Association Between a Functional Polymorphism in the MAOA Gene and Both Emotional Coping Style and Neuroticism

Objective: Identification of genetic risk factors for major depressive disorder (MDD) represents a major challenge around the world. Molecular studies of endophenotypes associated with MDD, such as personality traits and coping, are useful for the identification of candidate genes. The aim of this study was to evaluate the possible association between a functional polymorphism in the monoamine oxidase A (MAOA) gene and scores in coping and neuroticism in young adults. Results: A sample of 251 healthy young participants from Colombia were evaluated with the short forms of the Coping Inventory for Stressful Situations (CISS-SF) and the Big Five Inventory (BFI-S) and genotyped for MAOA-VNTR polymorphism. A statistically significant association of the functional MAOA-VNTR for scores in both emotion-oriented coping and neuroticism was found. Individuals carrying the 4 allele (3/4 or 4/4 genotypes) had higher scores for both emotion-oriented coping and neuroticism than individuals with a 3/3 genotype. Our results are the first description about a significant association between a functional polymorphism in the MAOA gene and coping and add evidence to the association of this gene with neuroticism. Our findings support the hypothesis of a broad effect of the MAOA gene on several dimensions of human behavior of psychiatric relevance.


Introduction
The identification of genetic risk factors for major depressive disorder (MDD) represents a major challenge around the world (1)(2)(3). There is the need for more studies to find the molecular risk factors and pathophysiological mechanisms underlying MDD (3,4). Genetic studies of the endophenotypes associated with MDD, such as personality traits and coping, are useful for the identification of candidate genes (1). Personality traits have been studied extensively for decades, using approaches from psychology, neurosciences and genetics (5,6). The association of different personality dimensions with psychopathology has been explored in multiple populations around the world (6). Particularly, neuroticism has been strongly associated with MDD, among other psychiatric disorders (6). An important number of genes, such as DRD4 and SLC6A4, have been explored as possible molecular correlates for neuroticism in samples of healthy individuals (6).
Coping strategies represent important approaches for managing stressful situations, with major implications for the risk for psychopathology (7). When an individual is confronted with a stressful situation in life, their coping strategy plays a role in their ability to adequately adapt to the situation. Some individuals tend to use emotions, others are avoidant and others are more task oriented. Individuals who are neurotic who tend to use an emotion-oriented copying style are more likely to suffer from a mood disorder (8,9). It has been found that coping has a moderate heritability; however, few studies have analyzed genetic factors associated with coping in healthy individuals (7).
Polymorphisms in multiple genes that are involved in the dopaminergic and serotoninergic systems have been postulated as novel candidates for MDD, considering the role of these circuits in neural processes related to emotion, motivation and reward (3). The monoamine oxidase A (MAOA) has a major role in the regulation of levels of dopamine, norepinephrine, and serotonin neurotransmitters (10). The MAOA gene is located at the Xp.11.4-Xp11.3 genomic region, with a length of 90,660 bp and it is expressed in several brain regions (11). A functional variable-number tandem repeat (VNTR) has been found in the promoter region of MAOA gene (MAOA-uVNTR), involving a 30 bp repeat sequence (12). The polymorphism consists of 2, 3, 3.5, 4 and 5 30bp repeats, being the 3 and 4 alleles more common. Some studies group the short forms (3 repeats and shorter) and the long alleles (3.5, repeats and longer). Functional studies have shown that MAOA gene transcription is regulated by this VNTR, with the four repeat allele (or longer alleles) associated to higher expression levels (10,13). This functional polymorphism has been studied as a possible candidate for a number of neuropsychiatric disorders and a metaanalysis has found that variants in the MAOA gene could play an important role in the molecular mechanisms of response to behavioral stress and development of psychopathology (14). A polymorphism in the MAOA gene (rs1137070) was found as associated with MDD in females in a recent meta-analysis (11). The MAOA gene has been analyzed previously as a candidate for neuroticism in populations of European and Asian descent, with conflicting results ( Table 1) ( 15,16).
The main aim of this work was to evaluate the possible association between the functional polymorphism in the MAOA gene and neuroticism and coping scores in young Colombian adults.

Participants
The current study analyzed a sample of 251 young adults, living in Bogotá, Colombia (17,18). All participants signed a written informed consent and the study was approved by the institutional ethics committee (Universidad Antonio Nariño).

Assessment of Neuroticism and Coping
The Big Five Inventory (BFI-S; 15-items) was employed to evaluate personality dimensions (19). The Big Five personality trait model is one of the most established and used approaches to measure individual differences in personality. This inventory based in selfreport measures five dimensions of personality: N (Neuroticism), E (Extraversion), O (Openness to experience), C (Conscientiousness) and A (Agreeableness), on a Likert scale of 7-points. It has been widely used in several countries, such as Spain and Colombia (17,18) and had an adequate internal consistency in this sample.
The Short Form of the Coping Inventory for Stressful Situations (CISS-SF, with 21 items) was used for the analysis of coping (20). This tool assesses three coping styles (taskoriented, emotional, and avoidant). CISS-SF items exemplify different ways of coping in a stressful situation. It has been previously used in the Spanish language (18)

Statistical analysis
To assess the normal distributions of the CISS-SF and BFI-S scores, an analysis of skewness and kurtosis was used (23). These statistical analyses were conducted with the Statistical Package for the Social Sciences (SPSS v. 18). Allelic and genotype frequencies, Hardy-Weinberg equilibrium in females and the analysis of a possible association of the MAOA genotypes with the CISS-SF and BFI-S scores were calculated using the SNPStats program (24) (male hemizygous subjects were combined with female homozygous subjects), using a linear regression model, which was adjusted by age and gender (21,22).

Results
Participants were at least 18 years or older, were unrelated and, according to self-report, did not have personal history of neuropsychiatric disorders. Subjects had a mean age of 21 years (SD = 1.4) and 75 % were women. The socioeconomic status of the total sample (SES) was represented mainly by low (34%) and medium (46%) strata, according to selfreport. Scores for both scales had a normal distribution (p>0.05). The only alleles found in the sample were 3 and 4. The 3 allele of MAOA-uVNTR was found in 36% of the sample.
Genotype frequencies in females were in Hardy Weinberg equilibrium (p = 0.33).
A significant association was found for MAOA-uVNTR and scores in emotion-oriented coping, with carriers of the 3/4 and 4/4 genotypes showing higher scores (p = 0.009) ( Table 2).. A statistically significant association was also found between genotype groups of the MAOA-uVNTR and scores in neuroticism, with carriers of the 3/4 and 4/4 genotypes showing higher scores (p = 0.02) ( Table 2).. No significant association were found for the scores in the other dimensions of personality or copying.

Discussion
In the current work, we report the novel association of a functional polymorphism in the MAOA gene with scores in emotion-oriented coping and neuroticism, in a sample of young subjects. Our study is the first to report the significant association of a polymorphism in the MAOA gene and coping.
Several studies have analyzed the association of MAOA gene with neuroticism in populations of European and Asian descent (15,16,(25)(26)(27), with conflicting results ( Table   1) (26); in a Japanese sample no association was found by Tochigi et al (27); in a Polish sample no association with neuroticism was found by Pełka-Wysiecka (25); in a British sample no association was found by Xu et al (16).
The MAOA gene encodes a protein that is a key enzyme in the regulation of several neurotransmitters, such as dopamine, noradrenaline, and serotonin, which are fundamental for the regulation of sleep and other behavioral phenotypes (10). Studies using MAOA knockout mice models have established that its deficiency leads to neurochemical imbalances, which culminates in neuroanatomical abnormalities such as reduced thickness of corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of cerebellum (28). It has been demonstrated that the 4-repeat allele of the human MAOA-uVNTR is transcriptionally and enzymatically more active (2 to 10 times) than the 3-repeat allele (12).

Consent for publication
Not applicable

Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding authors.

Competing interests
The authors declare that they have no competing interests.