Elsevier

Biological Psychiatry

Volume 60, Issue 10, 15 November 2006, Pages 1053-1061
Biological Psychiatry

Original article
Association of Fatty Acid Desaturase Genes with Attention-Deficit/Hyperactivity Disorder

https://doi.org/10.1016/j.biopsych.2006.04.025Get rights and content

Background

Fatty acids, in particular omega-3 fatty acids, have been found to affect behavior and cognition both directly and indirectly. Evidence to suggest a link with attention-deficit/hyperactivity disorder (ADHD) derives from three key areas: 1) animal dietary restriction studies observed increased locomotive hyperactivity and reduced cognitive ability in offspring; 2) animal dietary studies indicate alterations in the dopamine pathway; and 3) human studies report reduced plasma omega-3 fatty acids in ADHD subjects.

Methods

We investigated three genes that encode essential enzymes (desaturases) for the metabolism of fatty acids by scanning for genetic association between 45 single nucleotide polymorphisms (SNPs) and ADHD.

Results

Our findings suggest a significant association of ADHD with SNP rs498793 (case-control p = .004, odds ratio [OR] 1.6, 95% confidence interval [CI] 1.15–2.23; transmission disequilibrium test [TDT] p = .014, OR 1.69) in the fatty acid desaturase 2 (FADS2) gene. As alcohol is known to decrease the activities of these desaturase enzymes, we also tested for interactions between ADHD subjects’ genotypes and maternal use of alcohol during pregnancy. Two SNPs in the fatty acid desaturase 1 (FADS1) gene were nominally associated with ADHD only in the prenatal alcohol-exposed group of children; formal test for interaction was not significant.

Conclusions

These preliminary findings are suggestive of an association between FADS2 and ADHD.

Section snippets

Neuronal Functions and Essential Fatty Acids: Omega-3 and Omega-6 Compounds

Every cell is enclosed in a cell membrane to create a barrier, which serves to regulate external and internal environments of the cell. This barrier is a fluid structure, allowing the passage of cell components enabling intercellular communication. The functionality of cell membranes is vital. Cell membranes are composed from different long-chain fatty acids: saturated (no double bonds); monounsaturated (one double bond); and polyunsaturated (two or more double bonds). The membrane function is

Metabolism of Essential Fatty Acids and Desaturases

It appears that the same enzymes catalyze the conversion of both omega-6 and omega-3 fatty acid precursors into PUFAs. Figure 1 illustrates the metabolic pathways of essential fatty acids. As reported by Pawlosky et al (2001), the first step of the conversion process, ALA to EPA, is the rate-limiting step, with only .2% of ALA converted to EPA. The enzyme responsible for this conversion also converts docosapentaenoic acid (DPA) to the final product DHA but at a much higher rate (37%),

Animal Studies of Dietary Restrictions

The main focus of animal EFA dietary restriction studies has been effects on cognition, learning, and behavior and the extent to which these correlate with changes in cerebral cell membrane fatty acid composition. Across the studies, it has been consistently observed that while the total percentage of fatty acids remain constant between different dietary regimes, the ratio of omega-3 to omega-6 fatty acids is altered. Omega-3 EFA dietary restriction results in a decrease in the concentration of

The Effect of Fatty Acids on Dopamine

The etiology of ADHD is thought to include abnormal regulation of neurotransmitter systems, particularly dopamine (Levy 1991). The predominant hypodopaminergic theory is based on the observation of marked clinical improvements in the level of ADHD symptoms in response to methylphenidate and other stimulants that increase the amount of available dopamine at the synapse. Fatty acid metabolism may play a role in the regulation of dopamine, since some studies on dietary fatty acids have shown

ADHD Case-Control Comparisons of Plasma Fatty Acid Composition

Studies of plasma fatty acids composition in ADHD subjects have consistently observed significant reductions in omega-3 fatty acids as compared with control subjects (Colquhoun and Bunday 1981, Mitchell et al 1987, Bekaroglu et al 1996, Young et al 2004, Chen et al 2004), despite failing to identify dietary deficits of omega-3 fatty acids among ADHD subjects. It is of interest to note that Clements et al (2003) identified lower levels of omega-3 fatty acids in the brain of the spontaneously

Clinical Sample Intervention Studies

Human intervention studies have reported inconsistent results that may be due, in part, to differences in methodologies, designs, and supplemental compounds used. Non-ADHD samples have shown some evidence for behavioral improvements when the experimental groups were placed on fatty acid supplements (Schoenthaler and Bier 2000, Richardson and Puri 2002, Gesch et al 2002). However, these supplements have not specifically consisted of only omega-3 fatty acids and were mixed with other compound

Current Investigation

Here, we aim to explore possible biological mechanisms that could lead to the deficiency of omega-3 fatty acids observed in ADHD subjects. We investigate possible associations of single nucleotide polymorphisms (SNPs) within three key desaturase enzymes in a population of ADHD children and ethnically matched control subjects. Three desaturase genes were identified (fatty acid desaturase 1 [FADS1], fatty acid desaturase 2 [FADS2], and fatty acid desaturase 3 [FADS3]) that share a high degree of

Study Design

Due to the large number of potential genetic variants that may be associated with complex disorders such as ADHD, we adopted a DNA pooling approach to increase the efficiency of the initial screening stages (Sham et al 2002). The DNA pools that we used in this study have previously been validated by comparisons between DNA pooling estimates of allele frequency differences and those of individual genotyping allele frequencies in studies investigating the synaptosomal associated protein genes

Results

Forty-five SNPs located within the three known human fatty acid desaturase genes (FADS1–3) were identified from dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) and were screened through a test pool of 50 unrelated Caucasian individuals. Selection criteria were based on the location of the SNP marker within coding regions and intron-exon boundaries and the selection of SNPs with minor allele frequencies greater than 5%. In addition, we identified SNPs from the HapMap panel (http://www.hapmap.org) that

Discussion

This study investigated genetic variation within fatty acid metabolic (desaturase) genes and their association with ADHD. A significant association was identified for a single SNP within the FADS2 gene using both case-control comparisons and within family tests of association. We identified an increased prevalence of the FADS2 gene rs498793 SNP marker C allele among ADHD cases with an odds ratio of 1.6 (95% CI: 1.15–2.23) and an increased transmission of the same allele to ADHD cases by TDT

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