Eicosapentaenoylcholine
Background
Section titled “Background”Eicosapentaenoylcholine is a type of phosphatidylcholine (PC), a class of glycerophospholipids that are fundamental components of cell membranes and play diverse roles in cellular signaling and metabolism. Phosphatidylcholines are characterized by a glycerol backbone esterified with two fatty acid chains and a phosphocholine head group. The “eicosapentaenoyl” part refers to eicosapentaenoic acid (EPA), a long-chain omega-3 polyunsaturated fatty acid (PUFA) with 20 carbon atoms and 5 double bonds. These complex lipids are critical for maintaining membrane fluidity and serving as precursors for various signaling molecules.
Biological Basis
Section titled “Biological Basis”The synthesis and metabolism of eicosapentaenoylcholine, like other long-chain polyunsaturated fatty acid-containing phospholipids, are influenced by a network of enzymes, notably those involved in fatty acid desaturation and elongation. A key enzyme in this pathway is fatty acid delta-5 desaturase, encoded by theFADS1 gene. [1]This enzyme is essential for introducing double bonds into fatty acid chains, converting precursors from essential fatty acids like linoleic acid (omega-6 pathway) and alpha-linolenic acid (omega-3 pathway) into more highly unsaturated forms, including eicosapentaenoic acid.[1]
Genetic variations can significantly impact the efficiency of these metabolic processes. For instance, the single nucleotide polymorphism (SNP)rs174548 , located within a linkage disequilibrium block containing the FADS1 gene, has been strongly associated with the concentrations of numerous glycerophospholipids in human serum. [1] Individuals carrying the minor allele of rs174548 exhibit a reduced efficiency of the fatty acid delta-5 desaturase reaction. This reduction is observed to lead to lower concentrations of polyunsaturated fatty acids with four or more double bonds in their side chains, such as those containing arachidonic acid (C20:4), and conversely, higher concentrations of less desaturated forms.[1] This genetic influence suggests that an individual’s genotype at loci like rs174548 can significantly shape their circulating lipid profiles.
Clinical Relevance
Section titled “Clinical Relevance”The levels of eicosapentaenoylcholine and other polyunsaturated fatty acid-containing phospholipids are clinically relevant due to their roles in various physiological processes. Omega-3 and omega-6 fatty acids are precursors to eicosanoids, which are signaling molecules involved in inflammation, immune responses, and cardiovascular function. Alterations in the balance of these fatty acids, influenced by genetic factors like variations inFADS1, can therefore have implications for health. While the provided context primarily focuses on the genetic determination of metabolite levels, the broader understanding of PUFA metabolism links these changes to conditions such as metabolic syndrome, cardiovascular disease, and inflammatory disorders. The association ofrs174548 with glycerophospholipid concentrations highlights a “genetically determined metabotype,” where genetic variations directly influence an individual’s metabolic profile.[1]
Social Importance
Section titled “Social Importance”The study of eicosapentaenoylcholine and its genetic determinants holds social importance for several reasons. It contributes to the growing field of personalized nutrition, where dietary recommendations can be tailored based on an individual’s genetic predisposition to metabolize specific nutrients. Understanding how genetic variants, such asrs174548 , affect the endogenous synthesis of critical fatty acids like EPA can inform public health strategies regarding dietary fat intake and supplementation. For instance, individuals with genetic profiles indicating lower desaturase efficiency might benefit differently from dietary sources of pre-formed long-chain PUFAs compared to those with higher efficiency. This knowledge can empower individuals and healthcare providers to make more informed decisions about diet and lifestyle to optimize health outcomes.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Studies investigating eicosapentaenoylcholine, like many other complex traits, often face limitations in statistical power and sample size, which can hinder the detection of genetic effects explaining only a small proportion of phenotypic variation.[2]While some research indicates sufficient power to detect associations explaining 4% or more of the total phenotypic variance, more modest genetic influences on eicosapentaenoylcholine may remain undetected.[2] This issue is exacerbated by the extensive multiple statistical testing inherent in genome-wide association studies, necessitating stringent significance thresholds and increasing the risk of both false positives and false negatives. [2]Consequently, the ultimate validation of initial findings for eicosapentaenoylcholine relies heavily on independent replication in other cohorts to distinguish true genetic associations from spurious ones.[3]
Further constraints arise from the scope of genetic coverage and the accuracy of imputation methods. Many genome-wide association studies, particularly earlier ones, utilized a subset of all known SNPs, potentially missing important genetic variants influencing eicosapentaenoylcholine due to incomplete genomic representation[4]. [5] While imputation helps infer missing genotypes, it introduces a degree of uncertainty, with reported error rates ranging from 1.46% to 2.14% per allele. [6]Additionally, the reliance on fixed-effects meta-analysis, although standard, assumes minimal heterogeneity across combined studies; despite assessments, underlying population differences could subtly influence the pooled estimates of genetic effects on eicosapentaenoylcholine[7]. [8]
Generalizability and Phenotype Assessment
Section titled “Generalizability and Phenotype Assessment”A significant limitation in understanding the genetic influences on eicosapentaenoylcholine is the predominant focus on populations of European ancestry across many initial genome-wide association studies[8], [9]. [10] This demographic bias restricts the generalizability of findings to other ethnic groups, as genetic architecture, allele frequencies, and linkage disequilibrium patterns can vary substantially, potentially leading to different associations or effect sizes in non-European populations. [9]Although some studies have attempted to extend findings to multi-ethnic samples, the initial narrow focus means that a comprehensive understanding of genetic influences on eicosapentaenoylcholine across diverse global populations remains incomplete.[9]
Phenotype assessment methods also introduce limitations. Many studies specifically excluded individuals receiving lipid-lowering therapies, which, while useful for examining genetic effects in an untreated context, limits the applicability of the findings to the broader population, including those on medication [9]. [6]Furthermore, to mitigate the multiple testing burden, sex-pooled analyses were often performed, potentially obscuring sex-specific genetic associations with eicosapentaenoylcholine that might manifest differently in males and females.[4] The practice of averaging phenotypic traits across multiple examinations, while enhancing reliability, might also mask acute or dynamic genetic influences. [2]
Unexplored Genetic and Environmental Interactions and Knowledge Gaps
Section titled “Unexplored Genetic and Environmental Interactions and Knowledge Gaps”The current understanding of eicosapentaenoylcholine is notably limited by a lack of comprehensive investigation into gene-environment interactions.[2]Genetic variants are known to influence phenotypes in context-specific ways, with environmental factors such as diet, lifestyle, or medication potentially modulating their effects.[2]Without explicitly studying these complex interactions, the full genetic landscape underlying eicosapentaenoylcholine cannot be fully elucidated, leaving a critical gap in predicting individual susceptibility or optimizing interventions.[2]
Despite the identification of novel genetic loci, a significant challenge persists in functionally validating these associations and elucidating the precise biological mechanisms through which they influence eicosapentaenoylcholine.[3] Genome-wide association studies primarily identify statistical correlations, and further functional studies are essential to move beyond association to causality and to comprehensively characterize candidate genes [3]. [4]This ongoing need for in-depth functional follow-up and the inherent difficulty in prioritizing numerous statistically significant SNPs contribute to remaining knowledge gaps about the complete polygenic architecture of eicosapentaenoylcholine.[3]
Variants
Section titled “Variants”The FADS1 and FADS2 genes are critical components of the fatty acid desaturase gene cluster, located on chromosome 11, which plays a pivotal role in human lipid metabolism. These genes encode enzymes responsible for synthesizing long-chain polyunsaturated fatty acids (PUFAs) from dietary precursors, which are essential for various physiological processes, including cell membrane structure and signaling. Genetic variations within this cluster, such as rs174551 , are known to significantly influence the efficiency of these metabolic pathways, thereby affecting the levels of circulating fatty acids and their complex lipid derivatives. [1] The coordinated action of FADS1 and FADS2ultimately determines the availability of substrates for the formation of complex lipids like eicosapentaenoylcholine, a phosphatidylcholine containing eicosapentaenoic acid (EPA).[1]
The FADS1gene encodes delta-5 desaturase, an enzyme crucial for the final steps in the synthesis of highly unsaturated fatty acids such as eicosapentaenoic acid (EPA) and arachidonic acid (AA). This enzyme catalyzes the introduction of a double bond at the fifth carbon position from the carboxyl end of fatty acid chains. Variants likers174551 are frequently associated with altered delta-5 desaturase activity, which can lead to changes in the balance of omega-3 and omega-6 PUFAs in the body. Studies have shown a positive association between the FADS1 genotype and specific phosphatidylcholines (PC aa C34:2 and PC aa C36:2) with fewer double bonds, suggesting that certain genotypes might lead to less efficient desaturation. [1] Consequently, these genetic influences on FADS1activity directly impact the production of EPA and, by extension, the levels of eicosapentaenoylcholine, a key lipid involved in cellular function and inflammation.[1]
Complementing FADS1, the FADS2gene encodes delta-6 desaturase, an enzyme that performs the initial and often rate-limiting step in the PUFA synthesis pathway. Delta-6 desaturase introduces a double bond at the sixth carbon position, converting essential fatty acids like linoleic acid and alpha-linolenic acid into their elongated and desaturated forms. Given the close proximity and functional interplay betweenFADS1 and FADS2 within the gene cluster, variants such as rs174551 can exert a widespread influence on the entire desaturation cascade. Alterations in FADS2 activity, often modulated by genetic factors, will subsequently affect the substrates available for FADS1activity and thus indirectly impact the synthesis of EPA and the formation of eicosapentaenoylcholine. The interplay between these enzymes is vital for maintaining the complex homeostasis of glycerophospholipids, including phosphatidylcholines and phosphatidylethanolamines, as demonstrated by their broad associations with various lipid metabolites.[1] This intricate metabolic network ensures the proper balance of fatty acids, which is essential for numerous biological processes, including the structural integrity of cell membranes. [1]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs174551 | FADS2, FADS1 | low density lipoprotein cholesterol measurement triglyceride measurement serum alanine aminotransferase amount level of phosphatidylcholine cholesteryl ester 18:3 measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Structural Definition and Lipid Class
Section titled “Structural Definition and Lipid Class”Eicosapentaenoylcholine is a specific type of glycerophospholipid, belonging to the phosphatidylcholine (PC) class, characterized by the presence of an eicosapentaenoyl fatty acid residue. Phosphatidylcholines are fundamental components of biological membranes, acting as structural elements and signaling molecules, and are distinguishable by their choline head group attached to a phosphate moiety at thesn-3 position of a glycerol backbone. [1]The “eicosapentaenoyl” component indicates a fatty acid chain derived from eicosapentaenoic acid (EPA), which is a polyunsaturated fatty acid (PUFA) with 20 carbon atoms and 5 double bonds (C20:5).[1]This makes eicosapentaenoylcholine a complex lipid, often found in serum and other biological fluids, where its concentration can be influenced by genetic factors and dietary intake.
Standardized Nomenclature and Subtypes
Section titled “Standardized Nomenclature and Subtypes”The systematic classification of phosphatidylcholines, including eicosapentaenoylcholine, employs a standardized nomenclature that describes the ester or ether bonds in the glycerol moiety and the composition of the attached fatty acid side chains.[1]A single letter ‘a’ (acyl) or ‘e’ (alkyl) indicates the presence of a single fatty acid residue, defining a lysophosphatidylcholine (e.g., PC a C20:5 for a lyso-eicosapentaenoylcholine).[1] If two glycerol positions are bound to fatty acid residues, ‘aa’ denotes diacyl (ester-linked), ‘ae’ denotes acyl-alkyl (one ester, one ether-linked), and ‘ee’ denotes dialkyl (two ether-linked) forms, such as “PC ae C33:1” for a plasmalogen/plasmenogen phosphatidylcholine. [1] The lipid side chain composition is further abbreviated as Cx:y, where ‘x’ represents the total number of carbons in the side chains and ‘y’ indicates the total number of double bonds, although the precise position of double bonds and their distribution across individual fatty acids cannot always be determined by certain analytical technologies. [1]
Analytical Approaches and Clinical Context
Section titled “Analytical Approaches and Clinical Context”The measurement of metabolites like eicosapentaenoylcholine in biological samples, such as serum, is crucial for understanding metabolic traits and their association with genetic variants.[1] These concentrations are typically determined using analytical methods, which can include techniques like mass spectrometry, allowing for the quantification of various phosphatidylcholine species. [1] Sample collection for such analyses often involves standardized procedures, such as drawing blood samples after overnight fasting, and may include exclusions for individuals on specific medications like lipid-lowering therapies or with certain health conditions like diabetes, to ensure consistent and comparable data. [11]The study of polyunsaturated fatty acid-containing glycerophospholipids, including those with C20:4 (arachidonic acid) and by extension C20:5 (eicosapentaenoic acid), has revealed strong associations with genetic polymorphisms, such as those in theFADS1 gene, highlighting their significance as biomarkers for metabolic health. [1]
Biological Background
Section titled “Biological Background”Biosynthesis of Long-Chain Polyunsaturated Fatty Acids and Phosphatidylcholines
Section titled “Biosynthesis of Long-Chain Polyunsaturated Fatty Acids and Phosphatidylcholines”Eicosapentaenoylcholine, a specific type of phosphatidylcholine, is a vital component of cellular membranes, with its eicosapentaenoic acid (EPA, C20:5) moiety being a crucial long-chain polyunsaturated fatty acid (LCPUFA). The human body produces LCPUFAs from essential dietary fatty acids such as linoleic acid (C18:2) via the omega-6 fatty acid synthesis pathway and alpha-linolenic acid (C18:3) through the omega-3 pathway.[1] These intricate metabolic pathways involve a series of desaturation and elongation reactions, which are essential for generating a diverse pool of fatty acids like eicosatrienoyl-CoA (C20:3) and arachidonyl-CoA (C20:4) for subsequent lipid synthesis. [1]
A key enzyme in this process is fatty acid delta-5 desaturase, encoded by the FADS1 gene, which is responsible for introducing a double bond at a specific position within the fatty acid chain. [1] This enzyme notably catalyzes the conversion of eicosatrienoyl-CoA (C20:3) to arachidonyl-CoA (C20:4), a critical step for the production of various glycerophospholipids. [1]Following fatty acid synthesis, the Kennedy pathway then orchestrates the formation of glycerol-phosphatidylcholines by esterifying two fatty acid moieties to glycerol 3-phosphate, which is subsequently dephosphorylated and coupled with a phosphocholine group, yielding the complex phosphatidylcholines with their characteristic fatty acid side chains.[1]
Genetic Regulation of Fatty Acid Metabolism
Section titled “Genetic Regulation of Fatty Acid Metabolism”The efficiency of LCPUFA biosynthesis and the subsequent formation of phosphatidylcholines are profoundly influenced by genetic variations, particularly within the FADS1 gene cluster. [1]A specific single nucleotide polymorphism,rs174548 , located within a region of strong linkage disequilibrium encompassing the FADS1 gene, is significantly associated with the concentrations of numerous glycerophospholipids in human serum. [1] This genetic variant can account for up to 10% of the observed variance in the levels of certain glycerophospholipids, indicating its substantial role in modulating lipid profiles. [1]
Individuals carrying the minor allele of rs174548 exhibit a reduced efficiency in the fatty acid delta-5 desaturase reaction, which alters the metabolic flux of fatty acids. [1] This diminished enzymatic activity leads to an accumulation of substrates, such as eicosatrienoyl-CoA (C20:3), and a decrease in the corresponding products, like arachidonyl-CoA (C20:4), directly impacting the fatty acid composition of complex lipids. [1] Consequently, this genetic influence is reflected in the serum concentrations of specific phosphatidylcholines, with an increase in those containing three double bonds (e.g., PC aa C36:3) and a reduction in those with four double bonds (e.g., PC aa C36:4), providing a measurable indicator of FADS1 enzymatic function. [1]
Cellular and Systemic Lipid Homeostasis
Section titled “Cellular and Systemic Lipid Homeostasis”Phosphatidylcholines are indispensable components of all biological membranes, where they contribute to membrane fluidity, facilitate cellular signaling, and enable the transport of molecules across cellular compartments. [1] Maintaining the precise fatty acid composition of these phospholipids, particularly the balance of LCPUFAs, is critical for preserving cellular integrity and ensuring proper physiological function. [1] Genetic variations that disrupt the efficiency of fatty acid desaturation, such as those impacting FADS1, consequently lead to alterations in the overall glycerophospholipid profile, thereby affecting the availability and incorporation of specific fatty acids into these essential cellular structures.[1]
Beyond their direct cellular roles, changes in phosphatidylcholine homeostasis have broader systemic implications, influencing the metabolism of other lipid classes throughout the body. [1]For example, an altered balance of phosphatidylcholines can impact the levels of sphingomyelins, as sphingomyelin synthase utilizes phosphatidylcholine as a substrate for its synthesis.[1]Similarly, the concentrations of lyso-phosphatidylethanolamines can be affected, collectively demonstrating how perturbations in specific glycerophospholipid pathways ripple through the intricate network of lipid metabolism, impacting various tissues and organs.[1]
Pathophysiological Relevance of Lipid Dysregulation
Section titled “Pathophysiological Relevance of Lipid Dysregulation”The meticulous regulation of LCPUFA and phosphatidylcholine metabolism is paramount for maintaining overall metabolic health, and disruptions driven by genetic factors can contribute to pathophysiological processes. [1] Polymorphisms within genes such as FADS1, which lead to altered fatty acid delta-5 desaturase efficiency, result in distinctive serum lipid profiles characterized by imbalances in various phosphatidylcholines and other glycerophospholipids. [1] These shifts in the lipid landscape represent a departure from normal homeostatic mechanisms, highlighting the significant genetic contributions to individual differences in lipid metabolism. [1]
Although the immediate clinical implications of specific eicosapentaenoylcholine levels are not explicitly detailed, the broader understanding of lipid metabolism indicates that dysregulation in LCPUFA synthesis and phospholipid composition can influence systemic metabolic pathways and potentially contribute to the risk of various conditions, including dyslipidemia.[1] These genetically determined lipid signatures, or metabotypes, provide valuable insights into the complex interplay between genetic predispositions, metabolic function, and human health. [1]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Fatty Acid Biosynthesis and Phospholipid Integration
Section titled “Fatty Acid Biosynthesis and Phospholipid Integration”The synthesis of eicosapentaenoylcholine involves intricate metabolic pathways, beginning with the production of long-chain polyunsaturated fatty acids (LCPUFAs). Essential fatty acids like linoleic acid (C18:2) in the omega-6 pathway and alpha-linolenic acid (C18:3) in the omega-3 pathway serve as foundational precursors.[1]From these, desaturation and elongation reactions generate LCPUFAs such as eicosapentaenoic acid (EPA, C20:5) or its precursor eicosatrienoyl-CoA (C20:3), which can then be incorporated into complex lipids.[1]The Kennedy pathway is central to the formation of glycerophosphatidylcholines (PC), where two fatty acid moieties, potentially including eicosapentaenoic acid, are linked to a glycerol 3-phosphate backbone, followed by dephosphorylation and the addition of a phosphocholine moiety to yield the final phosphatidylcholine structure.[1] This process ensures the precise assembly of phospholipids with diverse fatty acid side chains, critical for membrane structure and function.
Genetic and Enzymatic Regulation of Fatty Acid Desaturation
Section titled “Genetic and Enzymatic Regulation of Fatty Acid Desaturation”A key regulatory point in the synthesis of LCPUFAs, and consequently their incorporation into phosphatidylcholines like eicosapentaenoylcholine, is the activity of fatty acid desaturases. TheFADS1 gene encodes the fatty acid delta-5 desaturase, an enzyme crucial for converting eicosatrienoyl-CoA (C20:3) into arachidonyl-CoA (C20:4). [1]Genetic variations, such as the single nucleotide polymorphism (SNP)rs174548 located within the FADS1 gene cluster, significantly influence the efficiency of this desaturation reaction. [1] The minor allele variant of rs174548 can lead to reduced delta-5 desaturase activity, altering the availability of specific fatty acyl-CoAs for glycerophospholipid synthesis, thereby impacting the concentrations of various phosphatidylcholines, including those with particular polyunsaturated fatty acid compositions.[1] This genetic regulation exemplifies how subtle changes in enzyme function can control metabolic flux and the resulting lipid profiles.
Metabolic Interdependencies and Systems-Level Lipid Homeostasis
Section titled “Metabolic Interdependencies and Systems-Level Lipid Homeostasis”The synthesis of eicosapentaenoylcholine is intrinsically linked to broader lipid metabolism, demonstrating extensive pathway crosstalk and network interactions. The balance between omega-3 and omega-6 fatty acid synthesis pathways is critical, as both share desaturase enzymes, and their products compete for incorporation into phospholipids.[1] This interdependency means that alterations in one pathway can have ripple effects throughout the entire lipidome, influencing the composition and function of cellular membranes and lipid signaling molecules. [1] The overall efficiency of fatty acid desaturation, as determined by enzymes like delta-5 desaturase, therefore plays a hierarchical role in shaping the diverse array of glycerophospholipids present in the body, reflecting a complex interplay of genetic predisposition and metabolic flux control.
Disease Relevance and Pathway Dysregulation
Section titled “Disease Relevance and Pathway Dysregulation”Dysregulation in the pathways leading to eicosapentaenoylcholine and related phospholipids has significant implications for human health. Reduced efficiency of the delta-5 desaturase reaction, often due to genetic polymorphisms inFADS1, can lead to altered serum concentrations of specific glycerophospholipids, such as increased PC aa C36:3 and decreased PC aa C36:4. [1]These altered lipid profiles are considered genetically determined metabotypes and have been identified as biomarkers for cardiovascular disease.[12] Furthermore, variations in fatty acid desaturase genes have been associated with neurological conditions like attention-deficit/hyperactivity disorder, underscoring the broad clinical relevance of maintaining optimal LCPUFA metabolism. [13] Understanding these dysregulations provides potential therapeutic targets for managing lipid-related disorders and improving overall metabolic health.
References
Section titled “References”[1] Gieger, C. et al. “Genetics Meets Metabolomics: A Genome-Wide Association Study of Metabolite Profiles in Human Serum.”PLoS Genetics, vol. 4, no. 11, 2008, p. e1000282. PubMed, PMID: 19043545.
[2] Vasan, R. S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S2.
[3] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S11.
[4] Yang, Q., et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S12.
[5] O’Donnell, C. J., et al. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.”BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S10.
[6] Willer, C. J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161–169.
[7] Yuan, X., et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet, vol. 83, no. 5, 2008, pp. 520–528.
[8] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, no. 1, 2008, pp. 60–69.
[9] Kathiresan, S. et al. “Common Variants at 30 Loci Contribute to Polygenic Dyslipidemia.” Nature Genetics, vol. 41, no. 1, 2009, pp. 56-65. PubMed, PMID: 19060906.
[10] Melzer, D., et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet, vol. 4, no. 5, 2008, p. e1000072.
[11] Sabatti, C. et al. “Genome-Wide Association Analysis of Metabolic Traits in a Birth Cohort from a Founder Population.”Nature Genetics, vol. 41, no. 1, 2009, pp. 35-42. PubMed, PMID: 19060910.
[12] Wallace, Cathryn, et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”American Journal of Human Genetics, vol. 82, no. 1, 2008, pp. 139-149.
[13] Brookes, K. J., et al. “Association of fatty acid desaturase genes with attention-deficit/hyperactivity disorder.” Biological Psychiatry, vol. 60, no. 10, 2006, pp. 1053-1061.