ABSTRACT
Title
Influence of GRIK4 and GNB3 polymorphisms on diagnosis and treatment outcome in major depression disorders
Authors
C. Crisafulli1,2, M. Calabrò1, E. Spina2, A. Chiesa3, I. Massat4, S. Linotte5, R. Calati3, S. Kasper6, U. Bailer6, Y. Lecrubier7, M. Fink6, I. Antonijevic8, C. Forray8, L. Snyder8, J. Bollen9, J. Zohar10, D. De Ronchi3, D. Souery11, J. Mendlewicz5 and A. Serretti3
1) Department of Biomorphology and Biotechologies, Division of Biology and Genetics. Schoolof Medicine,University of Messina, Messina, Italy
2) Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy
3) Institute of Psychiatry, University of Bologna, Bologna, Italy
4) Neurological Experimental Laboratory, ULB, FNRS
5) Universite´ Libre de Bruxelles
6) Department of Psychiatry and Psychoterapy, Medical University Vienna, Austria,
7) Hopital la Salpetriere, INSERM U302, Paris, France - Deceased
8)Translational Research, Lundbeck Research, USA
9) Sint-Truiden, Psychiatric Center, Sint-Truiden,
10) Chaim Sheba Medical Center, Tel-Hashomer, Israel
11) Laboratoire de Psychologie Medicale, Universite´ Libre de Bruxelles and Psy Pluriel, Centre Europe´en de Psychologie Medicale, Brussels
1) Department of Biomorphology and Biotechologies, Division of Biology and Genetics. Schoolof Medicine,University of Messina, Messina, Italy
2) Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy
3) Institute of Psychiatry, University of Bologna, Bologna, Italy
4) Neurological Experimental Laboratory, ULB, FNRS
5) Universite´ Libre de Bruxelles
6) Department of Psychiatry and Psychoterapy, Medical University Vienna, Austria,
7) Hopital la Salpetriere, INSERM U302, Paris, France - Deceased
8)Translational Research, Lundbeck Research, USA
9) Sint-Truiden, Psychiatric Center, Sint-Truiden,
10) Chaim Sheba Medical Center, Tel-Hashomer, Israel
11) Laboratoire de Psychologie Medicale, Universite´ Libre de Bruxelles and Psy Pluriel, Centre Europe´en de Psychologie Medicale, Brussels
Abstract
Introduction: Several genes including those coding for the glutamate ionotropic kainate 4 receptor (GRIK4) and the guanine nucleotide binding protein beta polypeptide 3 (GNB3) have been repeatedly involved in the aetiology and response to treatments of major depression (MD). Taking into account the dearth of studies focusing on such SNPs and the substantial risk for Type I (false positive) errors in genetic association studies, the aim of the present paper is to investigate whether a set of single nucleotide polymorphisms (SNPs) within GRIK4(rs1954787) and GNB3 (rs5443) geneswas associated with MD as well with antidepressant response, remission and treatment resistance in an independent sample of patients suffering from MD. Our study design also included the investigation of possible correlations between GRIK4 rs1954787, GNB3 rs5443SNPs and the secondary outcome variables (melancholic features, suicidal risk, comorbidity with an anxiety disorder and personal history of suicide attempt).
Methods: Two hundred twenty-three MD patients were recruited in the context of the European multicentre project ‘Patterns of treatment resistance and switching strategies in unipolar affective disorder’. MD patients were treated with antidepressants at adequate doses for at least 4 weeks.A sample of 76 healthy control subjects collected in the Erasme Hospital and clinically screened for absence of psychiatric disorders was also included in order to investigate possible differences in terms of genotypic and allelic frequencies between MD patients and healthy subjects. MD patients and healthy controls were genotyped for GRIK4and GNB3 SNPs. Response, remission and treatment resistance were recorded.
Results: We did not observe any significant association between the genotypes or alleles under investigation and response, remission in the whole sample, resistance to treatment in the sample of subjects for whom such information was available, and secondary outcome variables. However, it is worth mentioning that patients with GRIK4 CC genotype had a slightly higher likelihood of response to treatment, even though such association did not reach statistical significance.
Conclusion: There is no evidence suggesting any association between GRIK4and GNB3andtreatment response or remission and with MD. Our results are consistent with those of some studies but not with those of other ones. These conflicting data may result from the difficulties in the replication of candidate gene association studies. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, different definitions of responders, or different antidepressants.
We also found neither effects of epistatic interactions between GRIK4 rs1954787 and GNB3rs5443 SNPs on the response, remission and resistance to current antidepressant treatment nor on diagnosis of MD.Independent replications with larger sample sizes are needed in order to better understand thepotential role of GRIK4 and GNB3 on the short term and long term antidepressant treatmentoutcome.
Methods: Two hundred twenty-three MD patients were recruited in the context of the European multicentre project ‘Patterns of treatment resistance and switching strategies in unipolar affective disorder’. MD patients were treated with antidepressants at adequate doses for at least 4 weeks.A sample of 76 healthy control subjects collected in the Erasme Hospital and clinically screened for absence of psychiatric disorders was also included in order to investigate possible differences in terms of genotypic and allelic frequencies between MD patients and healthy subjects. MD patients and healthy controls were genotyped for GRIK4and GNB3 SNPs. Response, remission and treatment resistance were recorded.
Results: We did not observe any significant association between the genotypes or alleles under investigation and response, remission in the whole sample, resistance to treatment in the sample of subjects for whom such information was available, and secondary outcome variables. However, it is worth mentioning that patients with GRIK4 CC genotype had a slightly higher likelihood of response to treatment, even though such association did not reach statistical significance.
Conclusion: There is no evidence suggesting any association between GRIK4and GNB3andtreatment response or remission and with MD. Our results are consistent with those of some studies but not with those of other ones. These conflicting data may result from the difficulties in the replication of candidate gene association studies. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, different definitions of responders, or different antidepressants.
We also found neither effects of epistatic interactions between GRIK4 rs1954787 and GNB3rs5443 SNPs on the response, remission and resistance to current antidepressant treatment nor on diagnosis of MD.Independent replications with larger sample sizes are needed in order to better understand thepotential role of GRIK4 and GNB3 on the short term and long term antidepressant treatmentoutcome.