News Release

Genetics, genes and intelligence

Peer-Reviewed Publication

Molecular Psychiatry

ARTICLE 1: "Cathepsin D exon 2 polymorphism associated with general intelligence in a healthy older population."

A Payton (1), F Holland (2), P Diggle (3), P Rabbitt (4), M Horan (5), Y Davidson (5), L Gibbons (5), J Worthington (1), W E R Ollier (1) and N Pendleton (5)

(1) Centre for Integrated Genomic Medical Research, Stopford Building, Manchester University, Oxford Road, Manchester M13 9PT, UK

(2) GlaxoSmithKline, NFSP (S), Third Avenue, Harlow CM19 5AW, UK

(3) Medical Statistics Unit, Department of Mathematics & Statistics, University of Lancaster, Lancaster LA1 4YF, UK

(4) Age & Cognitive Performance Research Centre, University of Manchester, Zochonis Building, Oxford Road, Manchester M13 9PL, UK

(5) Clinical Gerontology, University of Manchester, Clinical Sciences Building, Hope Hospital, Stott Lane, Salford, Greater Manchester M6 8HD, UK

General intelligence is a heritable trait that is a risk factor for both the onset of dementia and the rate of cognitive decline in community-dwelling older persons. Previous studies screening for quantitative trait loci (QTLs) that influence general intelligence in healthy individuals have identified four loci, two of which are located within the genes insulin-like growth factor 2 receptor (IGF2R) and the Msx1 homeobox. Here, the authors report the finding of another QTL associated with general intelligence that is located within exon 2 of the cathepsin D (CTSD) gene. A group of 767 healthy adults with a follow-up period of over 15 years have been analyzed for cross-sectional and longitudinal trends in cognitive change using the Heim intelligence test score (AH4-1). The authors observed a significant association (P=0.01) between a functional C>T (Ala>Val) transition within exon 2 of the CTSD gene that increases the secretion of pro-CTSD from the cell, and the AH4-1 score at initial testing on entry to the longitudinal study. Interestingly, CTSD is transported by IGF2R from the trans Golgi network to the lysosome.

Citation source: Molecular Psychiatry 2003 Volume 8, number 1, pages 14-18.

For further information on this work, please contact Anthony (Tony) Payton, Centre for Integrated Genomic Medical Research, Stopford Building, Manchester University, Oxford Road, Manchester M13 9PT, UK. Phone: 44-161-275-7312. E-mail: tony@fs1.ser.man.ac.uk

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ARTICLE 2: "Role of the cholinergic muscarinic 2 receptor (CHRM2) gene in cognition."

D E Comings (1), S Wu (1), M Rostamkhani (1), M McGue (2), W G lacono (2), L S-C Cheng (4) and J P MacMurray (3)

(1) Department of Medical Genetics, City of Hope Medical Center, Duarte, CA 91010, USA

(2) Department of Psychology, University of Minnesóta, Minneapolis, MN, USA

(3) Department of Genomics, MGI Applied Genomics, Long Beach, CA, USA

(4) Department of Biostatistics, City of Hope Medical Center, Duarte, CA 91010, USA

Cholinergic pathways have been widely implicated in cognition and memory, making the respective genes excellent candidate markers for cognitive abilities. Identification of a possible role of cholinergic receptor genes in humans has been hampered by the lack of reported polymorphisms. The authors identified a common AT 1890 polymorphism in the 3'UTR of the CHRM2 gene. To determine if it was associated with IQ, the authors examined 358 adult males and 470 adult females for a total of 828 adults. The subjects were the parents of twins from the Minnesota Twin and Family Study, a long-term study of the genetics and environmental factors in substance abuse. All subjects in the CHRM2 study were of Caucasian ancestry. All were given the Wechsler Adult Intelligence Scale-Revised (Vocabulary, Information, Block Design, and Picture Arrangement) test. The study was approved by the internal review boards of both the University of Minnesota and the City of Hope Medical Center and all subjects gave written informed consent. Using the SSCP technique, the authors identified a common single nucleotide polymorphism, A 1890T in the 3'UTR of the CHRM2 gene based on accession No. M16404. To assess which variable was more closely associated with the CHRM2 gene, the authors performed a MONOVA using both total IQ and years of education as the dependent variables and the CHRM2 gene as the independent variable for the total set. The total MANOVA (Wilks) was significant at P<0.009. The F-ratio for IQ was 4.12, P<0.017, and for years of education the F-ratio was 5.86, P<0.003. The authors have replicated these findings using a quantitative TDT method developed by Abecasis et al. in 230 parent-child trios from the MTFS. While a marginally significant association was found between CHRM2 and total IQ, after stratifying parental origin of transmission, there was a highly significant association for paternal transmission (P=0.007). Although in need of replication, the authors believe these preliminary results are consistent with a role of the CHRM2 gene in cognitive processes in humans, as assessed by both total IQ and years of education.

Citation source: Molecular Psychiatry 2003 Volume 8, number 1, pages 10-11.

For further information on this work, please contact Dr. David E. Comings, Department of Medical Genetics, City of Hope Medical Center, Duarte, CA 91010, USA. Phone: 626-359-8111 x 2631. E-mail: dcomings@earthlink.net

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ARTICLE 3: "Neonatal perturbation of neurotrophic signaling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development."

T Futamura (1), A Kakita (2), M Tohmi (1), H Sotoyama (3), H Takahashi (2) and H Nawa (1)

(1) Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

(2) Pathology & Brain Disease Research Center, Brain Research Institute, Niigata University, Niigata, Japan

(3) Department of Psychiatry, Niigata University School of Medicine, Niigata, Japan

Epidermal growth factor (EGF) and its structurally related proteins are implicated in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. There are EGF and EGF receptor abnormalities in both brain tissues and blood from schizophrenic patients. The authors administered EGF to neonatal rats to transiently perturb endogenous EGF receptor signaling and evaluated the neurobehavioral consequences. EGF-treatment-induced transient impairment in tyrosine hydroxylase expression. The animals grew normally, exhibited normal weight increase, glial growth, and gross brain structures, and later lost the tyrosine hydroxylase abnormality. During and after development, however, the rats began to display various behavioral abnormalities. Abnormal sensorimotor gating was apparent, as measured by deficits in prepulse inhibition of acoustic startle. Motor activity and social interaction scores of the EGF-treated animals were also impaired in adult rats, though not in earlier developmental stages. In parallel, there was a significant abnormality in dopamine metabolism in the brain stem of the adult animals. Gross learning ability appeared to be normal as measured by active avoidance. These behavioral alterations, which are often present in schizophrenic models, were ameliorated by subchronic treatment with clozapine. Although the molecular and/or physiologic background(s) of these behavioral abnormalities await further investigation, the results of the present experiment indicate that abnormal EGF receptor stimulation given during limited neonatal stages can result in severe and persistent cognitive-behavioral dysfunctions, which appear only in adulthood.

Citation source: Molecular Psychiatry 2003 Volume 8, number 1, pages 19-29.

For further information on this work, please contact Dr. Hiroyuki Nawa, Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Asahimachi-dori 1-757, Niigata 951-8585, Japan. Phone: 81-25-227-0613. E-mail: hnawa@bri.niigata-u.ac.jp

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GUEST EDITORIAL: "Genetics, genes, genomics and g"

Robert Plomin

Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, London SE5 8AF, UK.

This is an invited editorial that offers a balanced overview of these new articles and a summary of the field of genetics of cognition and intelligence.

Citation source: Molecular Psychiatry 2003 Volume 8, number 1, pages 1-5.

For further information on this work, please contact Professor Robert Plomin, Kings College London, 123 Crooked Teeth Drive, London, UK. Phone: 44-207-848-0894 (or 0873 for receptionist). E-mail: r.plomin@iop.kcl.ac.uk

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Molecular Psychiatry is published by the Nature Publishing Group. http://www.nature.com/mp

Editor: Julio Licinio, M.D.; phone: 310-825-7113; FAX: 310-206-6715; e-mail: licinio@ucla.edu

Further information and PDF files of these articles, including accompanying editorial by Professor Robert Plomin (Institute of Psychiatry, London, UK), can be obtained from Aimee Midei, editorial assistant, e-mail: molecularpsychiatry@mednet.ucla.edu.

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PLEASE CITE MOLECULAR PSYCHIATRY AS THE SOURCE OF THIS MATERIAL.

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