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.
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References
Rogers LJ, Andrew R (eds). Comparative Vertebrate Lateralization. Cambridge University Press: Cambridge, UK, 2002.
Hugdahl K, Davidson RJ (eds). The Asymmetrical Brain. MIT Press: Cambridge, MA, 2003.
Mevorach C, Humphreys GW, Shalev L . Attending to local form while ignoring global aspects depends on handedness: evidence from TMS. Nat Neurosci 2005; 8: 276–277.
Geschwind DH, Miller BL, DeCarli C, Carmelli D . Heritability of lobar brain volumes in twins supports genetic models of cerebral laterality and handedness. Proc Natl Acad Sci USA 2002; 99: 3176–3181.
Francks C, Fisher SE, MacPhie IL, Richardson AJ, Marlow AJ, Stein JF et al. A genomewide linkage screen for relative hand skill in sibling pairs. Am J Hum Genet 2002; 70: 800–805.
Fisher SE, Francks C, Marlow AJ, MacPhie IL, Newbury DF, Cardon LR et al. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nat Genet 2002; 30: 86–91.
Francks C, Fisher SE, Marlow AJ, MacPhie IL, Taylor KE, Richardson AJ et al. Familial and genetic effects on motor coordination, laterality, and reading-related cognition. Am J Psychiatry 2003; 160: 1970–1977.
Francks C, DeLisi LE, Fisher SE, Laval SH, Rue JE, Stein JF et al. Confirmatory evidence for linkage of relative hand skill to 2p12-q11. Am J Hum Genet 2003; 72: 499–502.
Francks C, DeLisi LE, Shaw SH, Fisher SE, Richardson AJ, Stein JF et al. Parent-of-origin effects on handedness and schizophrenia susceptibility on chromosome 2p12-q11. Hum Mol Genet 2003; 12: 3225–3230.
DeLisi LE, Sakuma M, Kushner M, Finer DL, Hoff AL, Crow TJ . Anomalous cerebral asymmetry and language processing in schizophrenia. Schizophr Bull 1997; 23: 255–271.
Shenton ME, Dickey CC, Frumin M, McCarley RW . A review of MRI findings in schizophrenia. Schizophr Res 2001; 49: 1–52.
DeLisi LE, Svetina C, Razi K, Shields G, Wellman N, Crow TJ . Hand preference and hand skill in families with schizophrenia. Laterality 2002; 7: 321–332.
Orr KG, Cannon M, Gilvarry CM, Jones PB, Murray RM . Schizophrenic patients and their first-degree relatives show an excess of mixed-handedness. Schizophr Res 1999; 39: 167–176.
Berlim MT, Mattevi BS, Belmonte-de-Abreu P, Crow TJ . The etiology of schizophrenia and the origin of language: overview of a theory. Compr Psychiatry 2003; 44: 7–14.
Williams NA, Close JP, Giouzeli M, Crow TJ . Accelerated evolution of Protocadherin11X/Y: a candidate gene-pair for cerebral asymmetry and language. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 623–633.
Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet 2003; 73: 34–48.
DeLisi LE, Shaw SH, Crow TJ, Shields G, Smith AB, Larach VW et al. A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159: 803–812.
Abecasis GR, Cookson WO, Cardon LR . Pedigree tests of transmission disequilibrium. Eur J Hum Genet 2000; 8: 545–551.
Thiselton DL, Webb BT, Neale BM, Ribble RC, O'Neill FA, Walsh D et al. No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF). Mol Psychiatry 2004; 9: 777–783.
Xiong L, Rouleau GA, DeLisi LE, St Onge J, Najafee R, Riviere JB et al. CAA insertion polymorphism in the 3'UTR of Nogo gene on 2p14 is not associated with schizophrenia. Mol Brain Res 2005; 133: 153–156.
Abecasis GR, Burt RA, Hall D, Bochum S, Doheny KF, Lundy SL et al. Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1. Am J Hum Genet 2004; 74: 403–417.
Van den Oord EJCG, Rujescu D, Robles JR, Giegling I, Birrell C, Bukszar J et al. Factor structure and external validity of the PANSS revisited. Schizophr Res 2006; 82: 213–223.
Takahashi S, Cui YH, Kojima T, Han YH, Zhou RL, Kamioka M et al. Family-based association study of markers on chromosome 22 in schizophrenia using African-American, European-American, and Chinese families. Am J Med Genet B Neuropsychiatr Genet 2003; 120: 11–17.
Kugoh H, Mitsuya K, Meguro M, Shigenami K, Schulz TC, Oshimura M . Mouse A9 cells containing single human chromosomes for analysis of genomic imprinting. DNA Res 1999; 6: 165–172.
Mergenthaler S, Hitchins MP, Blagitko-Dorfs N, Monk D, Wollmann HA, Ranke MB et al. Conflicting reports of imprinting status of human GRB10 in developing brain: how reliable are somatic cell hybrids for predicting allelic origin of expression? Am J Hum Genet 2001; 68: 543–545.
Sakatani T, Wei M, Katoh M, Okita C, Wada D, Mitsuya K et al. Epigenetic heterogeneity at imprinted loci in normal populations. Biochem Biophys Res Commun 2001; 283: 1124–1130.
Yamasaki K, Joh K, Ohta T, Masuzaki H, Ishimaru T, Mukai T et al. Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. Hum Mol Genet 2003; 12: 837–847.
Khaitovich P, Hellmann I, Enard W, Nowick K, Leinweber M, Franz H et al. Parallel patterns of evolution in the genomes and transcriptomes of humans and chimpanzees. Science 2005; 309: 1850–1854.
Kochunov P, Fox P, Lancaster J, Tan LH, Amunts K, Zilles K et al. Localized morphological brain differences between English-speaking Caucasians and Chinese-speaking Asians: new evidence of anatomical plasticity. Neuroreport 2003; 14: 961–964.
Imprinted Gene Catalogue. http://igc.otago.ac.nz/home.html.Web 2006.
Reik W, Walter J . Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001; 2: 21–32.
Morison IM, Ramsay JP, Spencer HG . A census of mammalian imprinting. Trends Genet 2005; 21: 457–465.
Bunzel R, Blumcke I, Cichon S, Normann S, Schramm J, Propping P et al. Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain. Mol Brain Res 1998; 59: 90–92.
Fournier AE, GrandPre T, Gould G, Wang X, Strittmatter SM . Nogo and the Nogo-66 receptor. Prog Brain Res 2002; 137: 361–369.
Lauren J, Airaksinen MS, Saarma M, Timmusk T . A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system. Genomics 2003; 81: 411–421.
Andrews J, Wang L, Csernansky JG, Gado MH, Barch DM . Abnormalities of thalamic activation and cognition in schizophrenia. Am J Psychiatry 2006; 163: 463–469.
Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2004; 10: 40–68.
Sun T, Patoine C, Abu-Khalil A, Visvader J, Sum E, Cherry TJ et al. Early asymmetry of gene transcription in embryonic human left and right cerebral cortex. Science 2005; 308: 1794–1798.
Hering-Hanit R, Achiron R, Lipitz S, Achiron A . Asymmetry of fetal cerebral hemispheres: in utero ultrasound study. Arch Dis Child Fetal Neonat Ed 2001; 85: F194–F196.
Prabhakar S, Noonan JP, Paabo S, Rubin EM . Accelerated evolution of conserved noncoding sequences in humans. Science 2006; 314: 786.
Kimura MI, Kazuki Y, Kashiwagi A, Kai Y, Abe S, Barbieri O et al. Dlx5, the mouse homologue of the human-imprinted DLX5 gene, is biallelically expressed in the mouse brain. J Hum Genet 2004; 49: 273–277.
Wilkins JF, Haig D . What good is genomic imprinting: the function of parent-specific gene expression. Nat Rev Genet 2003; 4: 359–368.
Peters AH, Schubeler D . Methylation of histones: playing memory with DNA. Curr Opin Cell Biol 2005; 17: 230–238.
Ioannidis JPA, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG . Replication validity of genetic association studies. Nat Genet 2001; 29: 306–309.
Csernansky JG, Schindler MK, Splinter NR, Wang L, Gado M, Selemon LD et al. Abnormalities of thalamic volume and shape in schizophrenia. Am J Psychiatry 2004; 161: 896–902.
De Fosse L, Hodge SM, Makris N, Kennedy DN, Caviness Jr VS, McGrath L et al. Language-association cortex asymmetry in autism and specific language impairment. Ann Neurol 2004; 56: 757–766.
Herbert MR, Harris GJ, Adrien KT, Ziegler DA, Makris N, Kennedy DN et al. Abnormal asymmetry in language association cortex in autism. Ann Neurol 2002; 52: 588–596.
Paulesu E, Demonet JF, Fazio F, McCrory E, Chanoine V, Brunswick N et al. Dyslexia: cultural diversity and biological unity. Science 2001; 291: 2165–2167.
Sommer IE, Ramsey NF, Mandl RC, Kahn RS . Language lateralization in monozygotic twin pairs concordant and discordant for handedness. Brain 2002; 125: 2710–2718.
Majercak J, Ray WJ, Espeseth A, Simon A, Shi XP, Wolffe C et al. LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease. Proc Natl Acad Sci USA 2006; 103: 17967–17972.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.
Wright M, De Geus E, Ando J, Luciano M, Posthuma D, Ono Y et al. Genetics of cognition: outline of a collaborative twin study. Twin Res 2001; 4: 48–56.
Maegawa S, Yoshioka H, Itaba N, Kubota N, Nishihara S, Shirayoshi Y et al. Epigenetic silencing of PEG3 gene expression in human glioma cell lines. Mol Carcinog 2001; 31: 1–9.
Stanssens P, Zabeau M, Meersseman G, Remes G, Gansemans Y, Storm N et al. High-throughput MALDI-TOF discovery of genomic sequence polymorphisms. Genome Res 2004; 14: 126–133.
Ehrich M, Nelson MR, Stanssens P, Zabeau M, Liloglou T, Xinarianos G et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci USA 2005; 102: 15785–15790.
Klumperman J, Schweizer A, Clausen H, Tang BL, Hong W, Oorschot V et al. The recycling pathway of protein ERGIC-53 and dynamics of the ER-Golgi intermediate compartment. J Cell Sci 1998; 111: 3411–3425.
Acknowledgements
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
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DOI: https://doi.org/10.1038/sj.mp.4002053
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