Candidate gene studies

After reviewing evidence that rumination has a considerable proportion residing in genes, I move on to the details of candidate gene studies performed on rumination so far.

2.2.2.1. Glucocorticoid and mineralocorticoid receptors

Straightforward from biological findings on the role of cortisol (see chapter 2.1.4.2 for details), glucocorticoid receptor co-chaperone gene FKBP5 has been investigated along with stressors in determining rumination. Among school-aged children, attachment security was negatively associated with CRSQ rumination only in those with the FKBP5 rs3800373 CC genotype (96). Moreover, among adolescents, a high level of childhood trauma was associated with high CERQ (Cognitive Emotion Regulation Questionnaire)

26

rumination only in carriers of the CATT haplotype composed of FKBP5 rs9296158, rs3800373, rs1360780 and rs9470080 (97).

The mineralocorticoid receptor also mediates the effects of cortisol in stress response, and an activity-enhancing haplotype of its gene NR3C2, has been associated with decreased LEIDS-R (Leiden Index of Depression Sensitivity Revised) rumination among only female undergraduates but not in males (98).

2.2.2.2. Serotonergic system

Role of the serotonergic system has also emerged in the comprehensive framework of De Raedt and Koster, 2010 (73), integrating rumination into the complex system of multiple biological and cognitive factors determining recurrent depression (see chapter 2.1.4.4 for details). Among serotonergic genetic candidates, the extensively investigated functional length polymorphism, 5-HTTLPR (serotonin-transporter-linked polymorphic region), residing in the promoter region of the serotonin transporter gene SLC6A4, has also been widely studied regarding rumination. Its association with rumination has been proven to be a function of life stress: the short/short genotype was a risk on LEIDS-R rumination among undergraduates only in case of high childhood emotional maltreatment (99); the genotype moderated the association of life stress with RRS rumination among healthy adults, being the short allele a risk for their positive association (100); and the short allele conferred a risk for 10-item RRS rumination only in case of a high level of adverse events among healthy undergraduates if covarying BDI depression level (101).

However, 5-HTTLPR did not exert its effect in the absence of stress factors, neither among healthy undergraduates on 10-item RRS rumination (101, 102), or among children on RRS brooding (57) or CRSS (Children’s Response Styles Scale) brooding rumination (103).

2.2.2.3. Dopaminergic system

C957T polymorphism of the DRD2 gene encoding dopamine receptor D2 protein, has also been investigated in the background of rumination. CC homozygotes had a higher level of RRS brooding only in the clinically depressed group, but not in the never-depressed controls (104).

COMT gene encoding the catechol-O-methyltransferase enzyme has also been in focus of investigation. Among females in a community sample, the functional Val158Met

27

(rs4680) polymorphism was not associated with RRS brooding (105). Similarly, among adults, the 10-item RRS rumination was not associated to the rs4680 polymorphism, however, it was associated with COMT haplotypes composed of rs933271, rs740603, rs4680 and rs4646316 variants (106).

2.2.2.4. Neuronal plasticity

Importance of synaptic plasticity in the pathway leading to rumination has been demonstrated by a gene-gene interaction effect of rs2070995 residing in exon 3 of the KCNJ6 gene, encoding the GIRK2 (G protein-activated inwardly rectifying potassium channel subunit 2) protein, and rs2253206 within the promoter region of the CREB1 gene of cAMP-response element binding protein 1, on 10-item RRS rumination in two independent samples of community adults (107). Moreover, Juhasz et al, 2011 (108) proved a negative association between CREB1 rs2253206 A allele and 10-item RRS rumination in a partly overlapping sample of these community adults.

The BDNF gene encoding the brain-derived neurotrophic factor protein has widely been in focus of seeking genetic associations with rumination, especially its Val66Met (rs6265) polymorphism yielding an amino acid change from valine to methionine. In children, Val66Met was associated neither with RRS brooding (57, 103), nor with CRSS brooding rumination (103). In adolescents however, Val/Val genotype was associated with higher CRSS brooding rumination, but unrelated to RRS brooding (103). Similarly, among adolescent girls, the Val/Val genotype was related to higher CRSQ rumination, moreover, rumination mediated the association of this genotype with a higher level of depressive symptoms (109). Pointing to the same direction of effect also among adults, Juhasz et al, 2011 (108) got a negative association between the Met allele and 10-item RRS rumination, besides the negative association of rumination with a BDNF haplotype comprising also the Met allele of Val66Met but otherwise composed of the rs12273363, rs962369, rs988748, rs7127507 and rs1519480 single nucleotide polymorphisms (SNPs).

However, other studies with adults have found the Met allele as a risk for higher rumination. Hilt et al, 2007 (109) found that while the Val66Met polymorphism was unrelated to 22-item RRS rumination among never-depressed adult females, in females with adult-onset depression the Val/Met genotype conferred a risk for higher rumination, which association, like that of the Val/Val genotype in adolescent girls, mediated the

28

association of Val/Met with a higher level of depression. Similarly, among healthy undergraduates, the Val/Met group, compared to the Val/Val group, had a higher level of 10-item RRS rumination, which could be replicated in case of the reflection subscale but was only a trend in case of the brooding subscale (102). Finally, among healthy undergraduates and covarying BDI depression level, the Val/Met group had a higher level of 10-item RRS rumination than the Val/Val group, moreover, the Met/Met group was found to have a higher rumination than the Val/Val group as adverse events increased (101).

To sum up, as a cognitive endophenotype of major depression, rumination has a considerable variation residing in genetics, and some candidate genes, including: FKBP5, 5-HTTLPR polymorphism of SLC6A4, CREB1 and BDNF, have already been replicably found to account for this heritability.

In the next section, I am going to delineate a potential new direction of candidate gene studies in rumination: the folate metabolism.