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It has been suggested that alteration in the muscarinic-cholinergic system is involved in modulation of mood. Three studies have reported linkage on chromosome 7 with major depressive disorder (MDD) in or close to a region containing the muscarinic receptor CHRM2 gene. A haplotype of SNPs located in CHRM2 (rs1824024-rs2061174-rs324650) has been significantly associated with MDD in a previous study. We report the first study investigating this gene in a large, adequately powered, clinical depression case-control sample (n = 1420 cases, 1624 controls). Our data fail to support association with the CHRM2 polymorphisms previously implicated in the genetic aetiology of depression. It is possible our failure to replicate may be a consequence of differences in definition of the MDD phenotype and/or ethnic differences.

Background Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date. Methods Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine. Results MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63). Conclusions MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.

The High-Throughput Disease-specific target Identification Program (HiTDIP) aimed to study case–control association samples for 18 common diseases. Here we present the results of a follow-up case–control association study of HiTDIP in major depressive disorder (MDD). The HiTDIP in MDD was conducted in a sample of 974 cases of recurrent MDD of white German origin collected at the Max-Planck Institute (MP-GSK) and 968 ethnically matched controls screened for lifetime absence of depression. Six genes were identified as of interest for a follow-up, based on the strength of the association and based on the interest as potential candidate target for developing new treatment for depression: Solute Carrier Family 4 Member 10 (SLC4A10), Dipeptidyl Peptidase IV (DPP4), Dopamine Receptor D3 (DRD3), Zinc Finger Protein 80 (ZNF80), Nitric Oxide Synthase 2A (NOS2A) and Peroxisome Proliferator-Activated Receptor-Gamma, Coactivator 1, Alpha (PPARGC1A). Within the current study, we attempted to follow-up these findings in a sample from the UK, the Depression Case Control (DeCC) sample consisting of 1,196 cases and 842 screened controls, phenotyped using exactly the same methods as the MP-GSK sample. Performing Cochran–Mantel–Haenzel statistics to test for genotypic and/or allelic differences between the DeCC and MP-GSK samples, we found no significant differences, thus being able to combine the two samples for association testing. In the combined sample of 2,170 MDD cases and 1,810 controls, there were positive findings in the Nitric Oxide Synthase 2A (NOS2A) gene both using single SNP analysis and haplotype analysis.

The gene known as Disrupted-in-Schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX–DISC1 fusion protein. We explored the TSNAX–DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX–DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX–DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX–DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene.

Background Abnormalities in functioning of the central serotonergic system are believed to be involved in the pathogenesis of depressive illness and suicidal behaviour. Tryptophan hydroxylase (TPH) is a rate-limiting enzyme in the biosynthesis of serotonin, so the TPH gene (11p15.3-p14) is a good candidate for association studies with suicide. Several polymorphisms in the TPH gene have been studied for association with suicidal behaviour, but the results are inconclusive. The aim of the present study is to determine whether the TPH gene is a susceptibility factor for suicidal behaviour in males and females, separately.

The focus on gender-specific genes associated with female suicide is justified by the possible dimorphic nature of the serotonergic system and by the greater number of suicide attempts in females. We performed analysis of the promoter (5-HTTLPR) and intron 2 (STin2 VNTR) polymorphisms and haplotypes of the serotonin transporter gene in Russian suicide attempters, separately in men and women. Our findings indicate the contribution of the SLC6A4 gene to susceptibility for suicidal behavior in women, but not in men. The L/L genotype (p = 0.013, OR = 2.09) and L10 haplotype (p = 0.04, OR = 1.77) were associated with suicide in Russian women only. Further investigations of this gene in different phenotypic groups are necessary.