Serotonin 1-A receptors are key regulators of serotonin activity and their dysregulation might be implicated in the emergence of both major depression (MD) and generalized anxiety disorder (GAD). Previous studies have yielded inconclusive results as to whether the 5-HT1A receptor gene (HTR1A) has a role in the aetiology of MD and no study up to date has analysed this polymorphism on either pure MD or MD comorbid with GAD. In this study, 1059 patients taking part in the PREDICT-Gene study were ascertained for Diagnostic and Statistical Manual of Mental Disorders-IV MD and GAD diagnoses using the Composite International Diagnostic Interview and the Primary Care Evaluation of Mental Disorders questionnaire, respectively. They were also genotyped for the C(-1019)G functional polymorphism at the promoter region of HTR1A gene. Genetic variability at HTR1A was significantly associated with MD [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 1.14-2.44; P = 0.008], although this effect disappeared after adjusting for GAD (OR = 1.43; 95% CI = 0.96-2.14; P = 0.080). Similarly, a crude association between C(-1019)G polymorphism and GAD was found (OR = 2.54; 95% CI = 1.28-4.86; P = 0.003), but these results became no longer significant after adjusting for MD (OR = 1.97; 95% CI = 0.99-3.91; P = 0.050). However, a main effect of HTR1A G(-1019) allele on comorbid MD-GAD was found (OR = 3.41; 95% CI = 1.44-8.05; P = 0.005) and it remained robust and statistically significant after adjusting by sex, age and family history of psychological problems (OR = 2.82; 95% CI = 1.18-6.77; P = 0.020). In our study, the HTR1A C(-1019)G polymorphism was found to be associated to the frequent clinical presentation of comorbid MD and GAD, suggesting a common genetic background for mixed depression and anxiety states. These findings should be considered as preliminary. Future replications in independent samples would be needed to confirm or discard such association.

There is limited evidence for a moderating role of both serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) genes on the risk for major depression (MD) developing after childhood maltreatment. However, research on this topic remains inconclusive, and there is a lack of data from longitudinal studies with large and representative population samples. Our study aimed to clarify whether, in the presence of previous childhood maltreatment, individuals carrying low functional alleles for both SERT 5-HTTLPR and BDNF Val66Met polymorphisms had a higher risk for MD. We explored 2- and 3-way gene (SERT and BDNF) × environment (childhood maltreatment) interactions in a large sample of Spanish adults who were followed up over a 3-year period and assessed in person for both DSM-IV MD and exposure to childhood maltreatment. Our study included 2679 participants. Those with both the 5-HTTLPR s allele and the BDNF Met allele showed the highest risk of MD if they had previously experienced emotional (z = 2.08, p = 0.037), sexual (z = 2.19, p = 0.029) or any kind of childhood abuse (z = 2.37, p = 0.018). These 3-way interactions remained significant regardless of whether the 5-HTTLPR triallelic or the 5-HTTLPR biallelic polymorphisms were included in the analyses. Retrospective assessment of childhood maltreatment may have resulted in a moderate degree of recall bias. Our results confirm that the risk of depression conferred by childhood maltreatment is modified by variation at both SERT and BDNF genes.

Depression and obesity are major global health problems that frequently co-occur. The FTO gene has one of the strongest links with obesity and high body mass index (BMI) in humans. Besides, this gene is highly expressed in the brain, may play a role in the nervous system, and could confer risk for depression, although scarce literature is available in this respect. We perform a systematic review of the relationship between FTO and both conditions. We selected original articles with observational design or reviews, where depression was assessed with ICD-10, DSM-5 or previous versions, published from 2012 (when the first related paper was published) to November 2020, performed in adults, in English or Spanish and having an optimal methodological quality (evaluated with SIGN checklist). Five original studies were finally included. The results regarding the role of FTO in depression-obesity comorbidity were inconclusive. This leads us to endorse further research covering the role of this gene on both conditions, emphasising a more precise characterization of depression, in order to confirm this role.