Exploring Genetic Variability at PI, GSK3, HPA, and Glutamatergic Pathways in Lithium Response: Association With IMPA2, INPP1, and GSK3B Genes.
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.
From the *Department of Animal Biology, Anthropology Section, Faculty of Biology, University of Barcelona, IBUB, †Bipolar Disorder Program, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Catalonia; and ‡Department of Psychiatry, School of Medicine, University of Oviedo, Centro de Investigación Biomédica en Red de Salud Mental, INEUROPA, Oviedo, Asturias, Spain.
Marina
M
Mitjans
Bárbara
B
Arias
Esther
E
Jiménez
Jose M
JM
Goikolea
Pilar A
PA
Sáiz
M Paz
MP
García-Portilla
Patricia
P
Burón
Julio
J
Bobes
Eduard
E
Vieta
Antoni
A
Benabarre
D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics; D003430:Cross-Sectional Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D018698:Glutamic Acid / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018020:Lithium Compounds / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome
D018692:Antimanic Agents; D018020:Lithium Compounds; D018698:Glutamic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; C053087:inositol-1,4-bisphosphate 1-phosphatase