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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.
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