Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: Quantitative association analysis and positional candidate genes SEMA4F and OTX1

Clyde Francks, Simon E. Fisher, Richard K. Olson, Bruce F. Pennington, Shelley D Smith, John C. DeFries, Anthony P. Monaco

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

A locus on chromosome 2p12-16 has been implicated in dyslexia susceptibility by two independent linkage studies, including our own study of 119 nuclear twin-based families, each with at least one reading-disabled child. Nonetheless, no variant of any gene has been reported to show association with dyslexia, and no consistent clinical evidence exists to identify candidate genes with any strong a priori logic. We used 21 microsatellite markers spanning 2p12-16 to refine our 1-LOD unit linkage support interval to 12cM between D2S337 and D2S286. Then, in quantitative association analysis, two microsatellites yielded P values < 0.05 across a range of reading-related measures (D2S2378 and D2S2114). The exon/intron borders of two positional candidate genes within the region were characterized, and the exons were screened for polymorphisms. The genes were Semaphorin4F (SEMA4F), which encodes a protein involved in axonal growth cone guidance, and OTX1, encoding a homeodomain transcription factor involved in forebrain development. Two non-synonymous single nucleotide polymorphisms were found in SEMA4F, each with a heterozygosity of 0.03. One intronic single nucleotide polymorphism between exons 12 and 13 of SEMA4F was tested for quantitative association, but no significant association was found. Only one single nucleotide polymorphism was found in OTX1, which was exonic but silent. Our data therefore suggest that linkage with reading disability at 2p12-16 is not caused by coding variants of SEMA4F or OTX1. Our study outlines the approach necessary for the identification of genetic variants causing dyslexia susceptibility in an epidemiological population of dyslexics.

Original languageEnglish (US)
Pages (from-to)35-41
Number of pages7
JournalPsychiatric Genetics
Volume12
Issue number1
DOIs
StatePublished - Apr 15 2002

Fingerprint

Chromosomes, Human, Pair 16
Dyslexia
Genetic Association Studies
Single Nucleotide Polymorphism
Reading
Exons
Microsatellite Repeats
Genes
Growth Cones
Disabled Children
Prosencephalon
Introns
Transcription Factors
Population
Proteins

Keywords

  • Dyslexia
  • Linkage disequilibrium
  • Microsatellite repeats
  • Polymorphism
  • Quantitative trait
  • Single nucleotide

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus : Quantitative association analysis and positional candidate genes SEMA4F and OTX1. / Francks, Clyde; Fisher, Simon E.; Olson, Richard K.; Pennington, Bruce F.; Smith, Shelley D; DeFries, John C.; Monaco, Anthony P.

In: Psychiatric Genetics, Vol. 12, No. 1, 15.04.2002, p. 35-41.

Research output: Contribution to journalArticle

Francks, Clyde ; Fisher, Simon E. ; Olson, Richard K. ; Pennington, Bruce F. ; Smith, Shelley D ; DeFries, John C. ; Monaco, Anthony P. / Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus : Quantitative association analysis and positional candidate genes SEMA4F and OTX1. In: Psychiatric Genetics. 2002 ; Vol. 12, No. 1. pp. 35-41.
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