Linkage analyses of four regions previously implicated in dyslexia: Confirmation of a locus on chromosome 15q

Abstract

Dyslexia is a common, complex disorder, which is thought to have a genetic component. There have been numerous reports of linkage to several regions of the genome for dyslexia and continuous dyslexia-related phenotypes. We attempted to confirm linkage of continuous measures of (1) accuracy and efficiency of phonological decoding; and (2) accuracy of single word reading (WID) to regions on chromosomes 2p, 6p, 15q, and 18p, using 111 families with a total of 898 members. We used both single-marker and multipoint variance components linkage analysis and Markov Chain Monte Carlo (MCMC) joint segregation and linkage analysis for initial inspection of these regions. Positive results were followed with traditional parametric lod score analysis using a model estimated by MCMC segregation analysis. No positive linkage signals were found on chromosomes 2p, 6p, or 18p. Evidence of linkage of WID to chromosome 15q was found with both methods of analysis. The maximum single-marker parametric lod score of 2.34 was obtained at a distance of 3 cM from D15S143. Multipoint analyses localized the putative susceptibility gene to the interval between markers GATA50C03 and D15S143, which falls between a region implicated in a recent genome screen for attention-deficit/hyperactivity disorder, and DYX1C1, a candidate gene for dyslexia. This apparent multiplicity of linkage signals in the region for developmental disorders may be the result of errors in map and/or model specification obscuring the pleiotropic effect of a single gene on different phenotypes, or it may reflect the presence of multiple genes.

A genome scan in multigenerational families with dyslexia: Identification of a novel locus on chromosome 2q that contributes to phonological decoding efficiency

“…24,45 The remaining 57 families, Subset 2, were not submitted for genotyping but were included in both Markov-chain Monte Carlo (MCMC)-based segregation analysis and CSA because they provide additional information about the genetic basis of the traits. Together, subsets 1 and 2 make up the family set used in a prior analysis that investigated four specific regions with previous reports of linkage, 42 with the following exceptions: one previously used family was omitted because an individual in the pedigree was found to have Klinefelter syndrome, a known cause of learning disabilities, 51,52 and a recently discovered pedigree error removed eight individuals of a second family. Two other families were erroneously included in the Chapman et al 42 analysis, but because no phenotype or genotype data were available for these families, they did not affect the previous results.…”

“…53 A 10-cM (on average) genome-wide scan was performed by the NHLBI Mammalian Genotyping Service, Marshfield, WI, using screening set 10 (405 STRP markers, including 378 autosomal markers), on DNA from Subset 1. 42 The genotype data were checked for Mendelian inconsistencies and highly unlikely genotypes, and potential genotype errors were resolved as described previously. 42 Two markers were removed because of excessive errors and missing data and a third marker was removed because it was found to be a duplicate.…”

“…42 The genotype data were checked for Mendelian inconsistencies and highly unlikely genotypes, and potential genotype errors were resolved as described previously. 42 Two markers were removed because of excessive errors and missing data and a third marker was removed because it was found to be a duplicate. The set of markers used for the initial genomewide scans consisted of the remaining 375 autosomal markers from screening set 10 plus 13 additional markers on chromosomes 2p (D2S391, D2S337, D2S2368), 6p (D6S299, D6S276, D6S1629), 15q (D15S132, D15S143, D15S978, D15S117) and 18 (D18S1150, D18S453, D18S1107), which were typed earlier in our laboratory.…”

“…We then performed linkage analyses of continuous measures of accuracy and efficiency of phonological decoding and accuracy of single real word reading to specific regions on chromosomes 2p, 6p, 15q, and 18p, for which evidence of linkage had been reported by other groups. 42 Supportive evidence for linkage of single real word reading to chromosome 15q21 was found. However, no positive linkage signals were observed in the four selected regions for the phenotype of accuracy and efficiency of phonological decoding, despite our evidence for a major gene effect.…”

“…[22][23][24] However, studies in the general population show that dyslexia and its component processes are genetically heterogeneous and likely involve the influence of multiple genes. Targeted and genome-wide linkage analyses have reported possible localizations for genes contributing to reading and spelling and a variety of related processes on chromosomes 1p34-36 (DYX8) 25,26 , 2p16-15 (DYX3) 20,[27][28][29] , 3p12-q13 (DYX5) 21 , 6p21.3 (DYX2) [30][31][32][33][34][35] , 6q13-16.2 (DYX4) 36 , 11p15.5 (DYX7) 37 , 15q21 (DYX1) 32,[37][38][39][40][41][42] , and 18p11 (DYX6) 27 .…”