Although monoamines are thought to be involved in seasonal mood disorders, it is unknown how such concentrations may impact seasonal variation in mood symptoms. Studies of monoaminergic seasonality and a possible influence of the serotonin transporter gene, SLC6A4, on serotonin seasonality have yielded conflicting results. To study this comprehensively, we first performed a genome-wide association study (GWAS) of monoamine metabolites in human cerebrospinal fluid (CSF). We then examined whether the S/L promoter polymorphism of the serotonin transporter gene (5-HTTLPR) affects seasonal changes in CSF serotonin metabolite levels. To translate our findings to the behavioral level, we tested for correlations of 5-HT seasonality values with mood symptoms.

The GWAS yielded a locus significantly associated with monoamine metabolite levels 20kb from SSTR1 (P = 4.92 x 10−8), a locus that was shown to control expression of PDE9A, a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. We additionally show evidence for involvement of the S allele with 5-HT seasonality (standardized β = 0.12, P = 0.020). Moreover, 5-HT seasonality correlated positively with depressive symptoms (Spearman's rho = 0.13, P = 0.018).

We demonstrate how genetic variation in a range of genes involved with neuronal activity influences monoamine metabolite levels in human CSF. We furthermore highlight a dose-dependent association of the 5-HTTLPR with 5-HT seasonality and a positive correlation between 5-HT seasonality and depressive symptomatology. The presented data provide new insights into the genetic determinants of 5-HT seasonality and its role in affective disorders.