ABSTRACT
The pathophysiology of Alzheimer's disease (AD) is influenced by sorting-protein related receptor (sorLa) that is less expressed in AD patients. The gene encoding sorLa (SORL1) has been investigated as a susceptibility factor for late-onset AD (LOAD) with conflicting results. Our objectives were to confirm the association between SORL1 SNPs and LOAD in two independent South-European centers and to perform a mega-analysis of published samples. We analyzed three SORL1 SNPs (intron 6: rs668387; rs689021; rs641120) from the Greece-Italy Genetic Association Study on lateonset AD (GIGAS_LOAD). Greek sample included 96 patients with LOAD (DSM-IV) and 120 unrelated controls. In Italy, a community-based sample is ongoing. 47 LOAD patients and 165 controls were recruited until study endpoint. These samples and previously published ones (Alzgene) were pooled as in a single study. A test for trend was used to analyze genotype association. In the GIGAS_LOAD sample no association was detected between SORL1 genotypes and LOAD. Conversely all SNPs were associated with LOAD in mega-analysis based on ordinal classification of genotypes (Armitage's test: p < 0.001). Although our analysis of pooled samples has positive results for the association between SORL1 and AD, there is substantial heterogeneity across studies. Thus further examination into SORL1 SNPs and the population is necessary to determine the role of SORL1 in LOAD.
Subject(s)
Alzheimer Disease/genetics , Genetic Predisposition to Disease , LDL-Receptor Related Proteins/genetics , Membrane Transport Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Aged , Aged, 80 and over , Female , Gene Frequency , Genetic Association Studies , Genotype , Greece , Humans , International Cooperation , Italy , MaleABSTRACT
Abstract Lithium efficacy is, at least partially, under genetic control. We investigated the association between markers in BDNF and lithium prophylactic efficacy. A set of 10 SNPs within BDNF were genotyped in a sample of 83 bipolar patients. Response to lithium was assessed by presence or absence of any illness phases during a period of 3 years of longitudinal observation. No significant association was detected between the genetic variants tested in BDNF and lithium prophylaxis. Despite the negative association, limitations including small sample size suggest that larger scale genetic associations studies of these genes and lithium prophylaxis are nonetheless indicated.
ABSTRACT
BACKGROUND: Dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1) variants have been associated with several psychiatric conditions including mood disorders and antidepressant efficacy. We investigated dysbindin gene (DTNBP1) variants in major depression and clinical response to selective serotonin reuptake inhibitors. METHODS: In this study we investigated the role of DTNBP1 gene (rs3213207, rs2005976, rs760761 and rs2619522) in 313 major depressive outpatients and 149 healthy individuals. One hundred and forty-seven depressive patients were treated with citalopram and evaluated for response (4th week) and remission (12th week) by the 1-item Hamilton Depression Rating Scale. Single nucleotide polymorphisms (SNPs) were assayed by using Applied Biosystems TaqMan technology. RESULTS: Genotype and haplotype frequencies for four SNPs within DTNBP1 gene did not significantly differ between patients and controls. Allele distribution of SNP rs760761, however, showed a trend of difference between responders and nonresponders (4th week). Haplotype analyses produced a significant association with response to treatment at week 4. No differences were found in remission (12th week). DISCUSSION: DTNBP seems to have an effect on short-term clinical response to citalopram. New studies focused on other genes involved in glutamatergic neurotransmission and related proteins could help to elucidate the complex mechanism of clinical response to antidepressants.
Subject(s)
Carrier Proteins/genetics , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/genetics , Selective Serotonin Reuptake Inhibitors/therapeutic use , Case-Control Studies , Citalopram/therapeutic use , Depressive Disorder, Major/metabolism , Dysbindin , Dystrophin-Associated Proteins , Female , Genotype , Haplotypes , Humans , Linkage Disequilibrium , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
5-HT1A receptors are key components of the serotonin system, acting both pre- and post- synaptically in different brain areas. There is a growing amount of evidence showing the importance of 5-HT1A in different psychiatric disorders, from mood to anxiety disorders, moving through suicidal behaviour and psychotic disorders. Findings in the literature are not consistent with any definite 5-HT1A influence in psychiatric disorders. 5-HT1A gene variants have been reported to play some role in mood disorders, anxiety disorders and psychotic disorders. Again, the literature findings are not unequivocal. Concerning response to treatment, the C(-1019)G variant seems to be of primary interest in antidepressant response: C allele carriers generally show a better response to treatment, especially in Caucasian samples. Together with the C(-1019)G (rs6295) variant, the Ile28Val (rs1799921), Arg219Leu (rs1800044) and Gly22Ser (rs1799920) variants have been investigated in possible associations with psychiatric disorders, also with no definitive results. This lack of consistency can be also due to an incomplete gene investigation. To make progress on this point, a list of validated single nucleotide polymorphisms (SNPs) covering the whole gene is proposed for further investigations.