Meta-analyses of genetic studies on major depressive disorder

Abstract

The genetic basis of major depressive disorder (MDD) has been investigated extensively, but the identification of MDD genes has been hampered by conflicting results from underpowered studies. We review all MDD case-control genetic association studies published before June 2007 and perform meta-analyses for polymorphisms that had been investigated in at least three studies. The study selection and data extraction were performed in duplicate by two independent investigators. The 183 papers that met our criteria studied 393 polymorphisms in 102 genes. Twenty-two polymorphisms (6%) were investigated in at least three studies. Seven polymorphisms had been evaluated in previous meta-analyses, 5 of these had new data available. Hence, we performed meta-analyses for 20 polymorphisms in 18 genes. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistically significant associations were found for the APOE varepsilon2 (OR, 0.51), GNB3 825T (OR, 1.38), MTHFR 677T (OR, 1.20), SLC6A4 44 bp Ins/Del S (OR, 1.11) alleles and the SLC6A3 40 bpVNTR 9/10 genotype (OR, 2.06). To date, there is statistically significant evidence for six MDD susceptibility genes (APOE, DRD4, GNB3, MTHFR, SLC6A3 and SLC6A4).

Serotonin transporter gene (5-HTT) polymorphism and major depressive disorder in patients in Bogotá, Colombia

“…Regarding the controversial results reported in the literature on the association of the 5-HTT gene in/ del polymorphism and major depression, it may be that sample size in some of the non-conclusive studies was very small and, thus, hindered their statistical power for finding significant differences between patients and controls, or they may have been affected by the selection of cases with very heterogeneous psychiatric phenotypes, a lack of adequate classification of cases and controls, the age of the compared groups, or the geographic origin, among other reasons (20,21). With the increased number of studies of this polymorphism and the subsequent increase in sample size, a greater statistical significance has been registered for this association, especially in the meta-analyses that have been undertaken.…”

Biological Alterations in Depression

“…Lopez-Leon et al found a protective effect for the APOE 2 allele (combined OR,0.51;CI, with no evidence of between-study heterogeneity (Lopez-Leon et al, 2008). Alternatively, an increased risk were found for the methylenetetrahydrofolate reductase MTHFR C677T polymorphism (pooled OR, 1.36), the guanine nucleotide binding protein 3 GNB3 C825T variant (pooled OR, 1.38; CI, 1.13-1.69), and the dopamine transporter SLC6A3 40 bp VNTR (pooled OR, 2.06; CI, 1.25-3.40) (Lopez-Leon et al, 2008). Pharmacogenetic studies of antidepressants in the STAR*D trial have identified genes associated with treatment response (Hu et al, 2007;Lekman et al, 2008a;McMahon et al, 2006;Paddock, 2008), treatment resistance (Perlis et al, 2008), and treatment-emergent suicidal ideation (Laje et al, 2009;Laje et al, 2007;Perlis et al, 2007).…”

“…Carriers of the Met allele were reported to have better treatment outcomes (Gratacos et al, 2008;Kato & Serretti, 2010), however, others did not find any correlation between the Val66Met variant and treatment response (Kato & Serretti, 2010;Tsai et al, 2003;Wilkie et al, 2007). Furthermore, genetic susceptibility to depression was not associated with the BDNF Val166Met variant (Gratacos et al, 2007;Lopez-Leon et al, 2008). The Met allele is associated with impaired intra-cellular packaging and activity dependent secretion of BDNF, which disrupts hippocampal function (Egan et al, 2003).…”

“…Small low-powered studies were combined in a meta-analysis to clarify the associations of several genes with depression, which were unclear due to inconsistent or non-replicated findings. Lopez-Leon et al found a protective effect for the APOE 2 allele (combined OR,0.51;CI, with no evidence of between-study heterogeneity (Lopez-Leon et al, 2008). Alternatively, an increased risk were found for the methylenetetrahydrofolate reductase MTHFR C677T polymorphism (pooled OR, 1.36), the guanine nucleotide binding protein 3 GNB3 C825T variant (pooled OR, 1.38; CI, 1.13-1.69), and the dopamine transporter SLC6A3 40 bp VNTR (pooled OR, 2.06; CI, 1.25-3.40) (Lopez-Leon et al, 2008).…”

Evolutionary genetics of affective disorders

“…However, based on several criteria including patterns of shared phenotypes between disorders, patterns of inheritance within families, and the incidence of these disorders in neurogenetic syndromes (Boks et al 2007b;Gothelf 2007;Lin and Mitchell 2008), depression, bipolar disorder, and schizophrenia can usefully be characterized as encompassing a 'schizophrenia spectrum', 'psychotic spectrum', or, as described here, 'psychotic-affective spectrum' (Marneros and Akiskal 2006;Crespi and Badcock 2008;Ivleva et al 2008). These three conditions also partially overlap in their genetic underpinnings (Craddock and Forty 2006;Potash 2006;Blackwood et al 2007;Farmer et al 2007;López-León et al 2007;Owen et al 2007;Goes et al 2008), with some genes, such as DISC1 and G72, now known to harbor allelic variants that affect susceptibility to all three disorders (Chubb et al 2008;Rietschel et al 2008). Such patterns of partial phenotypic and genetic overlap in psychotic-affective disorders have motivated the hypothesis that major depression, bipolar disorder, and schizophrenia share some genetic risk factors, but are also underlain by genetic variants that are more or less specific to one or two of the disorders (Craddock et al 2006;Craddock and Forty 2006;Hamshere et al 2006).…”