Dense‐map genome scan for dyslexia supports loci at 4q13, 16p12, 17q22; suggests novel locus at 7q36

Abstract

Analysis of genetic linkage to dyslexia was performed using 133,165 array-based SNPs genotyped in 718 persons from 101 dyslexia-affected families. Results showed five linkage peaks with lod scores >2.3 (4q13.1, 7q36.1-q36.2, 7q36.3, 16p12.1, and 17q22). Of these five regions, three have been previously implicated in dyslexia (4q13.1, 16p12.1, and 17q22), three have been implicated in attention-deficit hyperactivity disorder (ADHD, which highly co-occurs with dyslexia; 4q13.1, 7q36.3, 16p12.1) and four have been implicated in autism (a condition characterized by language deficits; 7q36.1-q36.2, 7q36.3, 16p12.1, and 17q22). These results highlight the reproducibility of dyslexia linkage signals, even without formally significant lod scores, and suggest dyslexia predisposing genes with relatively major effects and locus heterogeneity. The largest lod score (2.80) occurred at 17q22 within the MSI2 gene, involved in neuronal stem cell lineage proliferation. Interestingly, the 4q13.1 linkage peak (lod 2.34) occurred immediately upstream of the LPHN3 gene, recently reported both linked and associated with ADHD. Separate analyses of larger pedigrees revealed lods >2.3 at 1-3 regions per family; one family showed strong linkage (lod 2.9) to a known dyslexia locus (18p11) not detected in our overall data, demonstrating the value of analyzing single large pedigrees. Association analysis identified no SNPs with genomewide significance, although a borderline significant SNP (P = 6 × 10 -7 ) occurred at 5q35.1 near FGF18, involved in laminar positioning of cortical neurons during development. We conclude that dyslexia genes with relatively major effects exist, are detectable by linkage analysis despite genetic heterogeneity, and show substantial overlapping predisposition with ADHD and autism.

Reading and Language Disorders: The Importance of Both Quantity and Quality

“…Field et al 2013, performed a joint linkage and association study on 718 individuals from 101 dyslexia families with 100,000 SNPs. Again, they did not find any associations that met the threshold of genome-wide significance (1 × 10 −8 [96]) [97]. They did however, find suggestive association ( p = 6.2 × 10 −7 ) with an SNP 77 Kb downstream of the FGF18 gene, which has been implicated in lateralization [97].…”

“…Again, they did not find any associations that met the threshold of genome-wide significance (1 × 10 −8 [96]) [97]. They did however, find suggestive association ( p = 6.2 × 10 −7 ) with an SNP 77 Kb downstream of the FGF18 gene, which has been implicated in lateralization [97]. Luciano et al reported a meta-analysis of quantitative reading and language measures across two relatively large population-based samples (1177 individuals from 538 families and approximately 5000 cases) [98].…”

Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci

“…Genotyping was performed on 36 PBC affected persons and 27 unaffected relatives from 27 affected families. Individuals were genotyped for 262 217 single nucleotide polymorphisms (SNPs) on the NspI array from the Affymetrix Human Mapping 500K Array Set using an Affymetrix GeneChip ® Instrument System, as previously described . There were 10 families that were informative for linkage.…”

Insights into the Genetic Foundations of Human Communication

“…To this end, novel loci of interest have recently been suggested by new linkage screens and the first GWAS in SLI, dyslexia and general population cohorts, and replication should be sought for these loci (Bartlett et al 2014;Field et al 2013;Nudel et al 2014;Luciano et al 2013;Harlaar et al 2014;Gialluisi et al 2014). These studies have highlighted the absence of single common variants of large effect on language-related phenotypes.…”