [33]
Of the remaining 1,692 miRNAs tested for the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous and 106 with the continuous treatment response
Summary
Bipolar disorder (BD) is a severe neuropsychiatric condition categorized by recurrent episodes of depression and mania. Mood stabilizers are used as the first-line mode of medication in the treatment of BD [6] Amongst these drugs, lithium is used as a preventive agent for manic and depressive episodes [7], suicide attempts, and death by suicide, and shows the greatest support for long-term relapse prevention [8, 9]. Evidence suggests that some of the variability in lithium response has a genetic basis [11, 12]. This hypothesis is supported by the largest genome-wide association study (GWAS) of lithium response to date, which was conducted by the International Consortium on Lithium Genetics (ConLiGen) [13, 14]. The study investigated genomic data of 2,563 BD patients, identifying a genome-wide significant locus on chromosome 21, which contains two long, non-coding RNA genes (lncRNAs) [14]
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