Journal of the Neurological Sciences 337 (2014) 176–179

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Journal of the Neurological Sciences

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A functional polymorphism in the promoter region of MAOA gene isassociated with daytime sleepiness in healthy subjects

Diego A. Ojeda a, Carmen L. Niño b, Sandra López-León c, Andrés Camargo b, Ana Adan d, Diego A. Forero a,⁎a Laboratory of Neuropsychiatric Genetics, Biomedical Sciences Research Group, School of Medicine, Universidad Antonio Nariño, Bogotá, Colombiab School of Nursing, Universidad de Ciencias Aplicadas y Ambientales UDCA, Bogotá, Colombiac Novartis Pharmaceuticals, Health Plaza, East Hanover, NJ, USAd Department of Psychiatry and Clinical Psychobiology, School of Psychology, University of Barcelona, Barcelona, Spain

⁎ Corresponding author at: Laboratory of NeuropsychiatUniversidad Antonio Nariño, Bogotá, Colombia. Tel.: +57

E-mail address: diego.forero@uan.edu.co (D.A. Forero)

0022-510X/$ – see front matter © 2013 Elsevier B.V. All rhttp://dx.doi.org/10.1016/j.jns.2013.12.005

a b s t r a c t

a r t i c l e i n f o

Article history:Received 16 September 2013Received in revised form 26 November 2013Accepted 3 December 2013Available online 11 December 2013

Keywords:NeurogeneticsLatin AmericaNeuropsychiatric geneticsCandidate genesEndophenotypesDaytime sleepinessMonoamine Oxidase A

Excessive daytime sleepiness (EDS) is one of the main causes of car and industrial accidents and it is associatedwith increasedmorbidity and alterations in quality of life. Prevalence of EDS in the general population around theworld ranges from 6.2 to 32.4%, with a heritability of 38–40%. However, few studies have explored the role ofcandidate genes in EDS. Monoamine oxidase A (MAOA) gene has an important role in the regulation ofneurotransmitter levels and a large number of human behaviors. We hypothesized that a functional VNTR inthe promoter region of the MAOA gene might be associated with daytime sleepiness in healthy individuals.The Epworth sleepiness scale (ESS) was applied to 210 Colombian healthy subjects (university students),which were genotyped for MAOA-uVNTR. MAOA-uVNTR showed a significant association with ESS scores(p = 0.01): 3/3 genotype carriers had the lowest scores. These results were supported by differences inMAOA-uVNTR frequencies between diurnal somnolence categories (p = 0.03). Our finding provides evidencefor the first time that MAOA-uVNTR has a significant association with EDS in healthy subjects. Finally, thesedata suggest that functional variations inMAOA gene could have a role in other phenotypes of neuropsychiatricrelevance.

© 2013 Elsevier B.V. All rights reserved.

1. Introduction

Excessive daytime sleepiness (EDS) is one of the main causes of carand industrial accidents around the world, being associated withdecreases in performance at school or work, increased morbidity andalterations in quality of life [1,2]. The Epworth sleepiness scale wascreated in 1991 as a tool to quantify levels of daytime sleepiness and ithas been used in a large number of clinical studies [3,4]. Prevalence ofEDS in the general population, defined by the ESS, in different countriesranges from 6.2 to 32.4% [5–17] (Table 1), with a moderate heritabilityof approximately 38% to 40% [18–21]. This evidence highlights theimportance of studying the role of genetic polymorphisms in increaseddiurnal somnolence [22]. However, very few studies have explored thepossible association of candidate genes with differences in daytimesleepiness [23–26].

Sleep is a complex physiological process and it is fundamental torestore and maintain an adequate physical and mental health [27,28].It is regulated by multiple environmental and molecular mechanisms,such as the circadian system [29]. In addition, many neurotransmittersare involved in the sleep process: norepinephrine, serotonin, dopamineand glutamate, among many others [28,30–32].

ric Genetics, School ofMedicine,313 2610427..

ights reserved.

Monoamine oxidase A (MAOA) is known to play a major role incatalyzing the oxidative deamination of norepinephrine, dopamine,and serotonin neurotransmitters [33,34], being a key enzyme for theregulation of monoamine levels. MAOA gene has a size of 90,660 bp, islocated on the X chromosome at Xp.11.3–Xp11.4 and is expressed inseveral brain tissues [34,35]. Different polymorphisms in the MAOAgene have been identified [33–36] and a functional variable-numbertandem repeat (VNTR) located in the promoter region of MAOA gene(MAOA-uVNTR) is commonly studied in neuropsychiatric genetics[35,36]. MAOA-uVNTR polymorphism consists of a 30 bp repeatsequence and functional studies have shown that this VNTR affects thetranscription of MAOA, indicating that the number of repeats is relatedto transcriptional activity [35,36].

We hypothesized that a functional VNTR in the promoter regionof the MAOA gene might be associated with differences in daytimesleepiness in healthy Colombian subjects.

2. Methods

2.1. Participants

Twohundred and ten unrelated young subjects (university students)living in Bogotá, Colombia were included. Participants were recruited intwo private Universities, through posters and informative talks. This

Table 1Prevalence of excessive daytime sleepiness (EDS), using the Epworth sleepiness scale, ingeneral populations around the worlda.

Author, year Country Sample size Age range % EDS

Pahwa, 2012 Canada 283 18–97 20.8Wu, 2012 China 3214 18–80 22.2Mume, 2011 Nigeria 634 17–31 11.2Joo, 2009 Korea 4405 49 ± 8 12.2Bouscoulet, 2008 Chile 1173 56.8 ± 0.5 22.7Bouscoulet, 2008 Mexico 1062 55.9 ± 0.5 17.7Bouscoulet, 2008 Uruguay 941 60.2 ± 0.5 9.5Bouscoulet, 2008 Venezuela 1357 55.1 ± 0.3 14.7Pallesen, 2007 Norway 2301 18–90 17.7Sanford, 2006 USA 703 20–98 32.4Gander, 2005 New Zealand 5441 30–60 21.6Moo-Estrella, 2005 Mexico 638 20 ± 3 31.6Soldatos, 2005 Austria 490 44.3 ± 18.8 9.2Soldatos, 2005 Belgium 6832 40.0 ± 16.3 17.5Soldatos, 2005 Brazil 1999 37.4 ± 15.0 14.3Soldatos, 2005 China 10,079 37.1 ± 14.9 6.2Soldatos, 2005 Germany 2016 49.8 ± 18.2 7.2Soldatos, 2005 Japan 10,424 36.1 ± 10.7 12.4Soldatos, 2005 Portugal 784 44.5 ± 22.8 18.3Soldatos, 2005 Slovakia 502 38.4 ± 16.0 13.7Soldatos, 2005 South Africa 202 37.7 ± 15.6 24.5Soldatos, 2005 Spain 1999 47.7 ± 18.4 12.7Walsleben, 2004 USA 470 40–91 23.9Shin, 2003 Korea 3871 Mean age: 16.8 15.9Souza, 2002 Brazil 408 N18 years 18.9Average EDS 17.2%

a Included papers used a cutpoint of ESS scores N 10 to define the presence of excessivedaytime sleepiness.

177D.A. Ojeda et al. / Journal of the Neurological Sciences 337 (2014) 176–179

research study was advertised as a genetic study of circadian phenotypesinhealthy subjects. Subjects completed the questionnaires, after receivingdetailed information from researchers trained in assessment of circadianphenotypes. There were 147 women (70%), with an age range between18 and 30 years (mean = 20.8; SD = 2.7). The population living inBogotá, the capital city of Colombia, is the result of a historical admixtureof Southern Europeans with Amerindians [37]. STRUCTURE program(Version 2.3.4) was used for an analysis of ancestry informative markersand did not show evidence of significant population stratification inthe samples used in this work [23,38]. We excluded subjects with self-report of personal history of neuropsychiatric diseases. InstitutionalEthics Committees of each participant institution approved this studyand all subjects provided written informed consent [39].

2.2. Measurement instruments

Participants completed a self-administered questionnaire, whichincluded socio-demographic variables such as age, sex and personaland familial history of neuropsychiatric disorders. We applied theEpworth sleepiness scale (ESS) [3], it is a self-completed questionnaire,broadly used and validated, to quantify the general level of daytimesleepiness. ESS is an 8-item questionnaire with a Likert-type responseand it evaluates the level of general sleepiness during eight dailysituations [3]. It ranges from 0 to 24, with higher scores related tomore sleepiness [4]. A Spanish version of the ESS has been previouslyvalidated and used in studies from Colombia and other Latin Americancountries [8,10,23,40]. The internal consistency of ESS (Cronbach'salpha) in this study was 0.712.

2.3. DNA extraction and genetic analysis

Peripheral blood samples were collected from participants intoethylene diamine tetra acetic acid (EDTA) tubes (Vacutainer, BectonDickinson, Rutherford, NJ, USA) and genomic DNA was extracted usinga salting out method [23,41]. PCR reactions were carried out in a LabnetMultiGene thermal cycler (Labnet International Inc., Edison, NJ, USA)

and their products were separated at 140 V in a 2% agarose gel stainedwith SYBR®-safe (Invitrogen, Carlsbad, CA, USA).

MAOA-uVNTR genotyping was carried out using two primers(F: 5-ACA GCC TGA CCG TGG AGA AG-3 and R: 5-GAA CGG ACG CTCCAT TCG GA-3) [36]. PCR program consisted of a 5-min denaturationstep at 94 °C (1 cycle), 94 °C for 20s, 64 °C for 20s, 72 °C for 40s(35 cycles) and 72 °C for 7 min (1 cycle). Polymerase chain reactionscontained 2 μl of genomic DNA (~50 ng), 1.5 mMMgCl2, 10× reactionBuffer, 1.0 μM of each primer, 1 mM of dNTPs, 1 M de Betaine, and0.8 U of Taq polymerase (Bioline, London, United Kingdom) in a totalvolume of 20 μl. For MAOA-uVNTR, five alelles have been reported:2 (294 bp), 3 (324 bp), 4 (354 bp), 5 (384 bp) and 3.5 (340 bp) [36].Fragment sizes were determined by comparison to molecular weightmarkers (HyperLadder V, Bioline, London, United Kingdom).

All genotypes were independently checked by two differentresearchers in order to confirm and validate the results. Additionally,to verify consistency in the genetic results, a random subsample(10% of subjects) was reanalyzed.

2.4. Statistical data analysis

Genotype frequencies were assessed for Hardy–Weinberg equilibri-um, only in females, with a χ2 test. ESS scores were tested for normaldistribution using the Shapiro–Wilk test. The 75th percentile of theESS score distribution was used as a cut-off point to determine Normal(scores ≤14) or High (scores ≥15) sleepiness categories for diurnalsomnolence in our sample. We used an approach based on percentilesfor the present sample, related to the possibility that it could be moreuseful than the implementation of a fixed cut-off [16,23].

A statistical analysis of ESS scores between genotypes was carriedout with PLINK software (version 1.07), using a linear regressionmodel. For this analysis, ESS scores and genotypes were the dependentand independent variables, respectively. For comparisons of genotypefrequencies between diurnal somnolence categories a logistic regres-sion was carried out in PLINK 1.07 software. In these analyses, malehemizygous subjects were combinedwith female homozygous subjects[42,43]. A nominal value of p b 0.05 was considered as statisticallysignificant.

3. Results

ESS scores ranged from0 to 21,with amean value of 11.32 (SD: 4.36).Shapiro–Wilk test showed that the ESS scores in our sample had anormal distribution (non-significant p value). In our sample, twoMAOA-uVNTR alleles were found (3 and 4 repeats) and this polymor-phism was in Hardy–Weinberg equilibrium (p = 0.84, in females).Frequency of the 3-repeat allele was 0.36 in females and 0.34 in males.Allele frequencies for the MAOA-uVNTR observed in this study weresimilar to those reported in another sample of Latin American subjects(χ2 = 0.03, p = 0.86) [44].

A linear regression model showed a statistically significant associa-tion between MAOA-uVNTR and ESS scores (p = 0.01). We observedthat MAOA 3/3 genotype carriers (mean 9.62) had the lowest scoresfor the ESS scale (Table 2). In addition,we found a significant associationbetween diurnal somnolence categories (normal and high) and geno-type frequencies for the MAOA-uVNTR (p = 0.03) using a logisticregression (Table 2). Frequency of the MAOA 3/3 genotype was higherin the normal diurnal somnolence category (22.7 vs. 8.9%).

4. Discussion

Excessive daytime sleepiness is quite common around the world(Table 1), being associated with increases in accidents, morbidity andimpairments in quality of life [1]. Although it has been shown thatgenetic factors have an important role in EDS [18,20], very few studieshave explored the role of polymorphisms in candidate genes, such as

Table 2Association of Epworth sleepiness scale (ESS) scores and diurnal somnolence categories (Normal or High) with MAOAu-VNTR.

MAOA groups N (%) Mean ESS scores (SD) MAOA groups Normal sleepiness n (%) High sleepiness n (%)

3/3 39 (18.6) 9.62 (3.99) 3/3 35 (22.7) 5 (8.9)3/4 71 (33.8) 11.83 (4.11) 3/4 49 (31.8) 21 (37.5)4/4 100 (47.6) 11.63 (4.55) 4/4 70 (45.5) 30 (53.6)Total 210 (100) 11.32 (4.36) Total 154 (100) 56 (100)p value: 0.01a p value: 0.03b

a p value for comparison of scores between genotype groups, using a linear regression model.b p value for comparison of MAOA frequencies between normal and high somnolence groups, using a logistic regression.

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PER3 gene, on diurnal somnolence [23–26]. In our sample, we found ahigh mean ESS score (11.32), which could be consistent with previousevidence of a higher prevalence of diurnal sleepiness in LatinAmerican countries (Table 1) [5,8,10].

In the present study, we found that a common functional VNTRin the promoter region of MAOA gene is significantly associated withindividual differences in daytime sleepiness in a sample of healthyColombian subjects. In our study, MAOA 3/3 genotype carriers had thelowest scores for the ESS scale. In addition, these resultswere supportedby a significant association between diurnal somnolence categories andfrequencies for the MAOA-uVNTR. In the context of genetic studies ofdiurnal somnolence in healthy subjects, the use of percentilescould be more useful than the analysis based on a predefined cut-off point (fixed cut-off points could be more useful in epidemiolog-ical studies, for example to compare prevalence rates betweendifferent populations).

Our results could be interpreted in the context of previous knowl-edge for MAOA biology [35]. MAOA gene encodes a key enzymefor the regulation of several neurotransmitters, such as dopamine,noradrenaline, and serotonin [28,30–32], which are fundamental forthe regulation of sleep and other behavioral phenotypes. In line withthis, mice that are deficient for MAOA show sleep alterations [45].It has been demonstrated that the 4-repeat allele of the humanMAOA-uVNTR is transcriptionally and enzymatically more active (2 to10 times) than the 3-repeat allele [35,36].

MAOA-uVNTR has been extensively studied as a possible candidatepolymorphism for a large number of neuropsychiatric disorders[33–35] However, our findings provide evidence for the first time thata functional MAOA-uVNTR has a significant association with daytimesleepiness in a sample of healthy subjects. These data suggest thatfunctional variations inMAOA gene could also affect sleep and behavior-al circadian phenotypes and disorders [23]. These findings shouldbe replicated in other ethnic groups, using larger samples, in order toconfirm and understand the role ofMAOA-uVNTR in sleep disturbances.

Conflict of interest

S. L-L is employee of Novartis Pharmaceuticals. All authors declarethat there is no conflict of interest.

Acknowledgments

This studywas supported by grants fromColciencias (Contract#765-2011), Universidad Antonio Nariño (VCTI-UAN) and Universidad deCiencias Aplicadas y Ambientales (UDCA). The authors thank all thosewho assisted with recruitment of subjects.

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