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Francks, C., Maegawa, S., Laurén, J., Abrahams, B. S., Velayos-Baeza, A., Medland, S. E., Colella, S., Groszer, M., McAuley, E. Z., Caffrey, T. M., Timmusk, T., Pruunsild, P., Koppel, I., Lind, P. A., Matsumoto-Itaba, N., Nicod, J., Xiong, L., Joober, R., Enard, W., Krinsky, B. and 22 moreFrancks, C., Maegawa, S., Laurén, J., Abrahams, B. S., Velayos-Baeza, A., Medland, S. E., Colella, S., Groszer, M., McAuley, E. Z., Caffrey, T. M., Timmusk, T., Pruunsild, P., Koppel, I., Lind, P. A., Matsumoto-Itaba, N., Nicod, J., Xiong, L., Joober, R., Enard, W., Krinsky, B., Nanba, E., Richardson, A. J., Riley, B. P., Martin, N. G., Strittmatter, S. M., Möller, H.-J., Rujescu, D., St Clair, D., Muglia, P., Roos, J. L., Fisher, S. E., Wade-Martins, R., Rouleau, G. A., Stein, J. F., Karayiorgou, M., Geschwind, D. H., Ragoussis, J., Kendler, K. S., Airaksinen, M. S., Oshimura, M., DeLisi, L. E., & Monaco, A. P. (2007). LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia. Molecular Psychiatry, 12, 1129-1139. doi:10.1038/sj.mp.4002053.
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.Additional information
http://www.nature.com/mp/journal/v12/n12/suppinfo/4002053s1.html?url=/mp/journa… -
Gayán, J., Willcutt, E. G., Fisher, S. E., Francks, C., Cardon, L. R., Olson, R. K., Pennington, B. F., Smith, S., Monaco, A. P., & DeFries, J. C. (2005). Bivariate linkage scan for reading disability and attention-deficit/hyperactivity disorder localizes pleiotropic loci. Journal of Child Psychology and Psychiatry, 46(10), 1045-1056. doi:10.1111/j.1469-7610.2005.01447.x.
Abstract
BACKGROUND: There is a growing interest in the study of the genetic origins of comorbidity, a direct consequence of the recent findings of genetic loci that are seemingly linked to more than one disorder. There are several potential causes for these shared regions of linkage, but one possibility is that these loci may harbor genes with manifold effects. The established genetic correlation between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD) suggests that their comorbidity is due at least in part to genes that have an impact on several phenotypes, a phenomenon known as pleiotropy. METHODS: We employ a bivariate linkage test for selected samples that could help identify these pleiotropic loci. This linkage method was employed to carry out the first bivariate genome-wide analysis for RD and ADHD, in a selected sample of 182 sibling pairs. RESULTS: We found evidence for a novel locus at chromosome 14q32 (multipoint LOD=2.5; singlepoint LOD=3.9) with a pleiotropic effect on RD and ADHD. Another locus at 13q32, which had been implicated in previous univariate scans of RD and ADHD, seems to have a pleiotropic effect on both disorders. 20q11 is also suggested as a pleiotropic locus. Other loci previously implicated in RD or ADHD did not exhibit bivariate linkage. CONCLUSIONS: Some loci are suggested as having pleiotropic effects on RD and ADHD, while others might have unique effects. These results highlight the utility of this bivariate linkage method to study pleiotropy. -
Bailey, A., Hervas, A., Matthews, N., Palferman, S., Wallace, S., Aubin, A., Michelotti, J., Wainhouse, C., Papanikolaou, K., Rutter, M., Maestrini, E., Marlow, A., Weeks, D. E., Lamb, J., Francks, C., Kearsley, G., Scudder, P., Monaco, A. P., Baird, G., Cox, A. and 46 moreBailey, A., Hervas, A., Matthews, N., Palferman, S., Wallace, S., Aubin, A., Michelotti, J., Wainhouse, C., Papanikolaou, K., Rutter, M., Maestrini, E., Marlow, A., Weeks, D. E., Lamb, J., Francks, C., Kearsley, G., Scudder, P., Monaco, A. P., Baird, G., Cox, A., Cockerill, H., Nuffield, F., Le Couteur, A., Berney, T., Cooper, H., Kelly, T., Green, J., Whittaker, J., Gilchrist, A., Bolton, P., Schönewald, A., Daker, M., Ogilvie, C., Docherty, Z., Deans, Z., Bolton, B., Packer, R., Poustka, F., Rühl, D., Schmötzer, G., Bölte, S., Klauck, S. M., Spieler, A., Poustka., A., Van Engeland, H., Kemner, C., De Jonge, M., Den Hartog, I., Lord, C., Cook, E., Leventhal, B., Volkmar, F., Pauls, D., Klin, A., Smalley, S., Fombonne, E., Rogé, B., Tauber, M., Arti-Vartayan, E., Fremolle-Kruck., J., Pederson, L., Haracopos, D., Brondum-Nielsen, K., & Cotterill, R. (1998). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Human Molecular Genetics, 7(3), 571-578. doi:10.1093/hmg/7.3.571.
Abstract
Autism is characterized by impairments in reciprocal social interaction and communication, and restricted and sterotyped patterns of interests and activities. Developmental difficulties are apparent before 3 years of age and there is evidence for strong genetic influences most likely involving more than one susceptibility gene. A two-stage genome search for susceptibility loci in autism was performed on 87 affected sib pairs plus 12 non-sib affected relative-pairs, from a total of 99 families identified by an international consortium. Regions on six chromosomes (4, 7, 10, 16, 19 and 22) were identified which generated a multipoint maximum lod score (MLS) > 1. A region on chromosome 7q was the most significant with an MLS of 3.55 near markers D7S530 and D7S684 in the subset of 56 UK affected sib-pair families, and an MLS of 2.53 in all 87 affected sib-pair families. An area on chromosome 16p near the telomere was the next most significant, with an MLS of 1.97 in the UK families, and 1.51 in all families. These results are an important step towards identifying genes predisposing to autism; establishing their general applicability requires further study.
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