Exploring Genetic Variability at PI, GSK3, HPA, and Glutamatergic Pathways in Lithium Response

Abstract

Lithium is considered the first-line treatment in bipolar disorder, although response could range from an excellent response to a complete lack of response. Response to lithium is a complex phenotype in which different factors, part of them genetics, are involved. In this sense, the aim of this study was to investigate the potential association of genetic variability at genes related to phosphoinositide, glycogen synthetase kinase-3 (GSK3), hypothalamic-pituitary-adrenal, and glutamatergic pathways with lithium response. A sample of 131 bipolar patients (99 type I, 32 type II) were grouped and compared according to their level of response: excellent responders (ER), partial responders (PR), and nonresponders (NR). Genotype and allele distributions of the rs669838 (IMPA2), rs909270 (INNP1), rs11921360 (GSK3B), and rs28522620 (GRIK2) polymorphisms significantly differed between ER, PR, and NR. When we compared the ER versus PR+NR, the logistic regression showed significant association for rs669838-C (IMPA2; P = 0.021), rs909270-G (INPP1; P = 0.009), and rs11921360-A (GSK3B; P = 0.004) with lithium nonresponse. Haplotype analysis showed significant association for the haplotypes rs3791809-rs4853694-rs909270 (INPP1) and rs1732170-rs11921360-rs334558 (GSK3B) and lithium response. Our study is in line with previous studies reporting association between genetic variability at these genes and lithium response, pointing to an effect of IMPA2, INPP1, and GSK3B genes to lithium response in bipolar disorder patients. Further studies with larger samples are warranted to assess the strength of the reported associations.

Can a systems approach produce a better understanding of mood disorders?

“…Amongst those genes identified as down regulated only in bipolar post-mortem brains were several associated with membrane receptors or transporters: specifically, the glutamate receptors GRM1 and GRIK2, the nucleoside transporter SLC29A1, the calcium channel CACNA1A, and the insulinlike growth factor binding protein IGFBP6. These observations are consistent with the reported literature: GRM1 and GRIK2 have both been identified as candidate genes via SNP analysis for both schizophrenia and bipolar disorder [79,80], while altered calcium dynamics has been suggested as both a cause of, and potential treatment for, affective disorder [81,82]. Such studies therefore support the use of omic-level analysis in post-mortem brains, with two important caveats: first, the correct controls are in place to ensure high quality data is extracted; second, that sufficient samples are used to correctly power a robust systems analysis.…”

The Pharmacoepigenomics Informatics Pipeline Defines a Pathway of Novel and Known Warfarin Pharmacogenomics Variants

“…In addition to this, in the period of time between the execution of the 2015 lithium experiment and the publication of this manuscript, other groups have reported connections between lithium response and absorption, distribution, metabolism and excretion and some of the genes we reported in this network [96,107].…”

Genetic and Epigenetic Markers of Lithium Response

“…In this study, no information regarding the number of women or whether gender was considered in the analyses was included. Support for a potential role of the same gene was provided by a more recent study from Mitjans and colleagues, showing a significant association between the rs3791809-rs4853694-rs909270 T-A-A haplotype and good lithium response (p = 0.018) [30]. The gene encoding the IMPA2 enzyme was also investigated.…”