Gene-environment factors in depressive disorders with a focus on circadian genes

Depressive disorders have a multifactorial etiology, where both environmental and genetic risk factors contribute. Depression is characterized by a depressed mood and accompanied by e.g. loss of interest and pleasure, disturbed sleep and appetite and difficulties in concentrating. A disturbed sleep-wake pattern as well as disruptions of other biological (circadian) rhythms is a hallmark of depression. This fact has led researchers to believe that disruptions of biological rhythms generated by the suprachiasmatic nucleus in the hypothalamus is one possible mechanism behind depressive disorders. A guiding hypothesis in this thesis is that there are protective and vulnerability variations in circadian clock genes regarding development of depressive disorders and that their identification will facilitate improvement of diagnosis and treatment. The main goal of this thesis was to identify circadian clock gene variants associated with depressive disorders in relation with environmental factors.

In paper I, two proposed etiological models for major depression, one model for females and one for males, were applied on the Swedish population-based material (PART) to test the ability of the models to predict major depression and other depressive disorders. Path- and correlation analyses were performed using 16 risk factors. The model was successfully replicated in both genders and predicted two-third of the liability to develop major depression as well as other subtypes of unipolar depression. These results support a similar etiology in major depression and other depressive disorders (Bipolar Disorder, Dysthymia, Mixed Anxiety Depression and Minor Depression).

In paper II, the Leu7Pro polymorphism in preproNPY was investigated in PART. The Pro7 allele was shown to be protective against major depression and dysthymia in a dominant model, and this was true also in an environment-induced vulnerable state in the depressed individuals. In paper III, genetic variants in 18 circadian genes were investigated for association to major depression and dysthymia in PART. Genetic variations in PER2 were found to be associated with depression vulnerability in two of three sample sets used. This genetic risk did not seem to require exposure to the potential sleep disturbance factors stressful life events and financial strain.

In paper IV, we investigated the involvement of circadian clock genes in comorbidity between major depression and alcohol abuse or dependence in the Finnish population-based cohort Health2000. This comorbid condition was found to be associated with variants in the CLOCK gene. Together with previous reports, our results indicate that CLOCK may be a vulnerability factor for depression in individuals with alcohol use disorders. In paper V the circadian gene CRY2 was investigated with regard to mRNA levels in healthy controls and patients with depression, before, during and after one night of sleep deprivation. We also aimed at identifying variations in the CRY2 gene associated with depression in Swedish and Finnish samples with seasonal affective disorder. CRY2 mRNA levels were reduced in blood from bipolar disorder patients in depressive state and mRNA levels were non-responsive to total sleep-deprivation. Furthermore, CRY2 SNPs were found to associate with seasonal affective disorder in both sample sets. To further investigate CRY2´s role in affective disorders, Swedish bipolar patients with the severe phenotype rapid cycling were investigated in paper VI. Risk and protective CRY2 haplotypes were identified that were similar to, and had similar effect sizes as, those in paper V.

In conclusion, results in this thesis support the involvement of circadian genes in depression, seasonal affective disorder and bipolar disorder. The associations found with NPY and PER2 didnot seem to be affected by exposure to the depression risk factors that were identified in paper I. The associations found here need to be replicated and investigated further.

List of scientific papers

I. Sjöholm L, Lavebratt C, Forsell Y (2009). "A multifactorial developmental model for the etiology of major depression in a population-based sample." J Affect Disord 113(1-2): 66-76. Epub 2008 Jun 16
https://pubmed.ncbi.nlm.nih.gov/18558436

II. Sjöholm LK, Melas PA, Forsell Y, Lavebratt C (2009). "PreproNPY Pro7 protects against depression despite exposure to environmental risk factors." J Affect Disord 118(1-3): 124-30. Epub 2009 Mar 4
https://pubmed.ncbi.nlm.nih.gov/19264362

III. Lavebratt C, Sjöholm LK, Partonen T, Schalling M, Forsell Y (2010). "PER2 variantion is associated with depression vulnerability." Am J Med Genet B Neuropsychiatr Genet 153B(2): 570-81
https://pubmed.ncbi.nlm.nih.gov/19693801

IV. Sjöholm LK, Kovanen L, Saarikoski ST, Schalling M, Lavebratt C, Partonen T (2010). "CLOCK is suggested to associate with comorbid alcohol use and depressive disorders." J Circadian Rhythms 8: 1
https://pubmed.ncbi.nlm.nih.gov/20180986

V. Lavebratt C, Sjöholm LK, Soronen P, Paunio T, Vawter MP, Bunney WE, Adolfsson R, Forsell Y, Wu JC, Kelsoe JR, Partonen T, Schalling M (2010). "CRY2 is associated with depression." PLoS One 5(2): e9407
https://pubmed.ncbi.nlm.nih.gov/20195522

VI. Sjöholm LK, Backlund L, Cheteh EH, Römer-Ek I, Frisén L, Schalling M, Ösby U, Lavebratt C, Nikamo P (2010). "CRY2 is associated with risk for rapid cycling in bipolar disorder patients." PLoS One (Submitted)