MENINOS COM O ALELO MAOA_LPR*2R APRESENTAM PREJUÍZOS COGNITIVOS E DE APRENDIZAGEM?

Silva, Emanuelle de Oliveira; Carvalho, André Henrique Barbosa de; Paiva, Giulia Moreira; Jorge, Carolina Andrade; Koltermann, Gabriella; Salles, Jerusa Fumagalli de; Haase, Vitor Geraldi; Carvalho, Maria Raquel Santos

Emanuelle de Oliveira Silva

Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Programa de Pós-graduação em Neurociências, Belo Horizonte MG, Brazil.

http://orcid.org/0000-0002-7756-3261

André Henrique Barbosa de Carvalho

Universidade Federal de Minas Gerais, Ecologia e Evolução, Instituto de Ciências Biológicas, Programa de Pós-Graduação em Genética, Departamento de Genética, Belo Horizonte MG, Brazil.

http://orcid.org/0000-0003-1973-8905

Giulia Moreira Paiva

Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Programa de Pós-graduação em Neurociências, Belo Horizonte MG, Brazil.

http://orcid.org/0000-0002-8505-0837

Carolina Andrade Jorge

Universidade Federal de Minas Gerais, Ecologia e Evolução, Instituto de Ciências Biológicas, Programa de Pós-Graduação em Genética, Departamento de Genética, Belo Horizonte MG, Brazil.

http://orcid.org/0000-0001-7867-613X

Gabriella Koltermann

Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação em Psicologia, Porto Alegre RS, Brazil.

http://orcid.org/0000-0002-1839-0575

Jerusa Fumagalli de Salles

Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação em Psicologia, Porto Alegre RS, Brazil.

http://orcid.org/0000-0003-0877-488X

Vitor Geraldi Haase

Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Programa de Pós-graduação em Neurociências, Belo Horizonte MG, Brazil.

Universidade Federal de Minas Gerais, Departamento de Psicologia, Faculdade de Filosofia e Ciências Humanas, Belo Horizonte MG, Brazil.

Universidade Federal de Minas Gerais, Faculdade de Filosofia e Ciências Humanas,Programa de Pós-Graduação em Psicologia: Cognição e Comportamento, Departamento de Psicologia, Belo Horizonte MG, Brazil.

Instituto Nacional de Ciência e Tecnologia sobre Cognição, Comportamento e Ensino, São Carlos SP, Brazil.

http://orcid.org/0000-0002-1906-7702

Maria Raquel Santos Carvalho

Universidade Federal de Minas Gerais, Ecologia e Evolução, Instituto de Ciências Biológicas, Programa de Pós-Graduação em Genética, Departamento de Genética, Belo Horizonte MG, Brazil.

Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Genética, Ecologia e Evolução, Belo Horizonte MG, Brazil.

http://orcid.org/0000-0002-1744-448X

Correspondence: Maria Raquel Santos Carvalho; E-mails: ma.raquel.carvalho@gmail.com; mraquel-carvalho@ufmg.br.

Disclosure: The authors report no conflicts of interest.

Authors’ contributions. All authors contributed to data collection and analysis. EOS, AHBC, VGH, MRSC: wrote the manuscript, which was reviewed by all the authors.

Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Programa de Pós-graduação em Neurociências, Belo Horizonte MG, Brazil.

Universidade Federal de Minas Gerais, Ecologia e Evolução, Instituto de Ciências Biológicas, Programa de Pós-Graduação em Genética, Departamento de Genética, Belo Horizonte MG, Brazil.

Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação em Psicologia, Porto Alegre RS, Brazil.

Universidade Federal de Minas Gerais, Departamento de Psicologia, Faculdade de Filosofia e Ciências Humanas, Belo Horizonte MG, Brazil.

Universidade Federal de Minas Gerais, Faculdade de Filosofia e Ciências Humanas,Programa de Pós-Graduação em Psicologia: Cognição e Comportamento, Departamento de Psicologia, Belo Horizonte MG, Brazil.

Instituto Nacional de Ciência e Tecnologia sobre Cognição, Comportamento e Ensino, São Carlos SP, Brazil.

Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Genética, Ecologia e Evolução, Belo Horizonte MG, Brazil.

References	n	Sex	Population/cohort	Phenotypes	Findings and conclusions
Guo et al.⁶6. Guo G, Ou XM, Roettger M, Shih JC. The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity. Eur J Hum Genet. 2008;16(5):626-34. https://doi.org/10.1038/sj.ejhg.5201999 https://doi.org/https://doi.org/10.1038/...	2,524	Both sexes	National Longitudinal Study of Adolescent Health (Add Health)	Delinquent behavior	Boys with the MAOA_LPR*2R allele had twice the chance of presenting delinquent and violent behaviors when compared with participants with other alleles. The same effect is observed in girls but with less intensity.
Åslund et al.¹⁹19. Åslund C, Nordquist N, Comasco E, Leppert J, Oreland L, Nilsson KW. Maltreatment, MAOA, and delinquency: sex differences in gene-environment interaction in a large population-based cohort of adolescents. Behav Genet. 2011;41(2):262-72. https://doi.org/10.1007/s10519-010-9356-y https://doi.org/https://doi.org/10.1007/...	1,825	Both sexes	Survey of Adolescent Life in Vestmanland 2006 (SALVe-2006)	Delinquent behavior	MAOA_LPR genotype (one short variant for boys and one or two long variants for girls) showed a significant effect on delinquency when controlled for maltreatment.
Roettger et al.²²22. Roettger ME, Boardman JD, Harris KM, Guo G. The association between the MAOA 2R genotype and delinquency over time among men: the interactive role of parental closeness and parental incarceration. Crim Justice Behav. 2016;43(8):1076-94. https://doi.org/10.1177/0093854816629184 https://doi.org/https://doi.org/10.1177/...	6,001	Males	National Longitudinal Study of Adolescent Health (Add Health)	Delinquent behavior	The relationship between delinquency and the MAOA_LPR*2R allele decreases in participants who were close to their biological or adoptive father, but not in those close to their mother.
Beaver et al.²³23. Beaver KM, Barnes JC, Boutwell BB. The 2-repeat allele of the MAOA gene confers an increased risk for shooting and stabbing behaviors. Psychiatr Q. 2014;85(3):257-65. https://doi.org/10.1007/s11126-013-9287-x https://doi.org/https://doi.org/10.1007/...	2,574	Males	National Longitudinal Study of Adolescent Health (Add Health)	Violent behaviors	African Americans carrying the MAOA_LPR*2R allele were more likely to engage in violent behaviors such as shooting or stabbing someone when compared to other MAOA_LPR genotypes.
Beaver et al.²⁴24. Beaver KM, Wright JP, Boutwell BB, Barnes JC, DeLisi M, Vaughn MG. Exploring the association between the 2-repeat allele of the MAOA gene promoter polymorphism and psychopathic personality traits, arrests, incarceration, and lifetime antisocial behavior. Pers Individ Dif. 2013;54(2):164-8. https://doi.org/10.1016/j.paid.2012.08.014 https://doi.org/https://doi.org/10.1016/...	167/174	Males	National Longitudinal Study of Adolescent Health (Add Health)	Anti-social phenotypes	African Americans with MAOA_LPR2R allele had higher scores on an antisocial phenotype scale. Individuals with the MAOA_LPR2R allele were also significantly more likely to be arrested, when compared to individuals with other alleles. There were no data for Caucasians.
Daw and Guo²⁵25. Daw J, Guo G. The influence of three genes on whether adolescents use contraception, USA 1994-2002. Popul Stud. 2011;65(3):253-71. https://doi.org/10.1080/00324728.2011.598942 https://doi.org/https://doi.org/10.1080/...	2,167	Both sexes	National Longitudinal Study of Adolescent Health (Add Health)	Contraceptive use	Females carrying the MAOA_LPR*2R allele have higher odds of having unprotected sex. The authors did not find this association in males.
Stetler et al.²⁶26. Stetler DA, Davis C, Leavitt K, Schriger I, Benson K, Bhakta S, et al. Association of low-activity MAOA allelic variants with violent crime in incarcerated offenders. J Psychiatr Res. 2014;58:69-75. https://doi.org/10.1016/j.jpsychires.2014.07.006 https://doi.org/https://doi.org/10.1016/...	89	Male	Imprisoned population	Violent behaviors	Violent crime charges were significantly more frequent in carriers of MAOA_LPR2R or MAOA_LPR3R alleles.
Barnett et al.²⁷27. Barnett JH, Xu K, Heron J, Goldman D, Jones PB. Cognitive effects of genetic variation in monoamine neurotransmitter systems: a population-based study of COMT, MAOA, and 5HTTLPR. Am J Med Genet B Neuropsychiatr Genet. 2011;156(2):158-67. https://doi.org/10.1002/ajmg.b.31150 https://doi.org/https://doi.org/10.1002/...	6,000	Both sexes	Avon Longitudinal Study of Parents and Children (ALSPAC)	Cognitive function	MAOA_LPR alone did not show a significant effect on cognitive function. The authors found an association between MAOA_LPR and COMT Val158Met genotypes with better working memory.
Belsky and Beaver²⁸28. Belsky J, Beaver KM. Cumulative-genetic plasticity, parenting and adolescent self-regulation. J Child Psychol Psychiatry. 2011;52(5):619-26. https://doi.org/10.1111/j.1469-7610.2010.02327.x https://doi.org/https://doi.org/10.1111/...	1,586	Both sexes	National Longitudinal Study of Adolescent Health (Add Health)	Self-regulation and adolescence parenting	Under different environmental conditions, MAOA_LPR could be one moderator of parenting and self-regulation in boys.
Rommelse et al.²⁹29. Rommelse NN, Altink ME, Arias-Vásquez A, Buschgens CJ, Fliers E, Faraone S V, et al. Differential association between MAOA, ADHD and neuropsychological functioning in boys and girls. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(8):1524-30. https://doi.org/10.1002/ajmg.b.30845 https://doi.org/https://doi.org/10.1002/...	545	Both sexes	Dutch part of the International Multicenter ADHD Genetics (IMAGE) cohort	ADHD and neuropsychological functioning	One of the haplotypes was associated with poorer motor control in boys and with better visuospatial working memory in girls.
Chien et al.³⁰30. Chien C-C, Lin C-H, Chang Y-Y, Lung F-W. Association of VNTR polymorphisms in the MAOA promoter and DRD4 exon 3 with heroin dependence in male Chinese addicts. World J Biol Psychiatry. 2010;11(2-2):409-16. https://doi.org/10.3109/15622970903304459 https://doi.org/https://doi.org/10.3109/...	1,074	Male	In custody population	Heroin dependence	MAOA_LPR polymorphism does not appear to be involved in heroin dependence.
Ko et al.³¹31. Ko C-H, Hsieh T-J, Wang P-W, Lin W-C, Chen C-S, Yen J-Y. The altered brain activation of phonological working memory, dual tasking, and distraction among participants with adult ADHD and the effect of the MAOA polymorphism. J Atten Disord. 2018;22(3):240-9. https://doi.org/10.1177/1087054715572609 https://doi.org/https://doi.org/10.1177/...	50	Males	ADHD and non-ADHD population	ADHD	ADHD carriers of rs1137070 T allele had higher activation of pars opercularis when compared with carriers of C allele.

Construct	Instrument	References
General cognitive abilities (Intelligence)	Raven’s Coloured Progressive Matrices (CPM)	Angelini et al.³²32. Angelini AL, Alves IC, Custódio EM, Duarte WF, Duarte JL. Matrizes progressivas coloridas de Raven: escala especial. São Paulo: Centro Editor de Testes e Pesquisas em Psicologia; 1999.
School achievement	TDE - Arithmetic subtest and Spelling subtest	Oliveira-Ferreira et al.³³33. Oliveira-Ferreira F, Costa DS, Micheli LR, Oliveira LF, Pinheiro-Chagas P, Haase VG. School Achievement Test: Normative data for a representative sample of elementary school children. Psychol Neurosci. 2012;5(2):157-64. https://doi.org/10.3922/j.psns.2012.2.05 https://doi.org/https://doi.org/10.3922/... , and Gomides et al.³⁴34. Gomides MR, Lopes-Silva JB, Moura R, de Salles JS, Haase VG. Bateria de avaliação do processamento númerico e cálculo - PRONUMERO. Vetor; 2021. ISBN: 978-65-89914-61-7
Verbal and visuospatial short-term and working memory	WISC-III Digits (Verbal Short Term and Working Memory) and Corsi Blocks	Figueiredo and Nascimento³⁵35. Figueiredo VL, Nascimento E. Performances in the forward and backward digit span in the WISC-III and WAIS-III. Psicol Teor Pesqui. 2007;23(3):313-8. https://doi.org/10.1590/S0102-37722007000300010 https://doi.org/https://doi.org/10.1590/... , and Galera and Souza³⁶36. Galera C, Souza AL. Memória visuoespacial e cinestésica de curto prazo em crianças de 7 a 10 anos. Estud Psicol. 2010;15(2):137-43. https://doi.org/10.1590/S1413-294X2010000200002 https://doi.org/10.1590/S1413-294X201000...
Numerical and arithmetic abilities	Arabic number dictation, Addition, Subtraction, Multiplication	Gomides et al.³⁴34. Gomides MR, Lopes-Silva JB, Moura R, de Salles JS, Haase VG. Bateria de avaliação do processamento númerico e cálculo - PRONUMERO. Vetor; 2021. ISBN: 978-65-89914-61-7

Initials	Grade/age	Neuropsychological results
Boy 1	5th grade/10 years	Superior normal intelligence (1.4 SD above mean). Verbal working memory (2.5 SD above mean) and arithmetic achievement superior (1.8 SD above mean) for age. Typical for age performance in visuospatial short and working memory tasks; spelling achievement.
Boy 2	3rd grade/8 years	Normal intelligence. Typical for age performance in verbal and visuospatial short-term memory; arithmetic; and spelling achievement. Low performance on visuospatial and verbal working memory tasks.
Boy 3	3rd grade/7 years	Superior normal intelligence (1.3 SD above mean). Typical for age performance in verbal and visuospatial short-term and working memory; arithmetic; and spelling achievement.
Boy 4	3rd grade/ 9 years old	Normal intelligence. Typical for age performance on verbal short-term and working memory, and spelling achievement. Low performance in visuospatial short-term and working memory, and arithmetic achievement.
Boy 5	2nd grade/7 years	Normal intelligence. Typical for age performance in verbal and visuospatial short-term and working memory; and in spelling tasks. Low achievement in spelling and arithmetic tasks.
Boy 6	2nd grade/7 years	Normal intelligence. Typical for age performance in verbal and visuospatial short memory; visuospatial working memory. Low performance in a visuospatial short-term memory task, arithmetic, and spelling achievement.
Boy 7	2nd grade/7 years	Normal intelligence. Typical for age performance in verbal and visuospatial working memory, verbal working memory. Low performance in visuospatial short memory, spelling, and arithmetic achievement.
Boy 8	5th grade/11 years	Normal intelligence. Typical for age performance in verbal and visuospatial short-term and working memory, and spelling achievement. Low achievement in arithmetic.

[1] Correspondence: Maria Raquel Santos Carvalho; E-mails: ma.raquel.carvalho@gmail.com; mraquel-carvalho@ufmg.br.

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MENINOS COM O ALELO MAOA_LPR*2R APRESENTAM PREJUÍZOS COGNITIVOS E DE APRENDIZAGEM?

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