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.

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.