DCDC2 is associated with reading disability and modulates neuronal development in the brain

doi:10.1073/pnas.0508591102

DCDC2 is associated with reading disability and modulates neuronal development in the brain

^aDepartment of Pediatrics, Yale Child Health Research Center, Yale University School of Medicine, New Haven, CT 06520; ^bMunroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198; ^cW. M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, CT 06511; ^dSoftGenetics, State College, PA 16803; ^eDepartment of Psychology and ^gInstitute for Behavioral Genetics, University of Colorado, Boulder, CO 80309; ^fDepartment of Psychology, University of Denver, Denver, CO 80210; ^hDepartment of Psychiatry, Veterans Affairs Medical Center, West Haven, CT 06516; Departments of ⁱPsychiatry and ^jInternal Medicine, Yale University School of Medicine, New Haven, CT 06519; ^kDepartment of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269; and ^lDepartment of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294

Communicated by Sherman M. Weissman, Yale University School of Medicine, New Haven, CT, October 3, 2005 (received for review July 19, 2005)

Abstract

DYX2 on 6p22 is the most replicated reading disability (RD) locus. By saturating a previously identified peak of association with single nucleotide polymorphism markers, we identified a large polymorphic deletion that encodes tandem repeats of putative brain-related transcription factor binding sites in intron 2 of DCDC2. Alleles of this compound repeat are in significant disequilibrium with multiple reading traits. RT-PCR data show that DCDC2 localizes to the regions of the brain where fluent reading occurs, and RNA interference studies show that down-regulation alters neuronal migration. The statistical and functional studies are complementary and are consistent with the latest clinical imaging data for RD. Thus, we propose that DCDC2 is a candidate gene for RD.

Footnotes

↵ m To whom correspondence should be addressed. E-mail: jeffrey.gruen{at}yale.edu.
Author contributions: H.M., J.J.L., and J.R.G. designed research; H.M., K.H., M.H., T.O.-P., Y.W., and M.P. performed research; S.D.S., J.L., R.K.O., B.F.P., J.C.D., J.G., S.S., P.S., S.E.S., B.A.S., K.M., and J.J.L. contributed new reagents/analytic tools; H.M., J.L., G.P.P., and J.R.G. analyzed data; and H.M., J.J.L., and J.R.G. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations: CLDRC, Colorado Learning Disabilities Research Center; DISC, discriminant score; ID, identification; IQ, intelligence quotient; LOH, loss-of-heterozygosity; RD, reading disability; RNAi, RNA interference; shRNA, small hairpin RNA; SNP, single nucleotide polymorphism; STR, short tandem repeat.
Data deposition: The sequences reported in this paper have been deposited in the dbSTS database, www.ncbi.nlm.nih.gov/projects/SNP (dbSTS ID no. 808238).
Freely available online through the PNAS open access option.