A variant of the FOLH1 gene was significantly associated with CES-D score and with moderate to severe depressive symptoms. However, there were no observed significant associations between CES-D score or depressive symptoms and any of the other SNPs in these genes related to folate uptake, retention and metabolism, after correction for multiple testing.
The frequencies of genotypes of the FOLH1
rs61886492 C>T polymorphism were similar to those observed in most previous studies of other populations (32
). In contrast, Halsted et al. did not find a significant association between the FOLH1
rs61886492 C>T polymorphism and depression score in the Hordaland Homocysteine Study in Norway (32
). This inconsistency may be due to study design and characteristics of participants. For example, the Hordaland Homocysteine Study did not use the CES-D to estimate depressive symptoms. In addition, only participants aged 70-72 years were included in their analyses (32
), whereas we recruited individuals with an age range of 45-75 years old and depressive symptoms was more common with younger age in our study.
Our previous study showed that those with the FOLH1
rs61886492 T alleles (combined CT and TT genotypes) had significantly higher folate concentration than those with the CC genotype in the same sample of participants (20
). That may partially explain why the FOLH1
rs61886492 C>T was associated with lower CES-D score. Interestingly, the association of FOLH1
with CES-D score was not mediated by either folate or homocysteine, and was not moderated by either vitamin B6 or vitamin B12 in this population. Alternatively, the hydrolase encoded by FOLH1
-acetylated α-linked acidic dipeptidase activity, and is therefore also known as glutamate carboxypeptidase II (GCPII) (32
). In the brain, FOLH1/GCPII catalyzes the cleavage of N
-glutamate to N
-aspartyl and glutamate (32
). Recent studies have implicated GCPII as an important regulator of glutamatergic neurotransmission, and have observed dysregulation of brain GCPII expression in psychiatric disorders, including schizophrenia, bipolar states and depression (33
). Reduced N
-aspartyl concentrations are thought to indicate neuronal or axonal loss, or dysfunction (34
). Inhibiting GCPII is protective in some animal models of neuropsychological disorders, possibly by decreasing glutamate (35
). In depression, glutamatergic transmission may be disturbed (36
) and antidepressants can change serum glutamate concentrations (37
). Together with these observations, our results raise the hypothesis that polymorphisms of FOLH1
could modify the risk of depressive symptoms by modifying GCPII activity. Further studies are needed to verify this hypothesis.
No SNPs of other studied genes were significantly associated with CES-D score or depressive symptoms. One potential reason is that very few participants had folate deficiency in this population because the food supply is now fortified with folic acid, as observed in the NHANES 1999-2000 (38
). Although some of the studied SNPs, such as MTHFR
C677T, may have functional effects on folate-dependent metabolism and thereby on depression (17
), such effects may only be apparent when folate concentrations are limiting. In addition, only a small proportion of our cohort had low plasma vitamin B12 concentrations. This may explain why folate, vitamin B12, as well as homocysteine, were not associated with CES-D score.
On the other hand, plasma PLP, the active form of vitamin B6, was inversely associated with CES-D score after adjustment for age, sex and educational attainment. This is consistent with several previous studies, including one in Hispanic elders (7
) but not all (39
). In contrast to adequate status of folate and vitamin B12, relatively high prevalence of vitamin B6 deficiency and insufficiency was observed in our study. Biologically, PLP is a key coenzyme in the metabolic pathways of neurotransmitters, including serotonin, dopamine and norepinephrine (40
). The role of these monoaminergic neurotransmitters has been well established in the pathophysiology of depression and available antidepressants are based on such mechanisms (41
). For example, selective serotonin re-uptake inhibitors and serotonin and norepinephrine re-uptake inhibitors work on serotonin to reduce depressive symptoms (42
). The potential beneficial effects of vitamin B6 on depression may be exerted through influencing production of monoaminergic neurotransmitters, and vitamin B6 has been suggested as a therapeutic adjunct to treat conditions with neurotransmitter abnormalities (43
Nevertheless, antidepressants based on monoaminergic systems require time (generally more than 3 to 4 weeks) to act, and are not effective in approximately 30% of patients with major depressive disorder (41
). In the past few years, new mechanisms have emerged, and a disturbed glutamatergic system has been implicated in the pathophysiological process of depression (41
). Indeed, drugs targeting the glutamatergic system have shown therapeutic effects on depression (41
). Our finding of associations of the FOLH1
) gene with mild and moderate to severe depressive symptoms is consistent with the role of the glutamatergic system in depression. More studies on other genes related to the glutamatergic system with depression will be useful to verify this hypothesis.
The prevalence of depressive symptoms (CES-D score ≥16, 60.5%) was higher for the current sample than those observed in previous studies of Puerto Ricans and other Hispanic adults (46
). However, a generally high prevalence of depressive symptoms (44.4%) was also >observed in our previous study including Puerto Ricans aged 60 and over in Massachusetts (25
). Due to limitations of the CES-D as a screening tool (47
), some of those with a high CES-D score may be misclassified and upon closer examination, may not be clinically diagnosed with major depressive disorder. However, a previous study demonstrated that the CES-D scale has high consistency, reliability, and strong discriminating ability between older Puerto Ricans with depression and non-patients, supporting the CES-D as a useful measure in this group (22
). To reduce the potential for false positive cases, we classified our participants with a higher cut-off point (>26) to define those with moderate to severe depressive symptoms, and results were stronger for this more severe level of depressive symptoms.
In conclusion, among this middle-aged and older population with high prevalence of mild and moderate to severe depressive symptoms, the FOLH1 rs61886492 (or 1561) C>T, but not SNPs of other studied genes related to folate uptake and metabolism, was associated with CES-D score and presence of depressive symptoms. No mediation effects of folate or homocysteine, or moderation effects of PLP or vitamin B12, were observed. CES-D score was associated with plasma PLP, but not with vitamin B12, folate, or homocysteine. Further investigation of the role of FOLH1 in depressive symptomatology in this and other populations is warranted.