First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children

Abstract

Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14eÀ08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71eÀ08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible transregulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks.

ATP2C2andDYX1C1are putative modulators of dyslexia‐related MMR

“…In accordance with the literature (Lovio et al., 2010; Roeske et al., 2011; Schulte‐Körne et al., 1998, 2001), the late MMR significantly discriminated between people with good and poor spelling further corroborating its value as potential endophenotype for dyslexia. Also in accordance with previous reports, discrimination was found to be strong in a time window near 400 ms (Figure 1, Alonso‐Búa et al., 2006; Cheour et al., 2001).…”

“…However, results for a few other SNPs associating with MMR are available: Roeske et al. (2011) reported an association with the two‐marker haplotype rs4234898‐rs11100040 with the late component of the MMR in a set of 200 dyslexic children in a GWAS. Both SNPs of the haplotype were associated with altered expression levels of SLC2A3 .…”

“…(2011) (see Materials and Methods). Therefore, we cannot exclude associations of other SNPs with the late component of the MMR at low effect sizes.…”

“…Nevertheless, our results are supported by in silico functional data and a previous genetic MMR study (Roeske et al. (2011) and are available for meta‐analysis in future studies.…”

“…Altered MMRs are reported for individuals with dyslexia and SLI, and are assumed to be associated with deficient phonological processing (Lovio, Näätänen, & Kujala, 2010; Schulte‐Körne, Deimel, Bartling, & Remschmidt, 1998, 2001). Indeed, first evidence for genetic variants affecting the late component of MMR was reported in a previous genome‐wide association study (GWAS) for common variants (Roeske et al., 2011) and, subsequently, for certain rare variants (Czamara et al., 2011). …”