Alleles of a polymorphic ETV6 binding site in DCDC2 confer risk of reading and language impairment

TY - JOUR

T1 - Alleles of a polymorphic ETV6 binding site in DCDC2 confer risk of reading and language impairment

AU - Powers, Natalie R

AU - Eicher, John D

AU - Butter, Falk

AU - Kong, Yong

AU - Miller, Laura L

AU - Ring, Susan M

AU - Mann, Matthias

AU - Gruen, Jeffrey R

N1 - Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2013/7/11

Y1 - 2013/7/11

N2 - Reading disability (RD) and language impairment (LI) are common learning disabilities that make acquisition and utilization of reading and verbal language skills, respectively, difficult for affected individuals. Both disorders have a substantial genetic component with complex inheritance. Despite decades of study, reading and language, like many other complex traits, consistently evade identification of causative and functional variants. We previously identified a putative functional risk variant, named BV677278 for its GenBank accession number, for RD in DCDC2. This variant consists of an intronic microdeletion and a highly polymorphic short tandem repeat (STR) within its breakpoints. We have also shown this STR to bind to an unknown nuclear protein with high specificity. Here, we replicate BV677278's association with RD, expand its association to LI, identify the BV677278-binding protein as the transcription factor ETV6, and provide compelling genetic evidence that BV677278 is a regulatory element that influences reading and language skills. We also provide evidence that BV677278 interacts nonadditively with KIAA0319, an RD-associated gene, to adversely affect several reading and cognitive phenotypes. On the basis of these data, we propose a new name for BV677278: "READ1" or "regulatory element associated with dyslexia 1."

AB - Reading disability (RD) and language impairment (LI) are common learning disabilities that make acquisition and utilization of reading and verbal language skills, respectively, difficult for affected individuals. Both disorders have a substantial genetic component with complex inheritance. Despite decades of study, reading and language, like many other complex traits, consistently evade identification of causative and functional variants. We previously identified a putative functional risk variant, named BV677278 for its GenBank accession number, for RD in DCDC2. This variant consists of an intronic microdeletion and a highly polymorphic short tandem repeat (STR) within its breakpoints. We have also shown this STR to bind to an unknown nuclear protein with high specificity. Here, we replicate BV677278's association with RD, expand its association to LI, identify the BV677278-binding protein as the transcription factor ETV6, and provide compelling genetic evidence that BV677278 is a regulatory element that influences reading and language skills. We also provide evidence that BV677278 interacts nonadditively with KIAA0319, an RD-associated gene, to adversely affect several reading and cognitive phenotypes. On the basis of these data, we propose a new name for BV677278: "READ1" or "regulatory element associated with dyslexia 1."

KW - Alleles

KW - Base Sequence

KW - Binding Sites

KW - Case-Control Studies

KW - Dyslexia

KW - Genetic Association Studies

KW - Haplotypes

KW - HeLa Cells

KW - Humans

KW - Language Development Disorders

KW - Language Tests

KW - Linkage Disequilibrium

KW - Microsatellite Repeats

KW - Microtubule-Associated Proteins

KW - Molecular Sequence Data

KW - Phylogeny

KW - Polymorphism, Genetic

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - Proto-Oncogene Proteins c-ets

KW - Repressor Proteins

KW - Risk Factors

U2 - 10.1016/j.ajhg.2013.05.008

DO - 10.1016/j.ajhg.2013.05.008

M3 - Journal article

C2 - 23746548

SN - 0002-9297

VL - 93

SP - 19

EP - 28

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -