Decreased cellular activities of folate and vitamin B12 play an important role in the pathogenesis of depression in perinatal period (Abou Saleh et al., 1995; Bodnar and Wisner, 2005; Leung and Kaplan, 2009). Functional polymorphisms of MTHFR gene might impact folate and vitamin B12 metabolism, as it is a key enzyme responsible for maintaining the active 5-methyl form of THF. In the present study, we explored the association between two common functional MTHFR gene polymorphisms i.e., C677T and A1298C with depressive symptoms in postpartum period, and analyzed the circulating levels of vitamin B12 and folate metabolites in circulation in South Indian Women.
Our results showed that the T allele of MTHFR C677T has association with the risk and severity (in terms of suicidal ideations) of PPD. Women with the risk allele T had higher levels of holotc, and lower levels of vitamin B12. Further, haplotype 677T-1298A associated with both the risk of probable PPD and suicidal ideations, whereas 677C-1298A was found to be protective against suicidal ideations. These findings support our hypothesis that polymorphic variants of MTHFR gene might be associated with probable depression in postpartum period.
Similar to our study, T allele of MTHFR C677T associated with general depression in Irish (Kelly et al., 2004), Norway (Folate, 2003), and Chinese Han populations (Shen, 2014). Gilbody et al., in their meta-review of MTHFR polymorphisms with psychiatric disorders observed an odd’s ratio of 1.36 (1.11-1.67) for homozygous variant (TT) of C677T compared to wild type (CC) in 1280 patients with unipolar depression (Gilbody et al., 2007). Furthermore, an association between MTHFR C677T with the risk of postmenopausal depression (Słopien et al., 2008) and depression related to childhood trauma (Lok et al., 2013) is also reported.
Although, many genetic variants are implicated in PPD, studies on the effect of MTHFR gene polymorphisms are limited. Lewis et al. in their recent study on 6809 pregnant women, observed that women with susceptible MTHFR C677T TT genotype were protected from postpartum depression at 21 months postpartum, by supplementing them with folate in pregnancy (Lewis et al., 2012).
We observed self-harm ideations in 24.4% of women who had an EPDS score of over 10. Wisner et al. (19.9%) and Lindahl et al. (20%) have observed similar results in American population (Lindahl et al., 2005; Wisner et al,. 2013). We also observed increased risk of suicidal ideations in women carrying T allele of MTHFR C677T gene. To the best of our knowledge this is the first report of such association. Recent studies have reported the role of polymorphisms in oxytocin receptor gene, CD38, Monoamine oxidase – A (MAO-A), Monoamine oxidase-B (MAO-B) and hypermethylation of TrK and Brain derived neurotrophic factor (BDNF) gene to be associated with suicidality (Balestri et al., 2017; Lockwood et al., 2015; Parris et al., 2018). None of the above studies targeted women in postpartum period. As suicides represent second most common cause of mortality in the postpartum period (Appleby, 1998), and folate supplementation can modulate the effect of MTHFR polymorphic variants, the observations of our study might be useful in recognizing the severity of PPD.
We found that haplotype 677T-1298A to be associated with the risk of probable PPD. It also conferred a high risk for suicidal ideation, whereas 677C-1298A was found to be protective against severe PPD. No study to date has examined the association of these haplotypes with the risk and severity of depressive symptoms in postpartum period.
On analyzing the association of MTHFR C677T and A1298C with circulating folate and vitamin B12 metabolites, we observed that the risk allele T of MTHFR C677T associated with higher levels of holotc and lower levels of vitamin B12 (Figure 1), whereas risk allele C of MTHFR A1298C associated with lower holotc levels (Fig 2). Rise of holotc levels with the risk allele of MTHFR C677T might be interpreted as a compensatory mechanism of the body to decreased vitamin B12 levels. The effect of MTHFR A1298C on vitamin B12 and holotc levels need to be confirmed further in larger prospective studies.
Strength of this study is the inclusion of ethnically similar population (Dravidians), where all the women received folate supplementation during pregnancy.
One limitation of our study is its cross-sectional nature. As, we could not follow these women for a longer time; effect of MTHFR genotype on the progression of probable PPD could not be determined. Also, there may be other social factors contributing to depression in postpartum period other than the ones collected by us in the study, which may influence the results.