Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome

Journal of Neurodevelopmental Disorders

Joseph Piven¹  Allan L Reiss²  Lea K Davis³  Heather C Hazlett¹  Thomas H Wassink⁴ 

[1] Neurodevelopmental Disorders Research Center and Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA;Department of Psychiatry and Behavioral Sciences, Center for Interdisciplinary Brain Sciences Research, School of Medicine, Stanford University, Stanford, California, USA;Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA;Department of Psychiatry, University of Iowa Carver College of Medicine, 1-191 MEB, Iowa City, Iowa 52242, USA

关键词: Polymorphism;    Monoamine oxidase A;    Brain structure;    Fragile X syndrome;    Autism;   

Others  :  804487
DOI  :  10.1186/1866-1955-6-6

 received in 2013-06-27, accepted in 2014-03-05,  发布年份 2014

【 摘 要 】

Background

Autism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS.

Methods

Participants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles.

Results

MAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10.

Conclusions

The MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS.

【 授权许可】

   
2014 Wassink et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

Figure 2.

【 参考文献 】

• [1]Abdelmoity AT, LePichon JB, Nyp SS, Soden SE, Daniel CA, Yu S: 15q11.2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features. J Dev Behav Pediatr 2012, 33:570-576.
• [2]Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L, Mace A, Ferrari C, Kutalik Z, Andrieux J, Aylward E, Barker M, Bernier R, Bouquillon S, Conus P, Delobel B, Faucett WA, Goin-Kochel RP, Grant E, Harewood L, Hunter JV, Lebon S, Ledbetter DH, Martin CL, Mannik K, Martinet D, Mukherjee P, Ramocki MB, Spence SJ, Steinman KJ, et al.: A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet 2012, 49:660-668.
• [3]Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G, Roberts SA, Gayan J, Brocklebank D, Cherny SS, Cardon LR, Gray J, Dlouhy SR, Wiktorski S, Hodes ME, Conneally PM, Penney JB, Gusella J, Cha JH, Irizarry M, Rosas D, Hersch S, Hollingsworth Z, MacDonald M, Young AB, Andresen JM, Housman DE, De Young MM, et al.: Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci U S A 2004, 101:3498-3503.
• [4]Loesch DZ, Huggins RM, Bui QM, Epstein JL, Taylor AK, Hagerman RJ: Effect of the deficits of fragile X mental retardation protein on cognitive status of fragile x males and females assessed by robust pedigree analysis. J Dev Behav Pediatr 2002, 23:416-423.
• [5]Loesch DZ, Huggins RM, Taylor AK: Application of robust pedigree analysis in studies of complex genotype-phenotype relationships in fragile X syndrome. Am J Med Genet 2002, 107:136-142.
• [6]Johnson AD, Newton-Cheh C, Chasman DI, Ehret GB, Johnson T, Rose L, Rice K, Verwoert GC, Launer LJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, Caulfield M, van Duijn CM, Ridker PM, Munroe PB, Levy D, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium; Global BPgen Consortium; Women’s Genome Health Study: Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. Hypertension 2011, 57:903-910.
• [7]Glover M, Zuber AM, O’Shaughnessy KM: Hypertension, dietary salt intake, and the role of the thiazide-sensitive sodium chloride transporter NCCT. Cardiovasc Ther 2011, 29:68-76.
• [8]Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD, Winiger E, Breier A, Shekhar A, Amdur R, Koller D, Nurnberger JI, Corvin A, Geyer M, Tsuang MT, Salomon D, Schork NJ, Fanous AH, O’Donovan MC, Niculescu AB: Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry 2012, 17:887-905.
• [9]Davis LK, Hazlett HC, Librant AL, Nopoulos P, Sheffield VC, Piven J, Wassink TH: Cortical enlargement in autism is associated with a functional VNTR in the monoamine oxidase A gene. Am J Med Genet B Neuropsychiatr Genet 2008, 147B:1145-1151.
• [10]Yoo HJ, Lee SK, Park M, Cho IH, Hyun SH, Lee JC, Yang SY, Kim SA: Family- and population-based association studies of monoamine oxidase A and autism spectrum disorders in Korean. Neurosci Res 2009, 63:172-176.
• [11]Tassone F, Qi L, Zhang W, Hansen RL, Pessah IN, Hertz-Picciotto I: MAOA, DBH, and SLC6A4 variants in CHARGE: a case-control study of autism spectrum disorders. Autism Res 2011, 4:250-261.
• [12]Bouma EM, Riese H, Doornbos B, Ormel J, Oldehinkel AJ: Genetically based reduced MAOA and COMT functioning is associated with the cortisol stress response: a replication study. Mol Psychiatry 2012, 17:119-121.
• [13]Kebir O, Joober R: Neuropsychological endophenotypes in attention-deficit/hyperactivity disorder: a review of genetic association studies. Eur Arch Psychiatry Clin Neurosci 2011, 261:583-594.
• [14]Dannlowski U, Ohrmann P, Konrad C, Domschke K, Bauer J, Kugel H, Hohoff C, Schoning S, Kersting A, Baune BT, Mortensen LS, Arolt V, Zwitserlood P, Deckert J, Heindel W, Suslow T: Reduced amygdala-prefrontal coupling in major depression: association with MAOA genotype and illness severity. Int J Neuropsychopharmacol 2009, 12:11-22.
• [15]Fergusson DM, Boden JM, Horwood LJ, Miller A, Kennedy MA: Moderating role of the MAOA genotype in antisocial behaviour. Br J Psychiatry 2012, 200:116-123.
• [16]Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, Gilmore J, Piven J: An MRI and head circumference study of brain size in autism: birth through age two years. Arch Gen Psychiatry 2005, 62:1366-1376.
• [17]Bailey DBJ, Mesibov GB, Hatton DD, Clark RD, Roberts JE, Mayhew L: Autistic behavior in young boys with fragile X syndrome. J Autism Dev Disord 1998, 28:499-508.
• [18]Hazlett HC, Poe MD, Lightbody AA, Gerig G, Macfall JR, Ross AK, Provenzale J, Martin A, Reiss AL, Piven J: Teasing apart the heterogeneity of autism: same behavior, different brains in toddlers with fragile X syndrome and autism. J Neurodev Disord 2009, 1:81-90.
• [19]Hazlett HC, Poe MD, Lightbody AA, Styner M, MacFall JR, Reiss AL, Piven J: Trajectories of early brain volume development in fragile X syndrome and autism. J Am Acad Child Adolesc Psychiatry 2012, 51:921-933.
• [20]Hoeft F, Lightbody AA, Hazlett HC, Patnaik S, Piven J, Reiss AL: Morphometric spatial patterns differentiating boys with fragile X syndrome, typically developing boys, and developmentally delayed boys aged 1 to 3 years. Arch Gen Psychiatry 2008, 65:1087-1097.
• [21]Hoeft F, Walter E, Lightbody AA, Hazlett HC, Chang C, Piven J, Reiss AL: Neuroanatomical differences in toddler boys with fragile x syndrome and idiopathic autism. Arch Gen Psychiatry 2011, 68:295-305.
• [22]Lord C, Rutter M, Le CA: Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994, 24:659-685.
• [23]DiLavore PC, Lord C, Rutter M: The pre-linguistic autism diagnostic observation schedule. J Autism Dev Disorders 1995, 25:355-379.
• [24]Mullen EM: Mullen scales of early learning: AGS edition. Circle Pines, MN: American Guidance Service; 1995.
• [25]Sparrow SS, Balla D, Cicchetti D: Vineland adaptive behavior scales (survey form). Circle Pines, MN: American Guidance Service; 1984.
• [26]Andreasen NC, Cizadlo T, Harris G, Swayze V, O’Leary DS, Cohen G, Ehrhardt J, Yuh WT: Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging. J Neuropsychiatr Clin Neurosci 1993, 5:121-130.
• [27]Andreasen NC, Cohen G, Harris G, Cizadlo T, Parkkinen J, Rezai K, Swayze VW: Image processing for the study of brain structure and function: problems and programs. J Neuropsychiatr Clin Neurosci 1992, 4:125-133.
• [28]Andreasen NC, Tamminga CA: Images in neuroscience: cortex. II: identifying lobes and landmarks. Am J Psychiatr 1994, 151:1722.
• [29]Cohen G, Andreasen NC, Alliger R, Arndt S, Kuan J, Yuh WTC, Ehrhardt J: Segmentation techniques for the classification of brain tissue using magnetic resonance imaging. Psychiatry Res Neuroimaging 1992, 45:33-51.
• [30]Magnotta VA, Harris G, Andreasen NC, O’Leary DS, Yuh WT, Heckel D: Structural MR image processing using the BRAINS2 toolbox. Comput Med Imaging Graph 2002, 26:251-264.
• [31]Talairach J, Tournoux P: Co-planar stereotaxic atlas of the human brain. New York, NY: Thieme; 1988.
• [32]Van Leemput K, Maes F, Vandermeulen D, Suetens P: Automated model-based bias field correction of MR images of the brain. IEEE Trans Med Imaging 1999, 18:885-896.
• [33]Sabol SZ, Hu S, Hamer D: A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998, 103:273-279.
• [34]Bonnin A, Levitt P: Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain. Neuroscience 2011, 197:1-7.
• [35]Deneris ES: Molecular genetics of mouse serotonin neurons across the lifespan. Neuroscience 2011, 197:17-27.
• [36]Abramson RK, Wright HH, Carpenter R, Brennan W, Lumpuy O, Cole E, Young SR: Elevated blood serotonin in autistic probands and their first-degree relatives. J Autism Dev Disord 1989, 19:397-407.
• [37]Devlin B, Cook EH Jr, Coon H, Dawson G, Grigorenko EL, McMahon W, Minshew N, Pauls D, Smith M, Spence MA, Rodier PM, Stodgell C, Schellenberg GD, CPEA Genetics Network: Autism and the serotonin transporter: the long and short of it. Mol Psychiatry 2005, 10:1110-1116.
• [38]Herault J, Petit E, Martineau J, Cherpi C, Perrot A, Barthelemy C, Lelord G, Muh JP: Serotonin and autism: biochemical and molecular biology features. Psychiatry Res 1996, 65:33-43.
• [39]Piven J, Tsai GC, Nehme E, Coyle JT, Chase GA, Folstein SE: Platelet serotonin, a possible marker for familial autism. J Autism Dev Disord 1991, 21:51-59.
• [40]Whitaker-Azmitia PM: Serotonin and brain development: role in human developmental diseases. Brain Res Bull 2001, 56:479-485.
• [41]Jonsson EG, Norton N, Gustavsson JP, Oreland L, Owen MJ, Sedvall GC: A promoter polymorphism in the monoamine oxidase A gene and its relationships to monoamine metabolite concentrations in CSF of healthy volunteers. J Psychiatr Res 2000, 34:239-244.
• [42]Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, Kuhn CM, Lewis JG, Schanberg SM, Stafford-Smith M, Suarez EC, Clary GL, Svenson IK, Siegler IC: Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology 2003, 28:533-541.
• [43]Zalsman G, Huang YY, Harkavy-Friedman JM, Oquendo MA, Ellis SP, Mann JJ: Relationship of MAO-a promoter (u-VNTR) and COMT (V158M) gene polymorphisms to CSF monoamine metabolites levels in a psychiatric sample of caucasians: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 2005, 132:100-103.
• [44]Ducci F, Newman TK, Funt S, Brown GL, Virkkunen M, Goldman D: A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index. Mol Psychiatry 2006, 11:858-866.
• [45]Dickinson JL, Sale MM, Passmore A, FitzGerald LM, Wheatley CM, Burdon KP, Craig JE, Tengtrisorn S, Carden SM, Maclean H, Mackey DA: Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clin Experiment Ophthalmol 2006, 34:682-688.
• [46]Halpin C, Owen G, Gutierrez-Espeleta GA, Sims K, Rehm HL: Audiologic features of Norrie disease. Ann Otol Rhinol Laryngol 2005, 114:533-538.
• [47]Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA: Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 1993, 262:578-580.
• [48]Brunner HG, Nelen MR, van Zandvoort P, Abeling NG, van Gennip AH, Wolters EC, Kuiper MA, Ropers HH, van Oost BA: X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am J Hum Genet 1993, 52:1032-1039.
• [49]Zhang H, Smith GN, Liu X, Holden JJ: Association of MAOA, 5-HTT, and NET promoter polymorphisms with gene expression and protein activity in human placentas. Physiol Genomics 2010, 42:85-92.
• [50]Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, Nothen MM, Maffei P, Franke P, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Lesch KP: Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 1999, 8:621-624.
• [51]Beitchman JH, Mik HM, Ehtesham S, Douglas L, Kennedy JL: MAOA and persistent, pervasive childhood aggression. Mol Psychiatry 2004, 9:546-547.
• [52]Fan M, Liu B, Jiang T, Jiang X, Zhao H, Zhang J: Meta-analysis of the association between the monoamine oxidase-A gene and mood disorders. Psychiatr Genet 2010, 20:1-7.
• [53]Nordquist N, Oreland L: Serotonin, genetic variability, behaviour, and psychiatric disorders–a review. Ups J Med Sci 2010, 115:2-10.
• [54]Cohen IL, Liu X, Schutz C, White BN, Jenkins EC, Brown WT, Holden JJ: Association of autism severity with a monoamine oxidase A functional polymorphism. Clin Genet 2003, 64:190-197.
• [55]Cohen IL, Liu X, Lewis ME, Chudley A, Forster-Gibson C, Gonzalez M, Jenkins EC, Brown WT, Holden JJ: Autism severity is associated with child and maternal MAOA genotypes. Clin Genet 2011, 79:355-362.
• [56]Lainhart JE, Piven J, Wzorek M, Landa R, Santangelo SL, Coon H, Folstein SE: Macrocephaly in children and adults with autism. J Am Acad Child Adolesc Psychiatry 1997, 36:282-290.
• [57]Wassink TH, Hazlett HC, Epping EA, Arndt S, Dager SR, Schellenberg GD, Dawson G, Piven J: Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism. Arch Gen Psychiatry 2007, 64:709-717.
• [58]Bradley SL, Dodelzon K, Sandhu HK, Philibert RA: Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription. Am J Med Genet B Neuropsychiatr Genet 2005, 136:58-61.
• [59]Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR, Piven J, Crawley JN: Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 2004, 3:287-302.
• [60]Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP, Barbaro JR, Wilson LM, Threadgill DW, Lauder JM, Magnuson TR, Crawley JN: Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 2007, 176:4-20.
• [61]Moy SS, Nadler JJ, Young NB, Nonneman RJ, Grossman AW, Murphy DL, D’Ercole AJ, Crawley JN, Magnuson TR, Lauder JM: Social approach in genetically engineered mouse lines relevant to autism. Genes Brain Behav 2009, 8:129-142.
• [62]Page DT, Kuti OJ, Prestia C, Sur M: Haploinsufficiency for pten and serotonin transporter cooperatively influences brain size and social behavior. Proc Natl Acad Sci U S A 2009, 106:1989-1994.