Home LiteratureArticle Details
PMID: 15717286 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

American journal of human genetics ·Vol. 76 ·No. 4 ·2005-04-00 ·Pages 581-91

Cope N, Harold D, Hill G, Moskvina V, Stevenson J, Holmans P, Owen MJ, O'Donovan MC, Williams J

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 (approximately 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.

MeSH Terms
Adolescent Chromosome Mapping Chromosomes, Human, Pair 6 Dyslexia/genetics Genetic Predisposition to Disease Haplotypes Humans Linkage Disequilibrium Nerve Tissue Proteins/genetics Polymorphism, Single Nucleotide
Chemicals
KIAA0319 protein, human Nerve Tissue Proteins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Cope Natalie
Department of Psychological Medicine, Wales College of Medicine, Cardiff University, Cardiff, United Kingdom.
Harold Denise
Hill Gary
Moskvina Valentina
Stevenson Jim
Holmans Peter
Owen Michael J
O'Donovan Michael C
Williams Julie
References (46)
46 references, click to expand
  1. A new antigen recognized by cytolytic T lymphocytes on a human kidney tumor results from reverse strand transcription.
    J Exp Med. 1999 Dec 20;190(12):1793-800 PMID: 10601354
  2. Cloning, expression and characterization of a novel human VMP gene.
    Mol Biol Rep. 2002 Sep;29(3):281-6 PMID: 12463420
  3. Chromosome 6p influences on different dyslexia-related cognitive processes: further confirmation.
    Am J Hum Genet. 2000 Feb;66(2):715-23 PMID: 10677331
  4. Family-based association mapping provides evidence for a gene for reading disability on chromosome 15q.
    Hum Mol Genet. 2000 Mar 22;9(5):843-8 PMID: 10749993
  5. Model-free analysis and permutation tests for allelic associations.
    Hum Hered. 2000 Mar-Apr;50(2):133-9 PMID: 10799972
  6. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation.
    J Biol Chem. 2000 Jun 16;275(24):18586-93 PMID: 10764746
  7. Fatty acid metabolism in neurodevelopmental disorder: a new perspective on associations between attention-deficit/hyperactivity disorder, dyslexia, dyspraxia and the autistic spectrum.
    Prostaglandins Leukot Essent Fatty Acids. 2000 Jul-Aug;63(1-2):1-9 PMID: 10970706
  8. Fatty acid deficiency signs predict the severity of reading and related difficulties in dyslexic children.
    Prostaglandins Leukot Essent Fatty Acids. 2000 Jul-Aug;63(1-2):69-74 PMID: 10970716
  9. Visual function, fatty acids and dyslexia.
    Prostaglandins Leukot Essent Fatty Acids. 2000 Jul-Aug;63(1-2):89-93 PMID: 10970719
  10. The human mitochondrial Mrs2 protein functionally substitutes for its yeast homologue, a candidate magnesium transporter.
    Genomics. 2001 Mar 1;72(2):158-68 PMID: 11401429
  11. Linkage studies suggest a possible locus for developmental dyslexia on chromosome 1p.
    Am J Med Genet. 2001 Jan 8;105(1):120-9 PMID: 11424982
  12. A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes.
    Am J Hum Genet. 2002 Jan;70(1):124-41 PMID: 11719900
  13. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia.
    Nat Genet. 2002 Jan;30(1):86-91 PMID: 11743577
  14. Supportive evidence for the DYX3 dyslexia susceptibility gene in Canadian families.
    J Med Genet. 2002 Feb;39(2):125-6 PMID: 11836362
  15. Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: quantitative association analysis and positional candidate genes SEMA4F and OTX1.
    Psychiatr Genet. 2002 Mar;12(1):35-41 PMID: 11901358
  16. Evidence for linkage and association with reading disability on 6p21.3-22.
    Am J Hum Genet. 2002 May;70(5):1287-98 PMID: 11951179
  17. Universal, robust, highly quantitative SNP allele frequency measurement in DNA pools.
    Hum Genet. 2002 May;110(5):471-8 PMID: 12073018
  18. Use of multivariate linkage analysis for dissection of a complex cognitive trait.
    Am J Hum Genet. 2003 Mar;72(3):561-70 PMID: 12587094
  19. Linkage disequilibrium mapping provides further evidence of a gene for reading disability on chromosome 6p21.3-22.
    Mol Psychiatry. 2003 Feb;8(2):176-85 PMID: 12610650
  20. Continuing the search for dyslexia genes on 6p.
    Am J Med Genet B Neuropsychiatr Genet. 2003 Apr 1;118B(1):89-98 PMID: 12627473
  21. A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32.
    J Med Genet. 2003 May;40(5):340-5 PMID: 12746395
  22. Functional analysis of PKD1 transgenic lines reveals a direct role for polycystin-1 in mediating cell-cell adhesion.
    J Am Soc Nephrol. 2003 Jul;14(7):1804-15 PMID: 12819240
  23. Pedigree disequilibrium tests for multilocus haplotypes.
    Genet Epidemiol. 2003 Sep;25(2):115-21 PMID: 12916020
  24. Forebrain-specific neuronal inhibition of nuclear factor-kappaB activity leads to loss of neuroprotection.
    J Neurosci. 2003 Oct 15;23(28):9403-8 PMID: 14561868
  25. Confirmation of a dyslexia susceptibility locus on chromosome 1p34-p36 in a set of 100 Canadian families.
    Am J Med Genet B Neuropsychiatr Genet. 2004 May 15;127B(1):117-24 PMID: 15108193
  26. DNA pooling as a tool for large-scale association studies in complex traits.
    Ann Med. 2004;36(2):146-52 PMID: 15119834
  27. A transcription map of the 6p22.3 reading disability locus identifying candidate genes.
    BMC Genomics. 2003 Jun 30;4(1):25 PMID: 12834540
  28. Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: linkage and association analyses.
    Hum Genet. 2004 Jul;115(2):128-38 PMID: 15138886
  29. A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States.
    Am J Hum Genet. 2004 Dec;75(6):1046-58 PMID: 15514892
  30. A twin study of genetic influences on reading and spelling ability and disability.
    J Child Psychol Psychiatry. 1987 Mar;28(2):229-47 PMID: 3584294
  31. Evidence for a genetic aetiology in reading disability of twins.
    Nature. 1987 Oct 8-14;329(6139):537-9 PMID: 3657975
  32. Evidence for major gene transmission of developmental dyslexia.
    JAMA. 1991 Sep 18;266(11):1527-34 PMID: 1880884
  33. Discrepancy compared to low achievement definitions of reading disability: results from the Connecticut Longitudinal Study.
    J Learn Disabil. 1992 Dec;25(10):639-48 PMID: 1460385
  34. Suggestive linkage of developmental dyslexia to chromosome 1p34-p36.
    Lancet. 1993 Jul 17;342(8864):178 PMID: 8101276
  35. Quantitative trait locus for reading disability on chromosome 6.
    Science. 1994 Oct 14;266(5183):276-9 PMID: 7939663
  36. Quantitative trait locus for reading disability: correction.
    Science. 1995 Jun 16;268(5217):1553 PMID: 7777847
  37. Familial aggregation of spelling disability.
    J Child Psychol Psychiatry. 1996 Oct;37(7):817-22 PMID: 8923224
  38. Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.
    Am J Hum Genet. 1997 Jan;60(1):27-39 PMID: 8981944
  39. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein.
    Cell. 1998 Jan 9;92(1):63-72 PMID: 9489700
  40. Evidence for linkage of spelling disability to chromosome 15.
    Am J Hum Genet. 1998 Jul;63(1):279-82 PMID: 9634517
  41. A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia.
    Am J Hum Genet. 1999 Jan;64(1):146-56 PMID: 9915953
  42. Quantitative-trait locus for specific language and reading deficits on chromosome 6p.
    Am J Hum Genet. 1999 Jan;64(1):157-64 PMID: 9915954
  43. The structure of genetic influences on general cognitive, language, phonological, and reading abilities.
    Dev Psychol. 1999 Mar;35(2):590-603 PMID: 10082029
  44. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons.
    Neuron. 1999 Jun;23(2):257-71 PMID: 10399933
  45. A new gene (DYX3) for dyslexia is located on chromosome 2.
    J Med Genet. 1999 Sep;36(9):664-9 PMID: 10507721
  46. Linkage analyses of four regions previously implicated in dyslexia: confirmation of a locus on chromosome 15q.
    Am J Med Genet B Neuropsychiatr Genet. 2004 Nov 15;131B(1):67-75 PMID: 15389770
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/429131
Published
2005-04-00
Epub
2005-00-16
Pages
581-91
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1199296
Subset
IM
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1086/429131 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2