ATP2C2andDYX1C1are putative modulators of dyslexia‐related MMR

Abstract

BackgroundDyslexia is a specific learning disorder affecting reading and spelling abilities. Its prevalence is ~5% in German‐speaking individuals. Although the etiology of dyslexia largely remains to be determined, comprehensive evidence supports deficient phonological processing as a major contributing factor. An important prerequisite for phonological processing is auditory discrimination and, thus, essential for acquiring reading and spelling skills. The event‐related potential Mismatch Response (MMR) is an indicator for auditory discrimination capabilities with dyslexics showing an altered late component of MMR in response to auditory input.MethodsIn this study, we comprehensively analyzed associations of dyslexia‐specific late MMRs with genetic variants previously reported to be associated with dyslexia‐related phenotypes in multiple studies comprising 25 independent single‐nucleotide polymorphisms (SNPs) within 10 genes.ResultsFirst, we demonstrated validity of these SNPs for dyslexia in our sample by showing that additional inclusion of a polygenic risk score improved prediction of impaired writing compared with a model that used MMR alone. Secondly, a multifactorial regression analysis was conducted to uncover the subset of the 25 SNPs that is associated with the dyslexia‐specific late component of MMR. In total, four independent SNPs within DYX1C1 and ATP2C2 were found to be associated with MMR stronger than expected from multiple testing. To explore potential pathomechanisms, we annotated these variants with functional data including tissue‐specific expression analysis and eQTLs.ConclusionOur findings corroborate the late component of MMR as a potential endophenotype for dyslexia and support tripartite relationships between dyslexia‐related SNPs, the late component of MMR and dyslexia.

Identification of Phonology-Related Genes and Functional Characterization of Broca’s and Wernicke’s Regions in Language and Learning Disorders

“…The literature analysis suggested an overlap between dyslexia and SLI for ATP2C2 (Newbury et al, 2011;Müller et al, 2017;Martinelli et al, 2021). In the enrichment analysis, it did not show up among our top findings but provided nominal significance in a gene set with ROBO1 for a non-brain related biological process (Supplementary Table 8).…”

“…In humans, two SNPs, rs17819126 in DNAAF4 and rs8053211 in ATP2C2, represented the only correction stable results in an association screen of ten candidate genes tagged by 23 independent SNPs for event-related potential mismatch response, an indicator for auditory discrimination capabilities in dyslexia patients (Müller et al, 2017). Müller et al (2017) provided evidence that genetic variation in ATP2C2 and DNAAF4 may be a putative modulator of mismatch response in dyslexia. This aspect is highly interesting since auditory discrimination is an essential prerequisite for phonological processing and should be investigated in a future study, especially in context with disease-dependent changes of structural and functional connectivity between Broca's and Wernicke's regions.…”

“…For dyslexia/SLI, we found ATP2C2 (Newbury et al, 2011;Müller et al, 2017;Martinelli et al, 2021), CCDC136 (Gialluisi et al, 2014;Adams et al, 2017), CMAHP (Eicher et al, 2014), CMIP (Newbury et al, 2011;Scerri et al, 2011;Luciano et al, 2018), CNTNAP2 (Newbury et al, 2011;Peter et al, 2011;Eicher et al, 2013;Luciano et al, 2018), COL4A2 (Eicher et al, 2013), FLNC (Gialluisi et al, 2014;Adams et al, 2017), FOXP2 (Peter et al, 2011;Wilcke et al, 2012;Eicher et al, 2013;Mozzi et al, 2017;Sánchez-Morán et al, 2018;Doust et al, 2020), KIAA0319 (Couto et al, 2010;Czamara et al, 2011;Elbert et al, 2011;König et al, 2011;Newbury et al, 2011;Scerri et al, 2011;Cope et al, 2012;Zou et al, 2012;Eicher et al, 2013Eicher et al, , 2014Powers et al, 2013Powers et al, , 2016Mascheretti et al, 2015;Adams et al, 2017;Carrion-Castillo et al, 2017;Neef et al, 2017;Centanni et al, 2018;Luciano et al, 2018;…”

“…Of note, knockdown of Dnaaf4 in rat embryos demonstrated effects on auditory processing, visual attention as well as cortical and thalamic anatomy (Szalkowski et al, 2013). In humans, two SNPs, rs17819126 in DNAAF4 and rs8053211 in ATP2C2, represented the only correction stable results in an association screen of ten candidate genes tagged by 23 independent SNPs for event-related potential mismatch response, an indicator for auditory discrimination capabilities in dyslexia patients (Müller et al, 2017). Müller et al (2017) provided evidence that genetic variation in ATP2C2 and DNAAF4 may be a putative modulator of mismatch response in dyslexia.…”

The Polygenic Nature and Complex Genetic Architecture of Specific Learning Disorder

“…MMN serves as a measure for speech perception and automatic speech deviance which has been found impaired in dyslexic children [ 97 ]. This mismatch response endophenotype was later shown to associate with common variants in DYX1C1 [ 112 ], unlike common variants in DCDC2 and KIAA0319 [ 113 ].…”