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Background Loss of parent during childhood or loss of partner has been associated with adulthood depression. The serotonin transporter polymorphism ( 5-HTTLPR ) has been reported to moderate stress sensitivity reflected for example in the relationship between childhood maltreatment and depression. Therefore, the effect of 5-HTT promoter variation on the relationship between the loss of parent or partner and depression was examined. Method 411 depressive cases and 1347 control subjects from a large well-characterized longitudinal population-based sample of adult Swedes with data on life history and life situation, including psychiatric diagnostic instruments, were studied. Their DNA was genotyped for the mini-haplotype 5-HTTLPR -rs25531. Results Individuals with low 5-HTT activity variants had an increased risk of depression given loss of partner last year compared to those with high activity variants. Conversely, 5-HTT activity variation appeared not to strongly influence the risk of depression given loss of parent during childhood. Limitation Small sample size for those with losses of both parent and partner. Limited power to detect small interaction effects. Conclusion The increased risk of depression given last year loss of partner appeared to be influenced by genetic variation regulating 5-HTT activity. This adds to previous findings of 5-HTT x stressful life events interactions on depression and is in agreement with stronger GxE effects when using objective environmental measures.

Background Environmental risk factors together with genetic vulnerability create a complex background to develop depression. Methods We investigated the associations between COMT Val158Met and depression in a Swedish population-based sample of 405 depressed individuals (major depression diagnosis, dysthymia or mixed anxiety depression defined according to DSM-IV) and 2,151 healthy controls. We also analyzed interaction between this genetic variation and some environmental risk factors for depression and the link between this polymorphism and the low motivational level and negative mood state found in depressed individuals. Results Depressed individuals displayed a higher frequency of the Met/Met and Met/Val genotypes compared to controls (OR = 1.49, CI95% = 1.11–2.00, P = 0.009). The association was found among men only (OR = 2.26, CI95% = 1.26–4.05, p = 0.008). Regression analysis including some potential risk factors for depression, did further indicate that Met/Met and Met/Val were associated with depression in men (P = 0.005). There was also an interaction between genotype and family childhood problems (RERI = 0.876, CI95% = 0.090–1.662 and AP = 0.426, CI95% = 0.030–0.821). Further, depressed men homozygous for the Val-allele, had a higher motivational level than depressed men with a Met-variant (P = 0.02). Limitations The sample size of depressed individuals per group when stratifying cases according to gender and genotypes is considered a limitation. Conclusions The Met-variants of COMT Val158Met are risk variants for depression and low motivational level in depressed Swedish men, but not women. Individuals with this risk variant in combination with a problematic childhood, have an even higher risk to develop depression.

Background There is extensive evidence, from both clinical cases and rodent models, for reduced levels of the widely expressed neuropeptide Y (NPY) in anxiety and depressive disorders. The rare allele of the Leu7Pro polymorphism in the signal peptide of preproNPY has been associated with higher processing into mature NPY, and higher NPY levels in plasma and cerebrospinal fluid. The Pro7 allele was proposed to protect against depression in a small Swedish clinical sample (Heilig M., Zachrisson O., Thorsell A., Ehnvall A., Mottagui-Tabar S., Sjogren M., Asberg M., Ekman R., Wahlestedt C., Agren H., 2004. Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism. J. Psychiatr. Res. 38, 113–121). Method Leu7Pro was analyzed in a large well-characterized longitudinal population-based sample of adult Swedes with data on life situation and life history, including 461 with depression diagnosis, 157 with anxiety diagnosis and 1514 healthy individuals with no symptom of psychopathology. Results Pro7 was rarer in depression cases than in healthy individuals (OR = 2.7; P = 0.0004). The protective effect of Pro7 was similar despite exposure to known environmental vulnerability factors. Pro7 appeared with similar effect size in those with an anxiety diagnosis, but this was not statistically significant (OR = 2.3; P = 0.06). Limitation The size of the anxiety sample and possibly some recall bias of childhood conditions. Conclusion Pro7 allele of preproNPY protected against depression among Swedes. Pro7 is not common, but was found to exert its protective effect also in an environment-induced vulnerable state. This supports a protective effect of NPY in line with previous reports suggesting anxiolytic-like and antidepressant-like effects of NPY.

Background Kendler et al. proposed gender specific developmental models for Major Depression (MD) using a population-based sample of north-American adult twins. The aim of this study was to test whether any of the models could predict both MD and other depressive disorders among unrelated Swedes of both sexes. To test depression specific prediction the sample was overrepresented for other psychiatric diagnoses. Methods Persons with and without psychiatric symptoms were randomly selected from a population-based questionnaire study and interviewed by psychiatrists. Diagnoses were made according to DSM-IV. The study included 81 persons with MD, 132 persons with other depressive disorders, 136 persons with other psychiatric diagnoses and 744 persons without diagnosis. Path and correlation analyses were performed using 16 risk factors. Results The path analysis revealed similar prediction values of MD for the female and male models, i.e. two-thirds of the variance in liability to MD and depression in general when controls consisted of persons without psychiatric diagnosis. Prediction of depression was only slightly weakened when distinguishing cases from those with other psychiatric diagnoses. The risk factors with the strongest unique influence on depression were from early adolescence: neuroticism, low self-esteem, anxiety; from late adolescence: trauma; and history of depression. Limitations Possibly some limited recall bias. Conclusions The model was successfully replicated in both genders of unrelated Swedes. In addition, the model highly predicted other subtypes of depression, despite that the sample was overrepresented for other psychiatric diagnoses. The results support similar etiology of MD and other depressive disorders.

Background Genetic variations in FKBP5, BDNF, P2RX7 and CACNA1 are current candidates for involvement in depression. Methods The single nucleotide polymorphisms FKBP5:rs1360780, BDNF:rs6265 (Val66Met), P2RX7:2230912 (Gln460Arg) and CACNA1C:rs1006737 were genotyped in DNA from 457 depression cases (major depression, dysthymia, and mixed anxiety depression) and 2286 healthy controls with no symptom of psychopathology. Cases and controls were derived from a large well-characterized longitudinal population-based sample of adult Swedes with data on life situation and life history. Association to depression was analyzed with and without consideration to problems during childhood and negative life events last year. Results FKBP5:rs1360780 allele T and genotype TT were overrepresented in depression for men. Childhood problems and negative life events (two or more) conferred a risk for depression (OR = 2.8, 95% CI: 2.2–3.5 and OR = 2.9, 95% CI: 2.4–3.7, respectively). The BDNF:rs6265 Met-allele was overrepresented in depression for women with problems during their childhood. No indication for association to depression was found for P2RX7:2230912 and CACNA1C:rs1006737 without or with consideration of childhood problems or negative life events. Limitations The sample size did not allow exclusion of true association to depression at low odds ratios. There was possibly some recall bias of childhood problems. Conclusions These data support previous reports on FKBP5:rs1360780 and show a gender difference. Likewise, they support previous reports on BDNF:rs6265 and show involvement of environmental stress. P2RX7:2230912 and CACNA1C:rs1006737 did not have a large or moderate-size effect on depression risk. Further studies are required to estimate the significance of these findings.