Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia

Fisher, Simon E.; Francks, Clyde; Marlow, Angela J.; MacPhie, I. Laurence; Newbury, Dianne F.; Cardon, Lon R.; Ishikawa-Brush, Yumiko; Richardson, Alex; Talcott, Joel B.; Gayán, Javier; Olson, Richard K.; Pennington, Bruce F.; Smith, Shelley D.; DeFries, John C.; Stein, John; Monaco, Anthony P.

doi:10.1038/ng792

Cited by 251 publications

(293 citation statements)

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“…20,21,27,29 Conversely, we found no evidence for linkage of phonological decoding accuracy (as measured by WA) or accuracy and speed (as measured by PDE) to locations on chromosomes 1p34-36 (DYX8), 2p16-15 (DYX3), 6p21.3 (DYX2), 11p15.5 (DYX7), 15q (DYX1), and 18p11 (DYX6) previously implicated in phonological decoding by others. For a complex and heterogeneous disorder, it is not surprising that different research groups have identified unique locations and have not always found supportive evidence for locations reported by others.…”

Section: Discussioncontrasting

confidence: 82%

“…In an earlier genome scan that identified a chromosome 18 location, there was also a discernible peak at D11S1314 at 79.5 cM for a composite measure of accuracy and speed of pseudoword reading using the DeFries-Fulker linkage analysis method (P ¼ 0.007) in a US sample. 27 That study also obtained P-values o0.01 for markers on chromosome 5p15 spanning the region identified in our study (D5S406 at 12.3 cM in the UK sample and D5S416 at 31.4 cM in the US sample) with measures of phonological decoding. Perhaps, it is the speed component of these phenotypes that is responsible for the signal.…”

Section: Discussionsupporting

confidence: 80%

“…[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 .…”

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confidence: 99%

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

et al. 2005

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Dyslexia is a common and complex developmental disorder manifested by unexpected difficulty in learning to read. Multiple different measures are used for diagnosis, and may reflect different biological pathways related to the disorder. Impaired phonological decoding (translation of written words without meaning cues into spoken words) is thought to be a core deficit. We present a genome scan of two continuous measures of phonological decoding ability: phonemic decoding efficiency (PDE) and word attack (WA). PDE measures both accuracy and speed of phonological decoding, whereas WA measures accuracy alone. Multipoint variance component linkage analyses (VC) and Markov chain Monte-Carlo (MCMC) multipoint joint linkage and segregation analyses were performed on 108 families. A strong signal was observed on chromosome 2 for PDE using both VC (LOD ¼ 2.65) and MCMC methods (intensity ratio (IR) ¼ 32.1). The IR is an estimate of the ratio of the posterior to prior probability of linkage in MCMC analysis. The chromosome 2 signal was not seen for WA. More detailed mapping with additional markers provided statistically significant evidence for linkage of PDE to chromosome 2, with VC-LOD ¼ 3.0 and IR ¼ 59.6 at D2S1399. Parametric analyses of PDE, using a model obtained by complex segregation analysis, provided a multipoint maximum LOD ¼ 2.89. The consistency of results from three analytic approaches provides strong evidence for a locus on chromosome 2 that influences speed but not accuracy of phonological decoding. Molecular Psychiatry (2005) 10, 699-711.

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Section: Discussioncontrasting

confidence: 82%

Section: Discussionsupporting

confidence: 80%

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confidence: 99%

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

et al. 2005

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“…The majority of families were recruited on the basis of having at least one proband whose single-word reading ability was > 2 s.d. below that predicted by tests of verbal or nonverbal reasoning 22,23 and where at least one sibling displayed evidence of DD. The remaining families were recruited through probands that were required to have single-word reading ability X1 s.d.…”

Section: Subjectsmentioning

confidence: 65%

“…All probands and siblings were administrated a battery of psychometric tests and we age-adjusted and standardized their scores against a normative control data set as previously described. 22,23 These included the following measures used in the present study for quantitative analysis: orthographic coding using irregular words (OC-irreg), phonological decoding ability (PD), orthographic coding assessed by a forced word choice test (OC-choice), single-word reading ability (READ), spelling ability (SPELL), phonemic awareness (PA), and tests of verbal (SIM) and nonverbal (MAT) reasoning. Multivariate linkage analysis had previously shown that the DYX2 QTL influenced variability shared by all the DD measures but did not influence IQ, 24 and univariate quantitative linkage analysis using IQ-adjusted traits refined the linkage signal.…”

Section: Subjectsmentioning

confidence: 99%

Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia

et al. 2006

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The DYX2 locus on chromosome 6p22.2 is the most replicated region of linkage to developmental dyslexia (DD). Two candidate genes within this region have recently been implicated in the disorder: KIAA0319 and DCDC2. Variants within DCDC2 have shown association with DD in a US and a German sample. However, when we genotyped these specific variants in two large, independent UK samples, we obtained only weak, inconsistent evidence for their involvement in DD. Having previously found evidence that variation in the KIAA0319 gene confers susceptibility to DD, we sought to refine this genetic association by genotyping 36 additional SNPs in the gene. Nine SNPs, predominantly clustered around the first exon, showed the most significant association with DD in one or both UK samples, including rs3212236 in the 5 0 flanking region (P = 0.00003) and rs761100 in intron 1 (P = 0.0004). We have thus refined the region of association with developmental dyslexia to putative regulatory sequences around the first exon of the KIAA0319 gene, supporting the presence of functional mutations that could affect gene expression. Our data also suggests a possible interaction between KIAA0319 and DCDC2, which requires further testing.

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Genetics of cognitive disorders

Abrahams

Geschwind

2005

Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics

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Disorders of cognition impair mental processes mediating awareness, perception, reasoning, or judgment, and consequently interfere with thought. Although interindividual differences in human cognition are easily observed, little is known about the genetic factors underlying such phenotypic variation, or the relationship of such variation to disease. Global measures of intelligence, such as Spearman's “g”, are heritable and thus likely to engender new links between genes and cognition. However, the breadth of these measures may limit the extent to which mechanistic insights are obtained. Finding readily measurable and heritable components of disease (endophenotypes) represents one of the most promising avenues for a precise understanding of how individual genes come to modulate brain function. The high heritability of interindividual differences in brain morphology suggests that a more thorough understanding of disease‐associated structural variation may clarify the relationship between individual genes and disorders of cognition. Identification and study of endophenotypes for autism and disorders of spoken and written language will facilitate a deeper understanding of how genetic variation comes to modulate the structure and function of particular neural systems and in turn contributes to specific cognitive deficits.

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Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia

Cited by 251 publications

References 20 publications

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

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

Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia

Genetics of cognitive disorders

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