Association of monoamine oxidase A and serotonin transporter gene functional variants with intellectual disability related behavioral problems Aneek Das Bhowmik, Gargi Mahapatra, Samikshan Dutta, Jyoti Shaw, Swagata Sinha and Kanchan Mukhopadhyay Psychiatric Genetics 2012, 22:152 Manovikas Biomedical Research and Diagnostic Centre, Kolkata, India Correspondence to Dr Kanchan Mukhopadhyay, MSc, PhD, Manovikas Biomedical Research and Diagnostic Centre, 482 Madudah, Plot I-24, Sec. J, E.M. Bypass, Kolkata-700107, India Tel: +91 33 40019179; fax: +91 33 2442 8275; e-mail: kanchanmvk@yahoo.com Received 23 June 2010 Revised 29 June 2011 Accepted 14 July 2011 Intellectual disability (ID) is characterized by signifi- cantly subaverage intellectual functioning with deficits in adaptive behavior. Approximately 30–50% ID cases pre- sent with unknown etiology and identified as Idiopathic ID (IID). Various behavioral problems cooccur with IID and role of the serotonergic system, known to control emotion, mood, and drive, has been extensively investi- gated (Ramamoorthy et al., 1993). Level of serotonin (5- HT) is maintained by the serotonin transporter (5-HTT), helping in reuptake, and monoamine oxidase A (MAOA), facilitating metabolism. In this study, association of four functional genetic polymorphisms, MAOA-u VNTR, rs6323, 5-HTTLPR, and STin2, with IID were explored in eastern Indian probands. Diagnosis was carried out by mental health professionals following the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria. Mental development status was measured by Develop- mental Screening Test (children below 5 years) or Wechsler Intelligence Scale (children above 5 years). Behavioral features like personality traits, mood, anxiety, impulsivity, hyperactivity, and depression were assessed using the Diagnostic Assessment for the Severely Handicapped-II scale. Informed written consent for participation was obtained from parents (n = 300) of IID probands (n = 198). Study protocol was approved by the institutional Human Ethical Committee. Individuals were divided as IID with severe/high behavioral problems (IID positive behavior, n = 107) and no remarkable behavioral problem (IID negative behavior, n = 91). For transmission disequilibrium test analysis, UNPHASED v2.404 (Dud- bridge, 2003) was used. Corrections for multiple compari- sons [Global significance (GS)] were performed after 10 000 permutation. Epistatic interaction analysis was performed using multifactor dimensionality reduction- phenomics v1 (Mei et al., 2007). Power of transmission disequilibrium test and multifactor dimensionality reduc- tion was calculated using Piface v1.72 (Lenth, 2007). Genotypic frequencies for both MAOA (uVNTR: 3.5R/ 3.5R = 0.34, 3.5R/4.5R = 0.53, 4.5R/4.5R = 0.08; rs6323: G/G = 0.36, G/T = 0.55, T/T = 0.09) and 5-HTT (5-HTTLPR: S/S = 0.37, S/L = 0.49, L/L = 0.14; STin2: 10R/10R = 0.06, 10R/12R = 0.37, 12R/12R = 0.57) were within Hardy–Weinberg equilibrium. Mild over transmis- sion of MAOA rs6323 ‘T’ allele [P = 0.046, GS ± standard error (SE) = 0.096 ± 0.003, relative risk (RR) = 3.33, confidence interval (CI) 95% = 1.18–9.39; power = 39.2%] and significant over transmission of 4.5R-T haplotype (P = 0.016, GS ± SE = 0.049 ± 0.002, RR = 5, CI 95% = 1.27–19.7) was noticed in female IID individuals. Fe- male IID positive behavior individuals also exhibited nominally higher transmission (P = 0.046, GS ± SE = 0.12 ± 0.003, RR = 6, CI 95% = 0.95–37.8; power = 72.9%). In the 5HTT , STin2 ‘10R’ (RR = 2.25, CI 95% = 0.92–5.49; power = 44.1%) and 5-HTTLPR ‘L’ (RR = 3, CI 95% = 1.07–8.43; power = 62.8%) alleles revealed over trans- mission and high RR values in female IID positive behavior individuals. Haplotype analysis revealed over transmission of the L-10R (RR = 3, CI 95% = 0.69–13.1) with significant nontransmission of the S-12R (P = 0.03, RR = 0.27, CI 95% = 0.09–0.83) in female IID positive behavior individuals. Significant epistatic interaction between MAOA-u VNTR and 5-HTTLPR was also observed in female IID probands (NonFixP = 0.012, Power = 99.9%). Data obtained indicate significant asso- ciation of these gene variants with IID in eastern Indian probands, especially in female with behavioral problems. Acknowledgements Conflicts of interest There are no conflicts of interest. References Dudbridge F (2003). Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–221. Lenth RV (2007). Statistical power calculations. J Anim Sci 85:E24–E29. Mei H, Cuccaro ML, Martin ER (2007). Multifactor dimentionality reduction- phenomics: a novel method of capture genetic heterogeneity with use of phenotypic variables. Am J Hum Genet 81:1251–1261. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, et al. (1993). Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA 90:2542–2456. 152 Brief association letter 0955-8829  c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YPG.0b013e32834c0c21 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.