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. Author manuscript; available in PMC: 2017 Apr 1.
Published in final edited form as: Psychiatr Genet. 2016 Apr;26(2):81–86. doi: 10.1097/YPG.0000000000000111

Lack of Association of SNPs from the FADS1-FADS2 Gene Cluster with Major Depression or Suicidal Behavior

M Elizabeth Sublette 1,2,*, Concepcion Vaquero 3, Enrique Baca-Garcia 1,3,4,5, Gabriela Pachano 1, Yung-yu Huang 2, Maria A Oquendo 1,2, J John Mann 1,2,6
PMCID: PMC4764474  NIHMSID: NIHMS725043  PMID: 26513616

Abstract

Fatty acid desaturase genes (FADS1-FADS2) encode for desaturases participating in biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Since LC-PUFAs are implicated in major depressive disorder (MDD) and suicide risk, and both are partly heritable, we studied the association of FADS1-FADS2 polymorphisms with MDD (635 cases, 480 controls), and suicide attempt status (291 attempters, 338 non-attempters).. Eighteen FADS-related single-nucleotide polymorphisms (SNPs) were genotyped from Caucasians enrolled in Madrid (n=791) or New York City (n=324), and entered as predictors into logistic regression analyses with diagnostic group or suicide attempt history as outcomes, and covariates location and sex. No associations were observed between any SNPs and diagnosis or attempt status. As statistical power was adequate, we conclude that FADS1-FADS2 genetic variants may not be a common determinant of MDD.

Keywords: fatty acid desaturase, major depression, suicidal behavior, polyunsaturated fatty acids

Introduction

The fatty acid desaturase (FADS1-FADS2) gene cluster (H. P. Cho, M. Nakamura, & S. D. Clarke, 1999; H. P. Cho, M. T. Nakamura, & S. D. Clarke, 1999), located in a head-to-head orientation on chromosome 11 (11q12 – 13.1), encodes for the Δ5- and Δ6-desaturases. These desaturases are key enzymes in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) such as docosahexaneoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3) from shorter-chain precursor α-linolenic acid (ALA, 18:3n-3) and arachidonic acid (AA, 20:5n-6) from precursor linoleic acid (LA, 18:2n-6) (Sprecher, 1981). The FADS3 gene shares a high sequence similarity (Marquardt, Stohr, White, & Weber, 2000) but its function is less clear (Blanchard, Boulier-Monthean, Legrand, & Pedrono, 2014; Reardon et al., 2013). Genotyping studies report that genetic variants of FADS1-FADS2, together with diet, affect levels of n-3 and n-6 LC-PUFAs in serum phospholipids (Koletzko, Demmelmair, Schaeffer, Illig, & Heinrich, 2008; Malerba et al., 2008; Schaeffer et al., 2006), plasma (Gillingham et al., 2013; Solakivi et al., 2013), erythrocytes (Harslof et al., 2013), and brain (Rizzi et al., 2013). Genetic polymorphisms of FADS1-FADS2 also are associated with oxidative stress markers (Hong, Kwak, Paik, Chae, & Lee, 2013), peroxidation susceptibility (Solakivi et al., 2013) and risk of coronary artery disease (Li et al., 2013; Molto-Puigmarti et al., 2013), and may act as a moderator for breastfeeding effects on infant intelligence quotient (IQ) (Caspi et al., 2007).

In addition to effects on cardiovascular health and inflammation (Martinelli et al., 2008), LC-PUFAs are critical for normal brain function and impact risk for psychiatric illness. For instance, a meta-analysis finds lower levels of n-3 PUFAs in depressed compared with healthy individuals (Lin, Huang, & Su, 2010). Lower n-3 PUFAs also are seen in suicide attempters, compared with other trauma visitors to the emergency room (Huan et al., 2004), and in suicides among military personnel, compared with other causes of death (Lewis et al., 2011; McNamara et al., 2013). We also have shown, in a small prospective study of patients with major depression, that low levels of DHA predict subsequent suicide attempts (Sublette, Hibbeln, Galfalvy, Oquendo, & Mann, 2006). Furthermore, in comparison with healthy volunteers, patients with bipolar disorder exhibit lower levels of LC-PUFAs DHA and AA (Chiu, 2003) and patients with schizophrenia exhibit lower DHA, AA and docosapentaenoic acid (DPA) (van der Kemp, Klomp, Kahn, Luijten, & Hulshoff Pol, 2012).

LC-PUFA status is regulated through dietary content (Simopoulos, 2011), LC-PUFA breakdown (Evans et al., 2003; Horrobin, Glen, & Vaddadi, 1994; Peet, Laugharne, Rangarajan, Horrobin, & Reynolds, 1995; Ross, Maxwell, & Glen, 2010), and synthesis of LC-PUFAs from LA and ALA. The physiologic importance of the latter pathway is unclear, however, given the low estimated rates of conversion: the proportion of ALA converted to EPA is less than 10% (Emken et al. 1994; Burdge et al. 2002), and to DHA is only about 0.05% (Burdge, Finnegan, Minihane, Williams, & Wootton, 2003; Emken, Adlof, & Gulley, 1994). However, studies in rats under conditions of dietary DHA deficiency find that liver conversion coefficients of ALA to DHA, a measure of increased activity of Δ5- and Δ6-desaturases and elongases 2 and 5, can increase as much as 7-fold (S. Rapoport, Rao, & Igarashi, 2007), with liver DHA synthesis that is 30 times in excess of the daily brain DHA consumption rate, if there is enough ALA from the diet (S. I. Rapoport, Ramadan, & Basselin, 2011). Thus the effects of FADS1-FADS2 genetic variants on Δ5- and Δ6-desaturase activity and phospholipid LC-PUFA levels could have important implications for mental health and disease. Elevated Δ6-desaturase expression has been demonstrated, postmortem, in schizophrenia (Liu, Jandacek, Rider, Tso, & McNamara, 2009), and antipsychotic medications appear to upregulate genes involved in lipid biosynthesis (Ferno et al., 2005; Raeder, Ferno, Vik-Mo, & Steen, 2006) including increased FADS1-FADS2 mRNA expression in human cell lines (Polymeropoulos et al., 2009).

The expression of FADS1 is lower in MDD suicides compared with nonpsychiatric controls postmortem (Lalovic, Klempan, Sequeira, Luheshi, & Turecki, 2010). Both suicide and major depression are partly heritable (Mann, 2003; Statham et al., 1998) but the specific genes involved remain to be identified. However, genetic variants of FADS1-FADS2 have not been directly examined in context of depression. Therefore we sought to test whether genetic polymorphisms in FADS1-FADS2 are associated with major depression and/or suicide attempts.

Method

Sample

Participants were Caucasian adults, aged 18–99 yrs, who provided written informed consent to participate in mood disorders studies at the New York State Psychiatric Institute in New York City (n=324) or the Fundacion Jimenez-Diaz in Madrid (n=791). The study was approved by the appropriate ethics committees (New York State Psychiatric Institute Institutional Review Board [IRB], Fundacion Jimenez Diaz IRB) and performed in accordance with the Declaration of Helsinki. All participants had a lifetime diagnosis of Major Depressive Disorder (MDD) (n=635) according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), or were healthy volunteers (n=480) with no history of any Axis I or Axis II psychiatric disorders with the exception of simple phobia. MDD diagnosis was established by consensus using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID I) (First, 2002b) in cases and the SCID non-patient edition (NP) (First, 2002a) for healthy volunteers. MDD participants did not have any other current Axis I disorders except comorbid anxiety disorders, and Axis II disorders were permitted. Participants did not have active medical or neurologic illness at time of enrollment in the study based on history, physical examination, and a battery of standard laboratory tests. History of suicide attempt, defined as a self-destructive act in context of some intent to die (Posner, Oquendo, Gould, Stanley, & Davies, 2007), was assessed using the Columbia Suicide History form (Oquendo, Halberstam, & Mann, 2003). Case and control ascertainment and clinical evaluations were standardized between sites as described previously (Baca-Garcia, Oquendo, Saiz-Ruiz, Mann, & de Leon, 2006). Genetic data from subsets of these research participants have been used in previous studies with different research objectives (Almoguera et al., 2011; Almoguera et al., 2013a, 2013b; Alonso et al., 2008; Baca-Garcia et al., 2005; Baca-Garcia et al., 2003; Baca-Garcia, Vaquero, Diaz-Sastre, Garcia-Resa, et al., 2004; Baca-Garcia, Vaquero, Diaz-Sastre, Jimenez-Trevino, et al., 2004; Baca-Garcia et al., 2002; Baca-Garcia et al., 2007; Baca-Garcia et al., 2010; Bermudo-Soriano et al., 2009; Blasco-Fontecilla et al., 2013; Costas et al., 2010; Fernandez-Navarro et al., 2012; Gratacos et al., 2009; Lopez-Castroman et al., 2009; Lorenzo et al., 2007; Penas-Lledo et al., 2012; Perroud et al., 2010; Sublette et al., 2008; Vaquero et al., 2004; Vaquero Lorenzo et al., 2006; Vaquero-Lorenzo et al., 2008; Vaquero-Lorenzo et al., 2014; Vaquero-Lorenzo et al., 2009).

Genetic analyses

Genomic DNA was extracted from peripheral blood samples collected from patients and controls using standard protocols (Gnome Whole Blood Kit and BIO 101, Qbiogene, Carlsbad, CA, USA). The SNPs were genotyped using high throughput multiplex assays with VeraCode Technology (Illumina®) at the Centro Nacional de Genotipado (CeGen, Madrid, Spain). In addition to our study samples, 90 cell-line DNA samples obtained from the Coriell Institute for Medical Research (Camden, NJ, USA; http://www.coriell.org/) were used as internal controls (in duplicate) for the accuracy and validity of the multiplex genotyping. Their genotypes and haplogroup affiliations had previously been determined in the HapMap Project. This control step also had the ability to detect cross-contamination, as sample and replication were located in the same plate in different positions. An additional control step, NTC (Non-Template Control), was also applied to ensure the accuracy of PCR amplification and to detect possible contamination by PCR reagents, employing all the reagents with nuclease-free water instead of DNA samples.

Statistical analyses

Statistical analyses were performed using IBM-SPSS-Statistics (version 22 [Apple, Inc., Cupertino, CA]), and PLINK software version 1.07 (Purcell et al., 2007) (http://pngu.mgh.harvard.edu/~purcell/plink/download.shtml; Boston, MA, USA) for association analysis. The association analysis procedure was performed as described previously (Clarke et al., 2011). Briefly, FADS-related SNPs were identified from the literature (Schaeffer et al., 2006). Two major hypotheses were tested: (1) To assess whether participants with MDD exhibited differences in FADs variants compared with healthy volunteers, separate logistic regression analyses were performed using the 18 identified SNPs as predictors and diagnostic group as outcome. (2) Similarly, to test for suicide attempt-related differences in FADs variants within the MDD group, separate logistic regression analyses were performed using the 18 identified SNPs as predictors and suicide attempt group as outcome (suicide attempters vs nonattempters). For each hypothesis, additional separate models were run using the Cochran-Mantel-Haenszel test (2×2×2) including location and sex as covariates. Significance levels were set a priori at α = 0.05 after Bonferroni correction for 18 comparison SNPs (p<0.003).

Results

Sample characteristics

Population characteristics are shown in Table 1. In this sample, 72% were from Madrid, the remainder from New York, with an average age of 38.5 yrs in the combined population. The majority of depressed study participants were female (64%), reflecting the gender distribution of the illness, in contrast to 42% of healthy volunteers.

Table 1.

Characterization of the New York – Madrid study population.

Madrid New York Total
Total MDD HV Total MDD HV Total MDD HV
Participants 791 377 414 324 258 66 1115 635 480
Suicide attempters (%) 203 (54%) - 88 (34%) - 291 (46%) -
Male (%) 376 (48%) 134 (36%) 242 (58%) 126 (39%) 89 (34%) 37 (56%) 502 (45%) 223 (35%) 279 (58%)
Mean age (SD) 38.1 (13.3) 40.6 (12.6) 35.5 (14.6) 39.6 (13.1) 40.5 (14.7) 35.6 (11.3) 38.5 (13.3) 40.6 (13.9) 35.5 (11.8)
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Association Analyses

We genotyped 18 SNPs (see Table 2) identified from public databases and literature concerning FADS1-FADS2 (Hester et al., 2014; Schaeffer et al., 2006) as potentially relevant based on known associations with human health. All SNPS had minor allele frequencies of at least 5%.

Table 2.

Genotype frequencies of FADS1 FADS2 polymorphisms in the New York – Madrid study populations.

SNP Major/minor Alleles (M/m) Percentage of participants with genotype
Minor Allele Frequencya
MDD MDD Suicide Attempters MDD Suicide Non-attempters Controls
MM Mm mm MM Mm mm MM Mm mm MM Mm mm
FADS1
rs174537 G/T 46.62 42.44 10.93 47.87 42.20 9.93 45.81 42.81 11.38 47.07 41.63 11.30 T=0.3029
rs174545 C/G 46.99 42.24 10.76 48.10 42.56 9.34 46.29 42.14 11.57 46.75 41.93 11.32 G=0.2979
rs174546 C/T 47.08 42.18 10.74 48.10 42.56 9.34 46.45 42.01 11.54 47.49 41.21 11.30 T=0.2975
rs174547 T/C 47.30 42.22 10.48 48.60 42.31 9.09 46.45 42.31 11.24 47.17 41.51 11.32 C=0.2979
rs174556 C/T 54.78 37.26 7.96 55.24 38.11 6.64 54.76 36.61 8.63 53.46 40.25 6.29 T=0.2796
rs174561 T/C 55.01 37.43 7.56 56.33 37.55 6.12 54.12 37.63 8.24 54.10 39.25 6.65 C=0.2796
FADS2
rs174568 C/T 47.53 41.63 10.85 48.60 41.95 9.44 46.87 41.49 11.64 47.18 41.54 11.27 T=0.2961
rs174570 C/T 71.95 24.56 3.49 72.66 23.88 3.46 71.72 25.30 2.98 70.83 27.71 1.46 T=0.2282
rs174583 C/T 43.06 42.74 14.20 45.02 42.27 12.71 41.54 43.32 15.13 42.50 44.38 13.12 T=0.3686
rs174589 G/C 64.63 31.99 3.38 66.43 30.39 3.18 63.36 33.03 3.60 66.18 28.57 5.25 C=0.1344
rs174602 A/G 55.56 37.78 6.67 58.13 37.72 4.15 53.43 38.21 8.36 57.32 38.08 4.60 G=0.4229
rs174620 T/C 28.25 52.38 19.37 28.72 51.56 19.72 27.16 53.43 19.40 33.05 46.86 20.08 G=0.3411
rs2072114 A/G 76.74 20.89 2.37 77.24 20.34 2.41 76.49 21.43 2.08 74.53 24.42 1.05 G=0.1949
rs2524299 A/T 75.55 21.77 2.68 76.98 19.93 3.09 74.48 23.44 2.08 73.28 25.26 1.46 T=0.2057
rs526126 C/G 64.07 31.80 4.13 65.97 29.51 4.51 61.79 34.33 3.88 63.96 30.83 5.21 G=0.3199
rs968567 G/A 76.27 21.68 2.06 77.08 21.87 1.04 75.44 21.60 2.96 74.48 23.64 1.88 A=0.0527
rs99780 C/T 43.06 43.06 13.88 45.14 43.06 11.81 41.44 43.24 15.32 42.59 44.68 12.73 T=0.3974
FADS2-FADS3 Intergenic
rs174627 C/T 78.21 20.35 1.43 79.86 18.06 2.08 76.72 22.39 0.90 75.73 23.43 0.84 T=0.0535
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a

Data obtained from http://www.ncbi.nlm.nih.gov/snp.

No associations were observed between any of the 18 SNPs and diagnosis of MDD or suicide attempt status, after controlling for location and sex. Statistical power to detect a 15% difference in SNP frequency between depressed and healthy groups was 0.98.

Discussion

Low levels of n-3 LC-PUFAs have been implicated in the pathophysiology of major depression (Lin et al., 2010) and suicidal behavior (Huan et al., 2004; Lewis et al., 2011; McNamara et al., 2013; Sublette et al., 2006), relevant to public health as the dietary intake of n-3 LC-PUFA is currently low in many countries (Hibbeln, Nieminen, Blasbalg, Riggs, & Lands, 2006), including Spain and the United States. Therefore, the conversion of short-chain to LC-PUFA, a compensatory, failsafe mechanism for maintaining EPA and DHA levels in times of deficiency, assumes potential importance. Both psychopathologies and this conversion are partly heritable. Our finding that the presence of FADS1-FADS2 polymorphisms did not differentiate depressed from healthy volunteer groups, does not support the hypothesis that genetically determined inefficient conversion of precursors to n-3 LC-PUFAs is a major contributor to the incidence of MDD or suicidal behavior. Although our study appears to be adequately powered, we cannot rule out the possibility that there may be subgroups of depressed patients in whom effects of FADS1-FADS2 polymorphisms have a more profound effect on LC-PUFA status. We sought to reduce stratification effects that may obscure a disease association by confining the subjects and controls to Caucasians and by inclusion of location in the statistical model because New York ethnicities were likely to be more heterogeneous, compared with Spain. Other factors could conceivably confound the FADS1-FADS2 differences between depressed and controls. For instance, LC-PUFA status is also a determinant of cardiovascular disease via effects on total cholesterol, HDL, LDL and triglyceride concentrations (Standl et al., 2012), and thus the efficacy of Δ5 and Δ6 desaturases could be low in atherosclerotic controls as well as in depressed patients, obscuring group differences. A similar confound has been seen in a postmortem study (McNamara et al., 2013), in which adult depressed suicides exhibited lower brain DHA concentrations than controls only when controls with cardiovascular disease were excluded. Given the mean age of 38 years in our study population, one might expect that those with genetic predispositions to cardiovascular disease may still be asymptomatic and thereby included in our study.

Limitations

This study did not measure dietary intake or blood levels of PUFA, which could be a confound, since effects of low functioning of Δ5 and Δ6 desaturases on depression could be mitigated by high dietary intake of n-3 LC-PUFA. Additionally, it is possible that alternative SNPs in the FADS1-FADS2 locus, not previously identified as functionally relevant and therefore not measured by us, may impact MDD or suicide risk.

Conclusions

Although the ability for endogenous conversion of short-chain to LC-PUFA has been shown to maintain brain LC-PUFA in times of low dietary LC-PUFA supply, FADS1-FADS2 genetic polymorphisms known to influence LC-PUFA levels were not associated with MDD or suicide attempts. Thus associations of low n-3 LC-PUFA levels with MDD and suicide risk are likely governed mostly by low dietary availability or other mechanisms such as higher metabolism or epigenetic regulation of biosynthesis.

Acknowledgments

Funding:

This work was funded in part by MH48514 (PI:Oquendo); MH062185 and MH040695 (PI:Mann); and MH079033 (PI:Sublette); Juan de la Cierva Programme JCI-2011-11050 (PI:Vaquero-Lorenzo); National Alliance for Research of Schizophrenia and Affective Disorders (NARSAD) and the Spanish Health Ministry (Instituto de Salud Carlos III PI13/02200 (PI:Baca-Garcia), CIBERSAM (PI:Baca-Garcia).

Footnotes

Financial Disclosure

Dr. Baca-Garcia is the Lilly Suicide Scholar at Columbia University. Dr. Mann received past unrelated grants from Novartis and GSK, and receives royalties for the Columbia Suicide Severity Rating Scale (C-SSRS) from the Research Foundation for Mental Health. Dr. Oquendo received unrestricted educational grants and/or lecture fees from Astra-Zeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Otsuka, Pfizer, Sanofi-Aventis, and Shire as well as financial compensation from Pfizer for the safety evaluation of a clinical facility, unrelated to the current manuscript. She was the recipient of a grant from Eli Lilly to support a year of the salary for a Lilly Suicide Scholar. In addition, her family owns stock in Bristol Myers Squibb. Dr. Sublette received a grant of nutritional supplements from Unicity International for an unrelated study. All other authors have no conflicts of interest to report.

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