Human Molecular Genetics Advance Access published online on February 19, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm009
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A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia
1 Department of Biosciences and Nutrition, Karolinska Institutet, 14157 Huddinge, Sweden 2 Max Planck Institute of Psychiatry, 80804 Munich, Germany 3 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany 4 Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland 5 Department of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland 6 Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, 97080 Würzburg, Germany 7 Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany 8 Department of Pediatric Neurology, Jorvi Hospital, 02740 Espoo, Finland 9 Department of Psychology, University of Jyväskylä, 40014 Jyväskylä, Finland 10 Department of Child and Adolescent Psychiatry and Psychotherapy, University of Marburg, 35039 Marburg, Germany 11 Department of Clinical Research Center, Karolinska Institutet, 14157 Huddinge, Sweden
* To whom corresponding should be addressed at: Department of Biosciences and Nutrition, Karolinska Institutet, 14157 Huddinge, Sweden. Tel: +46 8 6089158; Fax: +46 8 7745538; Email: juha.kere{at}biosci.ki.se
Received December 7, 2006; Revised February 2, 2007; Accepted February 2, 2007
DYX3, a locus for dyslexia, resides on chromosome 2p11-p15. We have refined its location on 2p12 to a 157 kb region in two rounds of linkage disequilibrium mapping in a set of Finnish families. The observed association was replicated in an independent set of 251 German families. Two overlapping risk haplotypes spanning 16 kb were identified in both sample sets separately as well as in a joint analysis. In the German sample set, the odds ratio for the most significantly associated haplotype increased with dyslexia severity from 2.2 to 5.2. The risk haplotypes are located in an intergenic region between FLJ13391 and MRPL19/C2ORF3. As no novel genes could be cloned from this region, we hypothesized that the risk haplotypes might affect long distance regulatory elements and characterized the three known genes. MRPL19 and C2ORF3 are in strong linkage disequilibrium and were highly co-expressed across a panel of tissues from regions of adult human brain. The expression of MRPL19 and C2ORF3, but not FLJ13391, were also correlated with the four dyslexia candidate genes identified so far (DYX1C1, ROBO1, DCDC2 and KIAA0319). Although several nonsynonymous changes were identified in MRPL19 and C2ORF3, none of them significantly associated with dyslexia. However, heterozygous carriers of the risk haplotype showed significantly attenuated expression of both MRPL19 and C2ORF3, as compared to non-carriers. Analysis of C2ORF3 orthologues in four non-human primates suggested different evolutionary rates for primates as compared to the out-group. In conclusion, our data support MRPL19 and C2ORF3 as candidate susceptibility genes for DYX3.
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