DNA Methylation Perturbations in Genes Involved in Polyunsaturated Fatty Acid Biosynthesis Associated with Depression and Suicide Risk

Fatemeh Haghighi,Yung-Yu Huang,Thomas B Cooper,Maria A Oquendo,Hanga Galfalvy,Ainsley K Burke,J John Mann,Sean Chen,M Elizabeth Sublette

doi:10.3389/fneur.2015.00092

Abstract

Polyunsaturated fatty acid (PUFA) status has been associated with neuropsychiatric disorders, including depression and risk of suicide. Long-chain PUFAs (LC-PUFAs) are obtained in the diet or produced by sequential desaturation and elongation of shorter-chain precursor fatty acids linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3). We compared DNA methylation patterns in genes involved in LC-PUFA biosynthesis in major depressive disorder (MDD) with (n = 22) and without (n = 39) history of suicide attempt, and age- and sex-matched healthy volunteers (n = 59). Plasma levels of selected PUFAs along the LC-PUFA biosynthesis pathway were determined by transesterification and gas chromatography. CpG methylation levels for the main human LC-PUFA biosynthetic genes, fatty acid desaturases 1 (Fads1) and 2 (Fads2), and elongation of very long-chain fatty acids protein 5 (Elovl5), were assayed by bisulfite pyrosequencing. Associations between PUFA levels and diagnosis or suicide attempt status did not survive correction for multiple testing. However, MDD diagnosis and suicide attempts were significantly associated with DNA methylation in Elovl5 gene regulatory regions. Also the relative roles of PUFA levels and DNA methylation with respect to diagnostic and suicide attempt status were determined by least absolute shrinkage and selection operator logistic regression analyses. We found that PUFA associations with suicide attempt status were explained by effects of Elovl5 DNA methylation within the regulatory regions. The observed link between plasma PUFA levels, DNA methylation, and suicide risk may have implications for modulation of disease-associated epigenetic marks by nutritional intervention.

Highlights

Imbalances in polyunsaturated fatty acids (PUFAs) may contribute to psychiatric illness, including mood disorders and suicidal behavior [1]
Fatty Acid Differences Across Diagnostic Groups We found pointwise significant differences between major depressive disorder (MDD) and healthy volunteer subjects, with respect to PUFAs (Table S2 in Supplementary Material); none were significant after multiple testing correction (k = 25 tests, using Benjamini–Hochberg adjustment)
We found that DNA methylation of genes involved in n-3 PUFA biosynthesis was associated with MDD and suicide risk

Summary

Introduction

Imbalances in polyunsaturated fatty acids (PUFAs) may contribute to psychiatric illness, including mood disorders and suicidal behavior [1]. PUFAs are not endogenously produced in humans and must be derived from diet. Eggs from n-3 (omega-3) PUFA-fed chickens, and oily fish – including salmon, herring, and sardines, tend to contain the highest levels of n-3 PUFAs compared to other sources. Relevant here is the sequential desaturation and elongation pathway that produces LC-PUFAs from shorter-chain precursor PUFAs linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3) (Figure 1). The principal enzymatic reactions involved are ∆6desaturation [2] and ∆8-desaturation [3] catalyzed by the fatty acid desaturase 2 (Fads2) gene product; ∆5-desaturation catalyzed by the fatty acid desaturase 1 (Fads1) gene product [4]; and elongase reactions catalyzed by the elongation of very long-chain fatty acids proteins (Elovl and Elovl2) gene products [5] (see Figure 1)

Methods

Results

Discussion

Conclusion