The Open Neurology Journal




ISSN: 1874-205X ― Volume 13, 2019
RESEARCH ARTICLE

Anxiety-related Endophenotypes and Hazardous Alcohol Use in Young Adults are Associated with a Functional Polymorphism in the SLC6A4 Gene



Karen M. Jiménez1, Angela J. Pereira-Morales1, Ana Adan2, 3, Sandra Lopez-Leon4, Diego A. Forero1, 5, 6, *
1 Laboratory of NeuroPsychiatric Genetics, Biomedical Sciences Research Group, School of Medicine, Universidad Antonio Nariño, Bogotá, Colombia
2 Department of Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain
3 Institute of Neurosciences, University of Barcelona, Barcelona, Spain
4 Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA
5 School of Medicine, Universidad Antonio Nariño, Bogotá, Colombia
6 Laboratory of NeuroPsychiatric Genetics, School of Medicine, Universidad Antonio Nariño, 110231, Bogotá, Colombia

Abstract

Background:

A functional polymorphism (5-HTTLPR, rs4795541) in the serotonin transporter (SLC6A4) gene has been shown as an important candidate for several psychiatric and behavioral traits.

Objective:

The objective of this study was to examine the possible interaction of this polymorphism with physical neglect in childhood on the presentation of anxiety traits and hazardous alcohol consumption in young Colombian subjects.

Methods:

272 young adults (mean age: 21.3 years) were evaluated with the Childhood Trauma Questionnaire, the Zung Self-rating Anxiety Scale, the Big Five Inventory, the Cohen’s Perceived Stress Scale, the Alcohol, Smoking, Substance Involvement Screening Test and the Alcohol Use Disorders Identification Test. Genotyping for the 5-HTTLPR polymorphism was carried out using conventional PCR. A linear regression model, corrected by age and gender, was used.

Results:

We found that individuals with the L/L genotype showed higher scores on physical neglect (p=0.0047), anxiety symptoms (p=0.028), neuroticism (p=0.019) and perceived stress (p=0.035). L/L genotype was a risk factor for hazardous alcohol use in young adults (OR=3.06, p=0.0003). No GxE interactions were observed in our data.

Conclusion:

Our results provide novel evidence for the role of a functional polymorphism in the SLC6A4 gene on the relationship of childhood trauma, anxiety-related traits and risky consumption of alcohol.

Keywords: Alcohol use, Anxiety, Candidate genes, Childhood trauma, Neuroticism, Psychiatric genetics.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 83
Last Page: 91
Publisher Id: TONEUJ-13-83
DOI: 10.2174/1874205X01913010083

Article History:

Received Date: 04/04/2019
Revision Received Date: 25/05/2019
Acceptance Date: 18/06/2019
Electronic publication date: 31/07/2019
Collection year: 2019

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© 2019 Jiménez et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Laboratory of NeuroPsychiatric Genetics, School of Medicine, Universidad Antonio Nariño, 110231, Bogotá, Colombia; Tel: +57 313 610427; Email: diego.forero@uan.edu.co




1. INTRODUCTION

Anxiety Disorders (AD), which include panic disorder, generalized anxiety disorder, post-traumatic stress disorder, phobias, and separation anxiety disorder, are among the most common mental disorders around the world [1Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence of anxiety disorders: A systematic review and meta-regression. Psychol Med 2013; 43(5): 897-910.[http://dx.doi.org/10.1017/S003329171200147X] [PMID: 22781489] , 2Kessler RC, Aguilar-Gaxiola S, Alonso J, et al. The global burden of mental disorders: An update from the WHO World Mental Health (WMH) surveys. Epidemiol Psichiatr Soc 2009; 18(1): 23-33.[http://dx.doi.org/10.1017/S1121189X00001421] [PMID: 19378696] ]. These disorders usually have an early onset followed by a chronic course, being the sixth leading cause of disability worldwide [3Baxter AJ, Vos T, Scott KM, Ferrari AJ, Whiteford HA. The global burden of anxiety disorders in 2010. Psychol Med 2014; 44(11): 2363-74.[http://dx.doi.org/10.1017/S0033291713003243] [PMID: 24451993] ]. The current global prevalence of anxiety disorders is 7.3%, suggesting that one in 14 people has an anxiety disorder at any given time [1Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence of anxiety disorders: A systematic review and meta-regression. Psychol Med 2013; 43(5): 897-910.[http://dx.doi.org/10.1017/S003329171200147X] [PMID: 22781489] ]. The prevalence is higher in women than in men, with women to men ratio of 1.9:1 and it has been remained relatively constant across time [4Baxter AJ, Scott KM, Ferrari AJ, Norman RE, Vos T, Whiteford HA. Challenging the myth of an “epidemic” of common mental disorders: trends in the global prevalence of anxiety and depression between 1990 and 2010. Depress Anxiety 2014; 31(6): 506-16.[http://dx.doi.org/10.1002/da.22230] [PMID: 24448889] ]. Prevalence estimates for AD were significantly higher in people exposed to an armed conflict [1Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence of anxiety disorders: A systematic review and meta-regression. Psychol Med 2013; 43(5): 897-910.[http://dx.doi.org/10.1017/S003329171200147X] [PMID: 22781489] ] and, in this context, the Colombian population has suffered from one of the longest internal armed conflicts in the world [5Rodriguez C, Sanchez F. Armed conflict exposure, human capital investments, and child labor: Evidence from Colombia. Defence Peace Econ 2012; 23(2): 161-84.[http://dx.doi.org/10.1080/10242694.2011.597239] ]. According to the DSM-V, substance use disorders are characterized by at least two of the diagnostic criteria (such as social and legal problems related to use, among others) [6Bhad R, Lal R, Balhara YP. Disorders related to use of psychoactive substances in DSM-5: Changes and challenges. Indian J Psychol Med 2015; 37(4): 470-2.[http://dx.doi.org/10.4103/0253-7176.168613] [PMID: 26702188] ] and are important contributors to the global burden of disease [7Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of Disease Study 2010. Lancet 2013; 382(9904): 1575-86.[http://dx.doi.org/10.1016/S0140-6736(13)61611-6] [PMID: 2399 3280] ]. Hazardous alcohol use has been defined as a pattern of consumption that leads to a higher risk of harmful effects for the individual [8Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption--II. Addiction 1993; 88(6): 791-804.[http://dx.doi.org/10.1111/j.1360-0443.1993.tb02093.x] [PMID: 8329 970] ].

AD and hazardous alcohol use are complex traits with a complex etiology. They both have an environmental and a genetic component. It is expected that the combination of several genetic polymorphisms interacts with environmental variables to increase the risk [9Forero DA, Vélez-van-Meerbeke A, Deshpande SN, Nicolini H, Perry G. Neuropsychiatric genetics in developing countries: Current challenges. World J Psychiatry 2014; 4(4): 69-71.[http://dx.doi.org/10.5498/wjp.v4.i4.69] [PMID: 25540721] -11Shimada-Sugimoto M, Otowa T, Hettema JM. Genetics of anxiety disorders: Genetic epidemiological and molecular studies in humans. Psychiatry Clin Neurosci 2015; 69(7): 388-401.[http://dx.doi.org/10.1111/pcn.12291] [PMID: 25762210] ]. Even though several genes are associated with both disorders, the SLC6A4 gene, which encodes the serotonin transporter, became a major candidate gene for AD and hazardous alcohol use [10Kim J, Park A. A systematic review: Candidate gene and environment interaction on alcohol use and misuse among adolescents and young adults. Am J Addict 2018.[http://dx.doi.org/10.1111/ajad.12755] [PMID: 29992684] , 12Gelernter J. SLC6A4 polymorphism, population genetics, and psychiatric traits. Hum Genet 2014; 133(4): 459-61.[http://dx.doi.org/10.1007/s00439-013-1412-2] [PMID: 24385047] ]. It is interesting in the context that several drugs of psychiatric use, such as paroxetine and citalopram, are inhibitors of this transporter [12Gelernter J. SLC6A4 polymorphism, population genetics, and psychiatric traits. Hum Genet 2014; 133(4): 459-61.[http://dx.doi.org/10.1007/s00439-013-1412-2] [PMID: 24385047] ].

The most commonly studied polymorphism in this gene is the non-coding variant 5-HTTLPR (rs4795541), which is located in the promoter region [13Iurescia S, Seripa D, Rinaldi M. Role of the 5-HTTLPR and SNP promoter polymorphisms on serotonin transporter gene expression: A closer look at genetic architecture and In Vitro functional studies of common and uncommon allelic variants. Mol Neurobiol 2016; 53(8): 5510-26.[http://dx.doi.org/10.1007/s12035-015-9409-6] [PMID: 26464328] ]. This polymorphism is a Variable Number Tandem Repeat (VNTR), composed of 24 bp repeats which generate different alleles. The two main alleles are the short (S) with 14 repeats and the long (L) with 16 repeats [13Iurescia S, Seripa D, Rinaldi M. Role of the 5-HTTLPR and SNP promoter polymorphisms on serotonin transporter gene expression: A closer look at genetic architecture and In Vitro functional studies of common and uncommon allelic variants. Mol Neurobiol 2016; 53(8): 5510-26.[http://dx.doi.org/10.1007/s12035-015-9409-6] [PMID: 26464328] ].

Functional studies have reported that the L allele is associated with higher levels of transcriptional activity and with a higher rate of serotonin uptake [14Hu XZ, Lipsky RH, Zhu G, et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006; 78(5): 815-26.[http://dx.doi.org/10.1086/503850] [PMID: 16642437] ]. In addition, several works have shown that the S allele, in general, is associated with a less favorable response to pharmacological treatment in affective and anxiety disorders [15Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry 2010; 15(5): 473-500.[http://dx.doi.org/10.1038/mp.2008.116] [PMID: 18982004] , 16Bauer IE, Graham DP, Soares JC, Nielsen DA. Serotonergic gene variation in substance use pharmacotherapy: A systematic review. Pharmacogenomics 2015; 16(11): 1307-14.[http://dx.doi.org/10.2217/pgs.15.72] [PMID: 26265436] ].

Lesch et al conducted the first study that found an association between the SLC6A4 promoter polymorphism and anxiety-related traits, including the neurotic personality trait [17Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274(5292): 1527-31.[http://dx.doi.org/10.1126/science.274.5292.1527] [PMID: 8929413] ], and the authors reported that the 5-HTTLPR poly-morphism accounted for 3-4% of population variability in neuroticism [17Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274(5292): 1527-31.[http://dx.doi.org/10.1126/science.274.5292.1527] [PMID: 8929413] ]. In other studies, it has been reported that individuals with the S/S genotype scored higher for neuroticism on the big five personality model. In addition, in patients with depression and anxiety disorders it has been observed a higher frequency of the S allele [18Munafò MR, Freimer NB, Ng W, et al. 5-HTTLPR genotype and anxiety-related personality traits: A meta-analysis and new data. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(2): 271-81.[http://dx.doi.org/10.1002/ajmg.b.30808] [PMID: 18546120] , 19Balestri M, Calati R, Serretti A, De Ronchi D. Genetic modulation of personality traits: A systematic review of the literature. Int Clin Psychopharmacol 2014; 29(1): 1-15.[http://dx.doi.org/10.1097/YIC.0b013e328364590b] [PMID: 2410 0617] ]. The 5-HTTLPR polymorphism has been investigated in the context of stressful life events, including childhood maltreatment, showing association with the increase in the susceptibility to depressive and anxious symptoms [20Stein MB, Schork NJ, Gelernter J. Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology 2008; 33(2): 312-9.[http://dx.doi.org/10.1038/sj.npp.1301422] [PMID: 17460615] ]. Subjects with both the S/S genotype and with high levels of childhood maltreatment have been shown to have a higher sensitivity to anxiety [20Stein MB, Schork NJ, Gelernter J. Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology 2008; 33(2): 312-9.[http://dx.doi.org/10.1038/sj.npp.1301422] [PMID: 17460615] ].

There is a growing evidence for the association of genes involved in the serotonergic system with hazardous alcohol use [10Kim J, Park A. A systematic review: Candidate gene and environment interaction on alcohol use and misuse among adolescents and young adults. Am J Addict 2018.[http://dx.doi.org/10.1111/ajad.12755] [PMID: 29992684] ]. A recent meta-analysis showed that the S allele is associated with an increased risk for alcohol dependence [21Cao J, Hudziak JJ, Li D. Multi-cultural association of the serotonin transporter gene (SLC6A4) with substance use disorder. Neuropsychopharmacology: Ameri College Neuropsychopharmacol 2013; 38(9): 1737-47.]. In addition, other studies have found that subjects with the S allele reported more frequent drinking [22Covault J, Tennen H, Armeli S, et al. Interactive effects of the serotonin transporter 5-HTTLPR polymorphism and stressful life events on college student drinking and drug use. Biol Psychiatry 2007; 61(5): 609-16.[http://dx.doi.org/10.1016/j.biopsych.2006.05.018] [PMID: 16920076] -24Kranzler HR, Scott D, Tennen H, et al. The 5-HTTLPR polymorphism moderates the effect of stressful life events on drinking behavior in college students of African descent. Am J Med Genet B Neuropsychiatr Genet 2012; 159B(5): 484-90.[http://dx.doi.org/10.1002/ajmg.b.32051] [PMID: 22488930] ]. In contrast, other works have found an association with hazardous drinking in subjects with the L allele [25Laucht M, Treutlein J, Blomeyer D, et al. Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: Evidence from a high-risk community sample of young adults. Int J Neuropsychopharmacol 2009; 12(6): 737-47.[http://dx.doi.org/10.1017/S1461145708009875] [PMID: 19154632] ].

The purpose of this study was to examine the hypothesis that the 5-HTTLPR polymorphism might interact with physical negligence in childhood on the risk for the presence of anxiety symptoms and hazardous alcohol consumption in young adulthood.

2. METHODS

2.1. Participants

Two hundred seventy-two Colombian young adults were included in this study (21.3 years of age, SD=3.8, 75% women) [26Pereira-Morales AJ, Adan A, Forero DA. Network analysis of multiple risk factors for mental health in young Colombian adults. J Ment Health 2019; 28(2): 153-60.[http://dx.doi.org/10.1080/09638237.2017.1417568] [PMID: 2926 5896] , 27Pereira-Morales AJ, Adan A, Lopez-Leon S, Forero DA. Personality traits and health-related quality of life: The mediator role of coping strategies and psychological distress. Ann Gen Psychiatry 2018; 17: 25.[http://dx.doi.org/10.1186/s12991-018-0196-0] [PMID: 29930692] ]. Participants were enrolled in medical and nursing schools and were invited to participate in the study [28Jimenez KM, Pereira-Morales AJ, Adan A, Forero DA. Telomere length and childhood trauma in Colombians with depressive symptoms. Rev Bras Psiquiatr 2018.[PMID: 30328966] , 29Jiménez KM, Pereira-Morales AJ, Adan A, Lopez-Leon S, Forero DA. Depressive symptoms are associated with a functional polymorphism in a miR-433 binding site in the FGF20 gene. Mol Brain 2018; 11(1): 53.[http://dx.doi.org/10.1186/s13041-018-0397-0] [PMID: 30241547] ]. All participants signed a written informed consent and this study was approved by the Institutional Ethics Committee of the Antonio Nariño University. The procedures performed were in accordance with the ethical standards of the insti-tutional research committee and with the 1964 Helsinki declaration and its later amendments.

A self-report instrument including general demographic and medical information was applied and it served to identify subjects with personal history of neuropsychiatric disorders. Ages over 18 years and absence of personal history of neuropsychiatric disorders were the inclusion criteria for the study (12 subjects were excluded due to it). All the phenotypic data were collected through self-report instruments, which were applied by a psychologist. The included individuals were mainly from low and medium socioeconomic status (34 and 45%, respectively), had mainly secondary as their education level (79%) and single was the most frequent marital status (93%).

2.2. Psychological Measurements

To evaluate physical negligence, the Childhood Trauma Questionnaire (CTQ)-brief version was used [30Bernstein DP, Stein JA, Newcomb MD, et al. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl 2003; 27(2): 169-90.[http://dx.doi.org/10.1016/S0145-2134(02)00541-0] [PMID: 1261 5092] ]. This questionnaire is a 28-item self-administered inventory that provides an assessment of child abuse and neglect through five dimensions: physical, sexual and emotional abuse and physical and emotional neglect. Scores of 9 (for both men and women) are indicative of physical abuse and physical neglect and of 5 and 7 for sexual abuse (in men and women, respectively) [31Hernandez A, Gallardo-Pujol D, Pereda N, et al. Initial validation of the Spanish childhood trauma questionnaire-short form: Factor structure, reliability and association with parenting. J Interpers Violence 2013; 28(7): 1498-518.[http://dx.doi.org/10.1177/0886260512468240] [PMID: 23266990] ]. The CTQ has adequate psychometric properties in different languages, included the Spanish [31Hernandez A, Gallardo-Pujol D, Pereda N, et al. Initial validation of the Spanish childhood trauma questionnaire-short form: Factor structure, reliability and association with parenting. J Interpers Violence 2013; 28(7): 1498-518.[http://dx.doi.org/10.1177/0886260512468240] [PMID: 23266990] ]. In the current study, the Cronbach´s alpha was 0.89.

Anxiety-related endophenotypes were measured using the Big Five Inventory (BFI-S) [32Lang FR, John D, Lüdtke O, Schupp J, Wagner GG. Short assessment of the Big Five: robust across survey methods except telephone interviewing. Behav Res Methods 2011; 43(2): 548-67.[http://dx.doi.org/10.3758/s13428-011-0066-z] [PMID: 21424189] ], in the short version (15 items), the Zung Self-Rating Anxiety Scale (ZSAS) [33Zung WW. A rating instrument for anxiety disorders. Psychosomatics 1971; 12(6): 371-9.[http://dx.doi.org/10.1016/S0033-3182(71)71479-0] [PMID: 5172928] ] and the Cohen’s Perceived Stress Scale (PSS) [34Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983; 24(4): 385-96.[http://dx.doi.org/10.2307/2136404] [PMID: 6668417] ].

Fig. (1)
Overview of the associations found in the current study.


The BFI-S inventory measures 5 dimensions of personality: Factor O (Openness), Factor C (Conscien-tiousness), Factor E (Extraversion), Factor A (Agreeableness) and Factor N (Neuroticism) on a 7-point Likert scale: from 1 (strongly disagree) to 7 (strongly agree) [32Lang FR, John D, Lüdtke O, Schupp J, Wagner GG. Short assessment of the Big Five: robust across survey methods except telephone interviewing. Behav Res Methods 2011; 43(2): 548-67.[http://dx.doi.org/10.3758/s13428-011-0066-z] [PMID: 21424189] ]. In our analysis, we only included the factor N (Neuroticism) because it is one of the most established risk factors for anxiety and mood disorders [35Middeldorp CM, Cath DC, Van Dyck R, Boomsma DI. The co-morbidity of anxiety and depression in the perspective of genetic epidemiology. A review of twin and family studies. Psychol Med 2005; 35(5): 611-24.[http://dx.doi.org/10.1017/S003329170400412X] [PMID: 15918338] ]. The Cronbach’s alpha was 0.62 for Neuroticism in the current study.

ZSAS is a self-report questionnaire designed to measure anxiety symptomatology in the general population. It is composed of 20 items with 4 possible responses: (1) never, (2) rarely/sometimes, (3) frequently and (4) always [33Zung WW. A rating instrument for anxiety disorders. Psychosomatics 1971; 12(6): 371-9.[http://dx.doi.org/10.1016/S0033-3182(71)71479-0] [PMID: 5172928] ]. Each item is scored from 1 to 4 according to the severity of anxiety symptoms and total scores range between 20 to 80 points. ZSAS has shown to have a good internal consistency in Colombia [36De La Ossa S, Martinez Y, Herazo E, Campo A. Study of internal consistency and factor structure of three versions of the Zung’s rating instrument for anxiety disorders. Colomb Med 2009; 40(1): 71-7.]. In the current study the Cronbach’s alpha was 0.85.

The PSS-10 items [34Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983; 24(4): 385-96.[http://dx.doi.org/10.2307/2136404] [PMID: 6668417] ] is a self-report scale used to assess an individual’s experience of general perceived stress over the past month. The scores of this scale range from 0 to 40, higher scores mean higher levels of stress. It has been validated in Colombia population [37Campo-Arias A, Oviedo HC, Herazo E. Escala de Estrés Percibido-10: Desempeño psicométrico en estudiantes de medicina de Bucaramanga, Colombia. Rev Fac Med (Caracas) 2014; 62(3): 1-24.]. In the current study, the Cronbach’s alpha was 0.85.

Hazardous alcohol use was measured with two different scales, searching for a better characterization of the con-sumption:

The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) [38Group WAW. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST): Development, reliability and feasibility. Addiction 2002; 97(9): 1183-94.[http://dx.doi.org/10.1046/j.1360-0443.2002.00185.x] [PMID: 1219 9834] ] is an instrument created by the World Health Organization (WHO) for the detection of risky or abusive consumption of substances. This instrument assesses the frequency, patterns of substance use and risky use of tobacco, alcohol, amphetamine-type substances, cannabis, cocaine, hallucinogens, inhalants, opioids, sedatives and other substances through eight questions. Total scores for each substance are categorized as ‘low-risk use’ (0-3), ‘moderate-risk use’ (4-26) or ‘high-risk use’ (>26) [38Group WAW. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST): Development, reliability and feasibility. Addiction 2002; 97(9): 1183-94.[http://dx.doi.org/10.1046/j.1360-0443.2002.00185.x] [PMID: 1219 9834] ]; it has been validated in different languages, included Spanish [39Soto-Brandt G, Portilla Huidobro R, Huepe Artigas D, et al. Validity evidence of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in Chile. Adicciones 2014; 26(4): 291-302. [Validity evidence of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in Chile].[http://dx.doi.org/10.20882/adicciones.27] [PMID: 25578000] ]. In this study, alcohol was the substance with higher consumption (42.3%) and for that reason we selected hazardous alcohol use as one of the outcome variables and their Cronbach’s alpha was of 0.75.

The Alcohol use disorders identification test (AUDIT) [8Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption--II. Addiction 1993; 88(6): 791-804.[http://dx.doi.org/10.1111/j.1360-0443.1993.tb02093.x] [PMID: 8329 970] ] is a brief written screening method to identify current harmful and hazardous drinking in primary care settings, in both developing and developed countries. The 10-item scale was designed to assess three conceptual domains: drinking, behavior/dependence and alcohol-related problems. It has been validated in a Colombian sample [40Campo-Arias A, Villamil-Vargas M, Herazo E. Confiabilidad y dimensionalidad del AUDIT en estudiantes de medicina. Psicol Caribe 2013; 30(1): 21-35.]. The cut-off point used in the current study was ≥8 for risk of hazardous alcohol use, based on the recommendations by the WHO [8Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption--II. Addiction 1993; 88(6): 791-804.[http://dx.doi.org/10.1111/j.1360-0443.1993.tb02093.x] [PMID: 8329 970] ]. In the current sample, the Cronbach´s alpha was 0.78.

2.3. Genotyping

The extraction of DNA was performed by a salting out method, using 400 µl of peripheral blood [41Morales LC, Arboleda G, Rodríguez Y, et al. Absence of Lamin A/C gene mutations in four Wiedemann-Rautenstrauch syndrome patients. Am J Med Genet A 2009; 149A(12): 2695-9.[http://dx.doi.org/10.1002/ajmg.a.33090] [PMID: 19938095] ]. For the genotyping of the 5-HTTLPR polymorphism (rs4795541), a conventional PCR was carried out in a Labnet MultiGene 96-well thermal cycler (Labnet International Inc, Edison, NJ, USA). The PCR reaction was performed in a total volume of 20 µl, with 20 ng of DNA, 0.8 U of Taq polymerase (Bioline, London, United Kingdom), 10 µM of each primer (F: 5´ATG CCA GCA CCT AAC CCC TAA TGT 3´, R: 5´GGA CCG CAA GGT GGG CGG GA 3´), 0.25 mM of each dNTP, 10X reaction buffer and 1.5 mM MgCl2. The PCR program consisted in one cycle of 94 oC for 30 s, 35 cycles of 94oC for 30 s, 66 oC for 30 s, 72oC for 40 s, and a final step of 1 cycle of 72 oC for 5 min. The PCR products were allowed to run for 40 min at 140 V, in a 2% agarose gel. The genotypes were determined as follows: L/L: 419/419 pb, L/S: 419/375 bp, S/S: 375/375 bp. With the aim of verifying the genetic results, 10% of the samples were randomly selected and re-analyzed.

All mandatory health and safety procedures were accomp-lished in all the experiments carried out in this study.

2.4. Statistical Analysis

The psychometric analysis of the scales and questionnaires was performed using standard approaches: Internal consistency through Cronbach’s alpha and factorial structure of the tests using exploratory factorial analysis.

Normal distributions from the psychological scales scores were examined through skewness and kurtosis and bivariate correlations with Pearson Coefficient were used. These statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS v. 18)

A linear regression model corrected by age and gender, using SNPStats program, was used to identify the possible association of the SNP with anxiety symptoms, perceived stress, physical neglect, hazardous alcohol use and neuroticism [42Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: A web tool for the analysis of association studies. Bioinformatics 2006; 22(15): 1928-9.[http://dx.doi.org/10.1093/bioinformatics/btl268] [PMID: 16720584] ]. SNPStats program was also used to calculate genotype and allelic frequencies and Hardy-Weinberg equilibrium. The best genetic model was selected based on the Akaike Information Criterion [42Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: A web tool for the analysis of association studies. Bioinformatics 2006; 22(15): 1928-9.[http://dx.doi.org/10.1093/bioinformatics/btl268] [PMID: 16720584] ]. For the current study, the Bonferroni corrected p value (0.05 divided by 6), was 0.008.

In addition, multiple regression models were carried out to examine GxE Genotype (G) and Environment (E) interactions:

(A) Physical neglect in childhood x 5-HTTLPR genotypes to predict anxiety symptoms

(B) Physical neglect x 5-HTTLPR genotypes to predict neurotic trait

(C) Physical neglect x 5-HTTLPR genotypes to predict perceived stress

(D) Physical neglect x 5-HTTLPR genotypes to predict hazardous alcohol use, for both AUDIT and ASSIST alcohol subscale.

To know whether 5-HTTLPR genotype played a role as mediator, the mediation-in-serial models were employed, using multiple regressions, following the procedures recommended by Hayes [43Hayes AF. Introduction to mediation, moderation, and conditional process analysis: A regression-based approach 2013.]. The mediation effect occurs if the association between the Independent Variable (IV) and the Outcome Variable (DV) is eliminated (complete mediation) or reduced (partial mediation) when the Mediator Variable (MV) is introduced in the analysis. The following mediation models were carried out:

  1. Physical neglect in childhood was inserted as an IV, anxiety-related phenotypes were inserted as DVs separately and 5-HTTLPR genotype was inserted as the MV.
  2. Physical neglect was inserted as an IV, alcohol use was inserted as DV for AUDIT and ASSIST alcohol subscale, separately and 5-HTTLPR genotype was inserted as the MV.

Direct, indirect and total effects, standard errors and 95% confidence intervals (biased-corrected bootstrapped; 1000= repetitions) for each model, were calculated using speci-fication model 4 of the PROCESS plug in (V.2014) [43Hayes AF. Introduction to mediation, moderation, and conditional process analysis: A regression-based approach 2013.] in SPSS (v. 18).

3. RESULTS

In our sample, the factorial structures found were the expected: six-factor solution for CTQ (64.1% of variance), five-factor solution for BFI-S and ZSAS (62.1% and 56% of variance respectively), two-factor solution for PSS (56% of variance), one-factor solution (46.3% of variance) for alcohol use (ASSIST) and three-factor solution for AUDIT (59% of variance).

The allele frequencies in our sample were 0.51 and 0.49 for the S and L alleles, respectively. The S/S genotype was observed in 26% (n = 70), the S/L genotype in 50% (n = 136) and the L/L genotype in 24% (n = 65) of the subjects in the current sample. The genotype frequencies were in Hardy-Weinberg equilibrium (p = 1).

Correlations were significant only between physical neglect and anxiety symptoms (r = 0.278, p<0.01) and physical neglect and perceived stress (r = 0.221, p<0.01), no association was found between physical neglect and neurotic trait (r = 0.113, p>0.05), or for physical neglect and ASSIST alcohol subscale (r = 0.100, p>0.05) or AUDIT scores (r = 0.103, p>0.05).

We found significant associations between behavioral variables and 5-HTTLPR: anxiety symptoms (p = 0.029), physical neglect (p = 0.0047), alcohol use (p = 0.011), perceived stress (p = 0.035) and neuroticism (p = 0.019) (Table 1). The results for association with physical neglect were significant after a Bonferroni correction for multiple testing.

The risk of alcohol use based on recommended cut-off points in AUDIT (81 subjects for moderate risk) and ASSIST (150 subjects for moderate risk) was associated significantly with 5-HTTLPR polymorphism. The odds ratio was higher for carriers of the long variant of the 5-HTTLPR polymorphism (AUDIT, OR= 2.01, CI: 1.04 – 3.87; ASSIST alcohol subscale, OR= 3.06, 1.62 – 5.79) (Table 2). Results for the ASSIST alcohol subscale were significant after a Bonferroni correction for multiple testing. An overview of the associations found in our work is shown in Fig. (1).

No GxE interactions were observed in the data, for the multiple regression models, as well as for neither of the models of mediation analysis (Table 3). 5-HTTLPR genotype was excluded of all the regression models for anxiety symptoms, neurotic trait and perceived stress (as outcomes variables) and 5-HTTLPR genotypes and physical neglect in childhood (as predictors) (p = 0.467, p = 0.088, p = 0.809 respectively). For hazardous alcohol use models, physical negligence was excluded from both models (p = 0.397 for AUDIT and p = 0.871 for ASSIST alcohol subscale).

Table 1
Association between anxiety symptoms, physical negligence, hazardous alcohol use, neuroticism, perceived stress and 5–HTTLPR polymorphism.


Table 2
Association between 5 –HTTLPR and risk of hazardous alcohol use.


Table 3
Interaction between physical neglect and 5-HTTLPR genotypes to predict outcome variables.


In the mediation models, 5-HTTLPR genotype was not significant mediator for any relationship between variables (Table 3).

4. DISCUSSION

The findings of the present study show an association between physical neglect in childhood, anxiety-related phenotypes, hazardous alcohol use and 5-HTTLPR poly-morphism (Fig. 1). Our results suggest that 5-HTTLPR polymorphism could be an important risk factor for hazardous alcohol consumption and anxiety-related endophenotypes, such as the neurotic trait, anxiety symptoms and perceived stress in young adults. However, we did not find GXE interactions between 5-HTTLPR polymorphism and physical neglect to predict anxiety-related phenotypes or hazardous alcohol use.

Childhood maltreatment is an important risk factor for affective disorders and a major public health problem [44Norman RE, Byambaa M, De R, Butchart A, Scott J, Vos T. The long-term health consequences of child physical abuse, emotional abuse, and neglect: a systematic review and meta-analysis. PLoS Med 2012; 9(11)e1001349[http://dx.doi.org/10.1371/journal.pmed.1001349] [PMID: 23209385] ]. Exposure to emotional and physical neglect is associated with increased risk for a wide range of behavioral problems, including anxiety disorders, alcohol abuse, depression and suicidal behavior [45Organization WH. World report on violence and health 2002; 186.].

Previous findings have shown that many potential mechanisms may explain the mentioned association between neglect in childhood and increased risk for mental health problems and alcohol consumption. One of the most plausible explanations is that the neurobiological development can be altered by the maltreatment during childhood, which in turn can negatively affect a child's cognitive, emotional, and social growth, leading to behavioral and learning problems that can persist throughout life [44Norman RE, Byambaa M, De R, Butchart A, Scott J, Vos T. The long-term health consequences of child physical abuse, emotional abuse, and neglect: a systematic review and meta-analysis. PLoS Med 2012; 9(11)e1001349[http://dx.doi.org/10.1371/journal.pmed.1001349] [PMID: 23209385] ]. Moreover, it is widely accepted that in many cases some victims of childhood maltreatment may try to manage the subsequent distress through the use of alcohol, tobacco, medicaments and other drugs [46Shevlin M, Dorahy MJ, Adamson G. Trauma and psychosis: an analysis of the National Comorbidity Survey. Am J Psychiatry 2007; 164(1): 166-9.[http://dx.doi.org/10.1176/ajp.2007.164.1.166] [PMID: 17202562] ]. In addition, epigenetic studies have proposed that early life events affect DNA methylation of the SLC6A4 gene [47Duman EA, Canli T. Influence of life stress, 5-HTTLPR genotype, and SLC6A4 methylation on gene expression and stress response in healthy Caucasian males. Biol Mood Anxiety Disord 2015; 5: 2.[http://dx.doi.org/10.1186/s13587-015-0017-x] [PMID: 25995833] , 48Kang HJ, Kim JM, Stewart R, et al. Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression. Prog Neuropsychopharmacol Biol Psychiatry 2013; 44: 23-8.[http://dx.doi.org/10.1016/j.pnpbp.2013.01.006] [PMID: 23333376] ].

Previous findings have shown that the risk for affective disorders is elevated among carriers of the S allele when they were exposed to stressful life events [49Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 2003; 301(5631): 386-9.[http://dx.doi.org/10.1126/science.1083968] [PMID: 12869766] ]. However, our data suggest that the L/L genotype is likely to be important on psychosocial development, particularly in those settings that increase the risk of anxiety symptoms, neurotic trait and hazardous alcohol use. These findings are consistent with some studies that revealed an interaction between the L allele and the increased risk of depression in subjects exposed to stress [25Laucht M, Treutlein J, Blomeyer D, et al. Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: Evidence from a high-risk community sample of young adults. Int J Neuropsychopharmacol 2009; 12(6): 737-47.[http://dx.doi.org/10.1017/S1461145708009875] [PMID: 19154632] ]; however, few studies have replicated these findings in healthy young adults with measures of anxiety symptoms [25Laucht M, Treutlein J, Blomeyer D, et al. Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: Evidence from a high-risk community sample of young adults. Int J Neuropsychopharmacol 2009; 12(6): 737-47.[http://dx.doi.org/10.1017/S1461145708009875] [PMID: 19154632] ].

To date, there are few studies that have investigated the association of the functional 5-HTTLPR polymorphism with hazardous alcohol use in healthy subjects. While some studies showed evidence of an association between 5-HTTLPR and psychological variables related to hazardous alcohol use [50Lovallo WR, Enoch MA, Yechiam E, et al. Differential impact of serotonin transporter activity on temperament and behavior in persons with a family history of alcoholism in the Oklahoma Family Health Patterns Project. Alcohol Clin Exp Res 2014; 38(6): 1575-81.[http://dx.doi.org/10.1111/acer.12412] [PMID: 24796636] ], others found a significant result with higher alcohol intake [22Covault J, Tennen H, Armeli S, et al. Interactive effects of the serotonin transporter 5-HTTLPR polymorphism and stressful life events on college student drinking and drug use. Biol Psychiatry 2007; 61(5): 609-16.[http://dx.doi.org/10.1016/j.biopsych.2006.05.018] [PMID: 16920076] -25Laucht M, Treutlein J, Blomeyer D, et al. Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: Evidence from a high-risk community sample of young adults. Int J Neuropsychopharmacol 2009; 12(6): 737-47.[http://dx.doi.org/10.1017/S1461145708009875] [PMID: 19154632] ]. Our findings of a dominant model for the association of the S allele and hazardous alcohol use is supported by previous articles [23Daw J, Shanahan M, Harris KM, Smolen A, Haberstick B, Boardman JD. Genetic sensitivity to peer behaviors: 5HTTLPR, smoking, and alcohol consumption. J Health Soc Behav 2013; 54(1): 92-108.[http://dx.doi.org/10.1177/0022146512468591] [PMID: 23292504] , 51McHugh RK, Hofmann SG, Asnaani A, Sawyer AT, Otto MW. The serotonin transporter gene and risk for alcohol dependence: A meta-analytic review. Drug Alcohol Depend 2010; 108(1-2): 1-6.[http://dx.doi.org/10.1016/j.drugalcdep.2009.11.017] [PMID: 2006 0655] ]. In addition, our finding of heterosis in the association between HTTLPR and perceived stress is concordant with a previous study [52Nilsson KW, Sjöberg RL, Damberg M, et al. Role of the serotonin transporter gene and family function in adolescent alcohol consumption. Alcohol Clin Exp Res 2005; 29(4): 564-70.[http://dx.doi.org/10.1097/01.ALC.0000159112.98941.B0] [PMID: 15834221] ].

Multiple structural neuroimaging studies have shown that young adults with history of heavy drinking have lower volumes in prefrontal cortex [53Cservenka A, Brumback T. The burden of binge and heavy drinking on the brain: Effects on adolescent and young adult neural structure and function. Front Psychol 2017; 8: 1111.[http://dx.doi.org/10.3389/fpsyg.2017.01111] [PMID: 28713313] ], with some of these changes being partially reversible [54Bühler M, Mann K. Alcohol and the human brain: A systematic review of different neuroimaging methods. Alcohol Clin Exp Res 2011; 35(10): 1771-93.[http://dx.doi.org/10.1111/j.1530-0277.2011.01540.x] [PMID: 2177 7260] ]. In addition, several functional neuroimaging studies have shown that these young adults also have elevated levels of brain activity in fronto-parietal areas during cognitive tasks and increased levels of neural responses in several mesocorticolimbic areas, such as the anterior cingulate cortex, the amygdala and the striatum [53Cservenka A, Brumback T. The burden of binge and heavy drinking on the brain: Effects on adolescent and young adult neural structure and function. Front Psychol 2017; 8: 1111.[http://dx.doi.org/10.3389/fpsyg.2017.01111] [PMID: 28713313] ]. Animal models have also found that alcohol exposure affects neurochemical processes in mesocorticolimbic brain regions [55Alasmari F, Goodwani S, McCullumsmith RE, Sari Y. Role of glutamatergic system and mesocorticolimbic circuits in alcohol dependence. Prog Neurobiol 2018; 171: 32-49.[http://dx.doi.org/10.1016/j.pneurobio.2018.10.001] [PMID: 3031 6901] ].

In accordance with the above findings, the association of the 5-HTTLPR polymorphism with childhood maltreatment and anxiety-related phenotypes is not clearly understood and the reports of association have been inconsistent and difficult to replicate [56Olsson CA, Byrnes GB, Lotfi-Miri M, et al. Association between 5-HTTLPR genotypes and persisting patterns of anxiety and alcohol use: Results from a 10-year longitudinal study of adolescent mental health. Mol Psychiatry 2005; 10(9): 868-76.[http://dx.doi.org/10.1038/sj.mp.4001677] [PMID: 15852063] ]. Our results have further shown a protective role for the S allele in the risk for alcohol consumption and the development of anxiety symptoms and neuroticism. Our findings are supported in part by previous results where S/S genotype of the 5-HTTLPR polymorphism appeared to be protective against depressive symptomatology in a supportive early context [57Taylor SE, Way BM, Welch WT, Hilmert CJ, Lehman BJ, Eisenberger NI. Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology. Biol Psychiatry 2006; 60(7): 671-6.[http://dx.doi.org/10.1016/j.biopsych.2006.04.019] [PMID: 16934775] ]. However, several studies have reported the opposite effect, with the S/S genotype being a risk factor for affective disorders [49Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 2003; 301(5631): 386-9.[http://dx.doi.org/10.1126/science.1083968] [PMID: 12869766] ].

A possible contributory factor of this inconsistency may be heterogeneity in the measurements and characteristics of environmental adversity investigated in the different studies, particularly, the nature of the stressors studied. For example, the duration of exposure to adversity and the type of stressors studied [58Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Arch Gen Psychiatry 2011; 68(5): 444-54.[http://dx.doi.org/10.1001/archgenpsychiatry.2010.189] [PMID: 2119 9959] ]. Recall bias in the psychological assessment might be another cause of inconsistent findings; it is widely accepted that retrospective reports on traits or experiences are often discrepant (in comparison with prospective studies). In many cases, individuals may attempt to mentally reconstruct information about past events, personality trait or common behaviors, by generating detailed reports based on their general beliefs [59Solhan MB, Trull TJ, Jahng S, Wood PK. Clinical assessment of affective instability: Comparing EMA indices, questionnaire reports, and retrospective recall. Psychol Assess 2009; 21(3): 425-36.[http://dx.doi.org/10.1037/a0016869] [PMID: 19719353] ]. In patients with anxiety disorders, such as panic disorder and obsessive-compulsive disorder, it has been documented a negative recall bias in retrospective self-reports, resulting in a retrospective overestimation of the disorder-specific symptoms [60Ebner-Priemer UW, Kuo J, Welch SS, et al. A valence-dependent group-specific recall bias of retrospective self-reports: A study of borderline personality disorder in everyday life. J Nerv Ment Dis 2006; 194(10): 774-9.[http://dx.doi.org/10.1097/01.nmd.0000239900.46595.72] [PMID: 170 41290] ].

CONCLUSION

In the current study, two types of stress were found as associated with the SLC6A4 gene: chronic stress and acute stress, through physical neglect in childhood and perceived stress over the past month respectively; but only results for physical neglect were significant after a Bonferroni correction for multiple testing. This is consistent with the results of a meta-analysis [18Munafò MR, Freimer NB, Ng W, et al. 5-HTTLPR genotype and anxiety-related personality traits: A meta-analysis and new data. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(2): 271-81.[http://dx.doi.org/10.1002/ajmg.b.30808] [PMID: 18546120] ] that found that the effect of 5-HTTLPR polymorphism (S allele) on neurotic trait is only apparent when those carrying the short allele are exposed to the stressful environment and with the results of another meta-analysis [58Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Arch Gen Psychiatry 2011; 68(5): 444-54.[http://dx.doi.org/10.1001/archgenpsychiatry.2010.189] [PMID: 2119 9959] ] that reported robust evidence for 5-HTTLPR moderating the relationship between both childhood maltreatment and specific stressors and depressive symptoms.

Current understanding of the specific characteristics of the stressors that are moderated by 5-HTTLPR is insufficient [58Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Arch Gen Psychiatry 2011; 68(5): 444-54.[http://dx.doi.org/10.1001/archgenpsychiatry.2010.189] [PMID: 2119 9959] ]. However, considering previous data and our current results, specific and chronic stressors (such as childhood maltreatment) might be more important than acute stressors in the relationship of 5-HTTLPR polymorphism and anxiety related-traits.

Limitations of the current study include the analysis of a single polymorphism in the SLC6A4 gene and the use of a convenience sample design, which includes a higher proportion of females.

To our knowledge, the current study is the first work that explores the relationship between 5-HTTLPR polymorphism and anxiety-related phenotypes and hazardous alcohol consumption using validated scales for several psychosocial variables (Table S1) [18Munafò MR, Freimer NB, Ng W, et al. 5-HTTLPR genotype and anxiety-related personality traits: A meta-analysis and new data. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(2): 271-81.[http://dx.doi.org/10.1002/ajmg.b.30808] [PMID: 18546120] , 58Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Arch Gen Psychiatry 2011; 68(5): 444-54.[http://dx.doi.org/10.1001/archgenpsychiatry.2010.189] [PMID: 2119 9959] ]. Furthermore, this is the first study of this type in a Latin American sample.

FUTURE PERSPECTIVE

In futures studies, it could be important to examine the relationship between 5-HTTLPR polymorphism and exposure to environmental adversity, using different phenotypic characterizations as well as different types of adversity. In this context, future longitudinal studies, involving functional neuroimaging methods, will provide an interesting approach for analyzing the cumulative effect of genetic factors, early alcohol use and childhood trauma on brain function.

AUTHORS' CONTRIBUTIONS

KMJ participated in acquisition and analysis of genetic data and drafting and critical revision of the manuscript. AJP participated in study design, acquisition and analysis of psychological data and drafting and critical revision of the manuscript. SL-L participated in analysis of genetic data and drafting and critical revision of the manuscript. AA participated in analysis of psychological data and drafting and critical revision of the manuscript. D.A.F participated in study design, acquisition and analysis of genetic and psychological data, drafting and critical revision of the manuscript.

ETHICS APPROVAL AND CONSENT TO PARTI-CIPATE

The study was approved by the Institutional Ethics Committee of the Antonio Nariño University.

HUMAN AND ANIMAL RIGHTS

No animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experi-mentation (institutional and national), and with the 1964 Helsinki declaration and its later amendments.

CONSENT FOR PUBLICATION

Written informed consent has been obtained from all the participants.

AVAILABILITY OF DATA AND MATERIALS

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

FUNDING

This study was supported by a research grant from Colciencias (grant # 823-2015) and by a grant from the Spanish Ministry of Economy, Industry and Competitiveness PSI2015-65026 (MINECO/FEDER/UE).

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

The authors thank to Andres Camargo, who assisted with recruitment and evaluations of subjects.

SUPPLEMENTARY MATERIAL

Supplementary material is available on the publishers Website along with the published article.

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