Original Article

Molecular Psychiatry (2007) 12, 1129–1139; doi:10.1038/sj.mp.4002053; published online 31 July 2007

LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia

C Francks1,2, S Maegawa3,21, J Laurén4,21, B S Abrahams5, A Velayos-Baeza1, S E Medland6,7, S Colella1, M Groszer1, E Z McAuley1, T M Caffrey1, T Timmusk8, P Pruunsild8, I Koppel8, P A Lind7, N Matsumoto-Itaba9, J Nicod1, L Xiong10, R Joober11, W Enard12, B Krinsky12, E Nanba3, A J Richardson13, B P Riley5, N G Martin6, S M Strittmatter4, H-J Möller14, D Rujescu14, D St Clair15, P Muglia2, J L Roos16, S E Fisher1, R Wade-Martins1, G A Rouleau10, J F Stein13, M Karayiorgou17, D H Geschwind5, J Ragoussis1, K S Kendler5, M S Airaksinen18, M Oshimura9, L E DeLisi19,20 and A P Monaco1

  1. 1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  2. 2GlaxoSmithKline SpA, Research Centre, Verona, Italy
  3. 3Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Tottori, Japan
  4. 4Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
  5. 5Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
  6. 6Virginia Institute for Psychiatric and Behavioral Genetics, Department of Human Genetics, Virginia Commonwealth University, Richmond, VA, USA
  7. 7Queensland Institute of Medical Research, Brisbane, QLD, Australia
  8. 8Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia
  9. 9Department of Biomedical Science, Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Tottori, Japan
  10. 10Center for the Study of Brain Diseases, CHUM Research Center, Montreal University, Montreal, QC, Canada
  11. 11Departments of Psychiatry, Neurology and Human Genetics, McGill University, Douglas Hospital Research Centre, Montreal, QC, Canada
  12. 12Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
  13. 13Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
  14. 14Department of Psychiatry, Ludwig Maximilians University, Munich, Germany
  15. 15Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland
  16. 16Weskoppies Hospital, Department of Psychiatry, University of Pretoria, Pretoria, Republic of South Africa
  17. 17Laboratory of Human Neurogenetics, Rockefeller University, New York, NY, USA
  18. 18Neuroscience Center, University of Helsinki, Helsinki, Finland
  19. 19Department of Psychiatry, New York University, New York, NY, USA
  20. 20The Nathan S Kline Institute for Psychiatric Research, Orangeburg, New York, NY, USA

Correspondence: Dr C Francks, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. E-mail: clyde.francks@well.ox.ac.uk

21These authors contributed equally to this work.

Received 9 August 2006; Revised 6 June 2007; Accepted 19 June 2007; Published online 31 July 2007.

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Abstract

Left–right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.

Keywords:

handedness, schizophrenia, association, imprinted gene, brain asymmetry