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Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia

Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia
Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia
Linkage between developmental dyslexia (DD) and chromosome 6p has been replicated in a number of independent samples. Recent attempts to identify the gene responsible for the linkage have produced inconsistent evidence for association of DD with a number of genes in a 575-kb region of chromosome 6p22.2, including VMP, DCDC2, KIAA0319, TTRAP, and THEM2. We aimed to identify the specific gene or genes involved by performing a systematic, high-density (~2-3-kb intervals) linkage disequilibrium screen of these genes in an independent sample, incorporating family-based and case-control designs in which dyslexia was defined as an extreme representation of reading disability. Using DNA pooling, we first observed evidence for association with 17 single-nucleotide polymorphisms (SNPs), 13 of which were located in the KIAA0319 gene (P < .01.003). After redundant SNPs were excluded, 10 SNPs were individually genotyped in 223 subjects with DD and 273 controls. Those SNPs that were significant at P <_ .05 were next genotyped in a semi-independent sample of 143 trios of probands with DD and their parents, to control for possible population stratification. Six SNPs showed significant evidence of association in both samples (P <_ .04-.002), including a SNP (rs4504469) in exon 4 of the KIAA0319 gene that changes an amino acid (P = .002; odds ratio 1.5). Logistic regression analysis showed that two SNPs (rs4504469 and rs6935076) in the KIAA0319 gene best explained DD status. The haplotype composed of these two markers was significantly associated with DD (global P = .00001 in the case-control sample; P = .02 in trios). This finding was largely driven by underrepresentation of the most common haplotype in cases (P = .00003 in the case-control sample; P = .006 in trios; 1-degree-of-freedom tests). Our data strongly implicate KIAA0319 as a susceptibility gene for dyslexia. The gene product is expressed in brain, but its specific function is currently unknown.
0002-9297
581-591
Cope, Natalie
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Harold, Denise
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Hill, Gary
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Moskvina, Valentina
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Stevenson, Jim
0c85d29b-d294-43cb-ab8d-75e4737478e1
Holmans, Peter
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Owen, Michael J.
0e3a340c-b3a3-4631-94f6-b3f50c0d50b1
O'Donovan,, Michael C.
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Julie, Williams
de10fbac-1448-4ed8-900f-58f117389ed0
Cope, Natalie
4b77576c-ad1b-43b0-a82d-14befff75b4a
Harold, Denise
d37e566f-4ca4-49ae-8082-6368cc4c4b57
Hill, Gary
73f8846b-bd41-40fa-abf3-fddfe4879978
Moskvina, Valentina
4232124b-ef58-429b-86fe-60cc970a7bbe
Stevenson, Jim
0c85d29b-d294-43cb-ab8d-75e4737478e1
Holmans, Peter
48b5a4c1-a9c4-498f-8acf-835f71957831
Owen, Michael J.
0e3a340c-b3a3-4631-94f6-b3f50c0d50b1
O'Donovan,, Michael C.
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Julie, Williams
de10fbac-1448-4ed8-900f-58f117389ed0

Cope, Natalie, Harold, Denise, Hill, Gary, Moskvina, Valentina, Stevenson, Jim, Holmans, Peter, Owen, Michael J., O'Donovan,, Michael C. and Julie, Williams (2005) Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia. American Journal of Human Genetics, 76 (4), 581-591. (doi:10.1086/429131).

Record type: Article

Abstract

Linkage between developmental dyslexia (DD) and chromosome 6p has been replicated in a number of independent samples. Recent attempts to identify the gene responsible for the linkage have produced inconsistent evidence for association of DD with a number of genes in a 575-kb region of chromosome 6p22.2, including VMP, DCDC2, KIAA0319, TTRAP, and THEM2. We aimed to identify the specific gene or genes involved by performing a systematic, high-density (~2-3-kb intervals) linkage disequilibrium screen of these genes in an independent sample, incorporating family-based and case-control designs in which dyslexia was defined as an extreme representation of reading disability. Using DNA pooling, we first observed evidence for association with 17 single-nucleotide polymorphisms (SNPs), 13 of which were located in the KIAA0319 gene (P < .01.003). After redundant SNPs were excluded, 10 SNPs were individually genotyped in 223 subjects with DD and 273 controls. Those SNPs that were significant at P <_ .05 were next genotyped in a semi-independent sample of 143 trios of probands with DD and their parents, to control for possible population stratification. Six SNPs showed significant evidence of association in both samples (P <_ .04-.002), including a SNP (rs4504469) in exon 4 of the KIAA0319 gene that changes an amino acid (P = .002; odds ratio 1.5). Logistic regression analysis showed that two SNPs (rs4504469 and rs6935076) in the KIAA0319 gene best explained DD status. The haplotype composed of these two markers was significantly associated with DD (global P = .00001 in the case-control sample; P = .02 in trios). This finding was largely driven by underrepresentation of the most common haplotype in cases (P = .00003 in the case-control sample; P = .006 in trios; 1-degree-of-freedom tests). Our data strongly implicate KIAA0319 as a susceptibility gene for dyslexia. The gene product is expressed in brain, but its specific function is currently unknown.

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Published date: 2005

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Local EPrints ID: 18398
URI: http://eprints.soton.ac.uk/id/eprint/18398
ISSN: 0002-9297
PURE UUID: 84ad264e-3771-43f7-8e95-1be7e801c258

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Date deposited: 05 Jan 2006
Last modified: 15 Mar 2024 06:05

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Contributors

Author: Natalie Cope
Author: Denise Harold
Author: Gary Hill
Author: Valentina Moskvina
Author: Jim Stevenson
Author: Peter Holmans
Author: Michael J. Owen
Author: Michael C. O'Donovan,
Author: Williams Julie

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