Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children.

OBJECTIVE The study aimed to determine the cognitive effect of the Val108/158Met polymorphism in the catechol-O-methyltransferase (COMT) gene in children before and during puberty. This polymorphism affects cognitive function in healthy adults and may contribute to risk for schizophrenia. METHOD COMT genotype was determined for 8,707 children from the Avon Longitudinal Study of Parents and Children (ALSPAC), a geographically defined general population cohort of children born between April 1, 1991, and Dec. 31, 1992, in the southwest of England. Fourteen measures of cognitive function--including working memory, verbal and motor inhibition, attentional control, and IQ--were assessed at ages 8 and 10 years. Any pubertal development at age 9 years was reported by parents. Effects of COMT genotype on cognition and interactions with gender and puberty were assessed using general linear models. RESULTS In boys, genotype significantly affected executive function and explained up to 10 points normal variation in verbal IQ. The effects on IQ were significantly greater in pubertal than in prepubertal boys. In girls, there were no significant effects of genotype on cognition. CONCLUSIONS This common polymorphism may be one of the genes of small effect that contribute to normal variation in IQ. The gender-specific nature of the effect and its possible interaction with puberty may be relevant to both normal cognitive and brain development and to abnormal development in disorders such as schizophrenia.

[1]  Kenneth K Kidd,et al.  Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles , 1999, Biological Psychiatry.

[2]  M. Keshavan,et al.  Sex differences in brain maturation during childhood and adolescence. , 2001, Cerebral cortex.

[3]  G. Logan.  On the ability to inhibit thought and action , 1984 .

[4]  P S Goldman-Rakic,et al.  Synaptogenesis in the prefrontal cortex of rhesus monkeys. , 1994, Cerebral cortex.

[5]  S. Ring,et al.  A new human genetic resource: a DNA bank established as part of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) , 2000, European Journal of Human Genetics.

[6]  A. Riecher-Rössler,et al.  The Influence of Age and Sex on the Onset and Early Course of Schizophrenia , 1993, British Journal of Psychiatry.

[7]  A. Diamond,et al.  Genetic and neurochemical modulation of prefrontal cognitive functions in children. , 2004, The American journal of psychiatry.

[8]  G. Logan,et al.  On the ability to inhibit simple and choice reaction time responses: a model and a method. , 1984, Journal of experimental psychology. Human perception and performance.

[9]  M. Egan,et al.  Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. , 2004, American journal of human genetics.

[10]  Shih-Jen Tsai,et al.  Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females , 2003, Neuroscience Letters.

[11]  M. Pembrey,et al.  ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology. , 2001, Paediatric and perinatal epidemiology.

[12]  S. Faraone,et al.  Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. , 2003, The American journal of psychiatry.

[13]  Robert Plomin,et al.  Genetics and general cognitive ability , 1999, Nature.

[14]  C. Pantelis,et al.  Normative Data From the Cantab. I: Development of Executive Function Over the Lifespan , 2003, Journal of clinical and experimental neuropsychology.

[15]  K K Kidd,et al.  COMT haplotypes suggest P2 promoter region relevance for schizophrenia , 2004, Molecular Psychiatry.

[16]  I. Deary,et al.  KLOTHO genotype and cognitive ability in childhood and old age in the same individuals , 2005, Neuroscience Letters.

[17]  Beng-Choon Ho,et al.  Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance. , 2002, The American journal of psychiatry.

[18]  Shumei S. Sun,et al.  National estimates of the timing of sexual maturation and racial differences among US children. , 2002, Pediatrics.

[19]  Caroline Hayward,et al.  Ageing: Cognitive change and the APOE ɛ4 allele , 2002, Nature.

[20]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Weinshilboum,et al.  Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. , 1996, Pharmacogenetics.

[22]  I. Deary,et al.  The functional COMT polymorphism, Val158Met, is associated with logical memory and the personality trait intellect/imagination in a cohort of healthy 79 year olds , 2005, Neuroscience Letters.

[23]  M. Egan,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[24]  A. Malhotra,et al.  A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. , 2002, The American journal of psychiatry.

[25]  F. Vecchi,et al.  Age at menarche and age of onset of pubertal characteristics in 6–14‐year‐old girls from the Province of L'Aquila (Abruzzo, Italy) , 2004, American journal of human biology : the official journal of the Human Biology Council.

[26]  M. Munafo,et al.  Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies , 2005, Molecular Psychiatry.

[27]  M C O'Donovan,et al.  The molecular genetics of schizophrenia: new findings promise new insights , 2004, Molecular Psychiatry.

[28]  C. Stefanis,et al.  Variation in catechol-o-methyltransferase val158 met genotype associated with schizotypy but not cognition: A population study in 543 young men , 2004, Biological Psychiatry.

[29]  C. Nelson,et al.  The functional emergence of prefrontally-guided working memory systems in four- to eight-year-old children , 1998, Neuropsychologia.

[30]  L. Fañanás,et al.  New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. , 2004, The American journal of psychiatry.

[31]  E. Walker,et al.  Intelligence in schizophrenia: meta-analysis of the research. , 1984, Schizophrenia bulletin.

[32]  G. Meco,et al.  Cognitive improvement during Tolcapone treatment in Parkinson's disease , 1997, Journal of Neural Transmission.

[33]  J. Giedd.  Structural Magnetic Resonance Imaging of the Adolescent Brain , 2004, Annals of the New York Academy of Sciences.

[34]  E. Bullmore,et al.  Functional frontalisation with age: mapping neurodevelopmental trajectories with fMRI , 2000, Neuroscience & Biobehavioral Reviews.

[35]  Newell,et al.  A neural basis for general intelligence , 2000, American journal of ophthalmology.

[36]  A. Haapalinna,et al.  Catechol 0-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats , 1997, Behavioural Brain Research.

[37]  B. J. Casey,et al.  Structural and functional brain development and its relation to cognitive development , 2000, Biological Psychology.

[38]  R. Case,et al.  Operational efficiency and the growth of short-term memory span , 1982 .

[39]  A. Toga,et al.  In vivo evidence for post-adolescent brain maturation in frontal and striatal regions , 1999, Nature Neuroscience.

[40]  J. Beckmann,et al.  A highly significant association between a COMT haplotype and schizophrenia. , 2002, American journal of human genetics.

[41]  I. Nimmo-Smith,et al.  The differential assessment of children's attention: the Test of Everyday Attention for Children (TEA-Ch), normative sample and ADHD performance. , 2001, Journal of child psychology and psychiatry, and allied disciplines.

[42]  D. Pfaff,et al.  Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. , 1998, Proceedings of the National Academy of Sciences of the United States of America.