Alleles of a Polymorphic ETV6 Binding Site in DCDC2 Confer Risk of Reading and Language Impairment

Abstract

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."

Association study of developmental dyslexia candidate genes DCDC2 and KIAA0319 in Chinese population

“…Previously identified functional variants have been replicated, including BV677278 of DCDC2 [Brkanac et al, 2007;Ludwig et al, 2008b;Wilcke et al, 2009;Meng et al, 2011;Marino et al, 2012;Powers et al, 2013] and rs9461045 of KIAA0319 [Elbert et al, 2011;Kirsten et al, 2012;Svidnicki et al, 2013;Venkatesh et al, 2013]. The results were inconclusive across different populations.…”

“…Functional studies found that BV677278 could modulate DCDC2 expression [Meng et al, 2011]. Recently, the transcription factor ETV6 was identified as BV677278-binding protein [Powers et al, 2013]. In the meantime, a fine-mapping study in German population reported significant association of DCDC2 with DD by identifying rs793862 and a two-marker haplotype rs793862-rs807701 [Schumacher et al, 2006].…”

An assessment of gene-by-gene interactions as a tool to unfold missing heritability in dyslexia

“…As mentioned above, only three studies investigated the effects of having more than one genetic risk variant at the same time (Harold et al 2006;Ludwig et al 2008;Powers et al 2013). By testing for both additive and dominant statistical interactions between DCDC2 and KIAA0319, Harold et al (2006) found nominally significant interactions between variants in the two genes in a sample of 419 probands and 273 controls.…”

“…Since the early 1980s at least nine DD risk loci have been mapped to chromosomes 1, 2, 3, 6, 15, 18, and X (Scerri and Schulte-Körne 2010) and evidence for involvement of several genes in the etiology of DD (i.e., DYX1C1, DCDC2, KIAA0319, C2ORF3, MRPL19, ROBO1, FAM176A, KIAA0319L, FMR1, PCNT, DIP2A, S100B, PRMT2, DOCK4, GTF2I, and GRIN2B;Ludwig et al 2009;Scerri and Schulte-Körne 2010;Poelmans et al 2011;Mascheretti et al 2014a) has been presented, although with varying degrees of support. Among the above-mentioned genes, seven DD candidate genes have been replicated in at least one independent sample, i.e., DYX1C1, DCDC2, KIAA0319, C2ORF3, MRPL19, ROBO1, and GRIN2B (Ludwig et al 2009;Scerri and Schulte-Körne 2010;Couto et al 2010;Lim et al 2011;Kirsten et al 2012;Marino et al 2012;Powers et al 2013;Venkatesh et al 2013Venkatesh et al , 2014Mascheretti et al 2014a, b;Tran et al 2014). We previously reported the association of single nucleotide polymorphisms (SNPs) spanning the DYX1C1, DCDC2, KIAA0319, ROBO1, and GRIN2B genes with DD and DD-related quantitative traits in affected Italian nuclear families (Marino et al 2007(Marino et al , 2011(Marino et al , 2012Mascheretti et al 2014a, b).…”

“…With few exceptions (Harold et al 2006;Ludwig et al 2008;Powers et al 2013), until now genes have been investigated one at a time and ascribed to a phenotype by either single, additive, or combinatorial effects. Nevertheless, these approaches failed to explain the strong degree of heritability reported for DD and DD-related neuropsychological traits.…”