The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles

Natalie R. Powers, John D. Eicher, Laura L. Miller, Yong Kong, Shelley D. Smith, Bruce F. Pennington, Erik G. Willcutt, Richard K. Olson, Susan M. Ring, Jeffrey R. Gruen

Research output: Contribution to journalArticle

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Abstract

Background Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6. Objective To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319. Methods We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap. Results and conclusions READ1 and KIAHap show interdependence-READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction.

Original languageEnglish (US)
Pages (from-to)163-171
Number of pages9
JournalJournal of medical genetics
Volume53
Issue number3
DOIs
StatePublished - Jan 1 2016

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Reading
Language
Alleles
Haplotypes
Learning Disorders
Linkage Disequilibrium
Microsatellite Repeats
Introns
Genes
Chromatin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles. / Powers, Natalie R.; Eicher, John D.; Miller, Laura L.; Kong, Yong; Smith, Shelley D.; Pennington, Bruce F.; Willcutt, Erik G.; Olson, Richard K.; Ring, Susan M.; Gruen, Jeffrey R.

In: Journal of medical genetics, Vol. 53, No. 3, 01.01.2016, p. 163-171.

Research output: Contribution to journalArticle

Powers, NR, Eicher, JD, Miller, LL, Kong, Y, Smith, SD, Pennington, BF, Willcutt, EG, Olson, RK, Ring, SM & Gruen, JR 2016, 'The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles', Journal of medical genetics, vol. 53, no. 3, pp. 163-171. https://doi.org/10.1136/jmedgenet-2015-103418
Powers, Natalie R. ; Eicher, John D. ; Miller, Laura L. ; Kong, Yong ; Smith, Shelley D. ; Pennington, Bruce F. ; Willcutt, Erik G. ; Olson, Richard K. ; Ring, Susan M. ; Gruen, Jeffrey R. / The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles. In: Journal of medical genetics. 2016 ; Vol. 53, No. 3. pp. 163-171.
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abstract = "Background Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6. Objective To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319. Methods We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap. Results and conclusions READ1 and KIAHap show interdependence-READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction.",
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AU - Powers, Natalie R.

AU - Eicher, John D.

AU - Miller, Laura L.

AU - Kong, Yong

AU - Smith, Shelley D.

AU - Pennington, Bruce F.

AU - Willcutt, Erik G.

AU - Olson, Richard K.

AU - Ring, Susan M.

AU - Gruen, Jeffrey R.

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N2 - Background Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6. Objective To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319. Methods We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap. Results and conclusions READ1 and KIAHap show interdependence-READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction.

AB - Background Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6. Objective To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319. Methods We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap. Results and conclusions READ1 and KIAHap show interdependence-READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction.

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