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.
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We thank the families who took part in this study; David Smith, Catherine Joachim and OPTIMA (Oxford Project to Investigate Memory and Ageing) for access to post-mortem brain tissue; Xiayi Ke for testing his screening algorithm for imprinted genes; Phil Burnet for plasmids and samples; Dianne Gerelli and the Human Developmental Brain Resource (London, UK) for pilot in situ hybridization studies; Jordana Tsenova for ideas on genetic analysis; Eris Duro for help with mutation screening; Abigail Woodroffe for handling genotype data; Julie V Perederiy for help with in situ experiments; Drs Dermot Walsh and F Anthony O'Neill made critical contributions to the collection of the Irish Study of High Density Schizophrenia Families (ISHDSF). Drs Enn Jõeste and Liina Kiho from North Estonian Regional Hospital, Tallinn, helped in collecting human brain tissue. David Goldstein, Kevin Shianna and Dongliang Ge provided genotype data. Han Chinese Schizophrenia Sample data and biomaterials were collected as a part of the National Institute of Mental Health (NIMH) Schizophrenia Genetics Initiative. A complete list of the people who contributed on the NIMH project is in the Supplementary material. CF was a NARSAD Young Investigator (National Alliance for Research on Schizophrenia and Depression). APM is a Wellcome Principal Research Fellow. RW-M is a Wellcome Trust Research Career Development Fellow. SEF is a Royal Society Research Fellow. TT is a Wellcome Trust International Senior Research Fellow in Biomedical Science in Central Europe. JN is supported by the Swiss National Science Foundation and by a Marie Curie Intra-European Fellowship. BSA was supported by a Fellowship from the Tourette Syndrome Association. This research was funded additionally by The Wellcome Trust (UK); the Schizophrenia Research Fund (UK); the Academy of Finland and the Sigrid Juselius Foundation (Finland); the Graham Boeckh Chair Program in Schizophrenia to GAR at McGill University; Warner-Lambert, Parke-Davis Pharmaceuticals Company, and National Institute of Mental Health grant R01 MH-44245 (LED); National Institute of Health grants MH41953 (collection and analysis of the ISHDSF) and MH61399 (MK); and by grant ‘Research on Psychiatric and Neurological disorders and Mental Health’ from the ministry of Health, Labor and Welfare of Japan (H14-Kokoro-002), and Grant-in-Aid for Scientific Research on Priority Areas (C) Medical Genome Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Clyde Francks conceived and directed this research.
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Francks, C., Maegawa, S., Laurén, J. et al. LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia. Mol Psychiatry 12, 1129–1139 (2007). https://doi.org/10.1038/sj.mp.4002053
- imprinted gene
- brain asymmetry
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