The Dyslexia Candidate Locus on 2p12 Is Associated with General Cognitive Ability and White Matter Structure

Peer reviewe

The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N&gt;5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.</p

Imaging results.

<p>(A) Main association of rs917235 with white matter volume. Sagittal view of the significant cluster associated with rs917235 at the MNI coordinates of X = −13, −8, 8, and 13 mm relative to the midline. The background image is the average of all individuals' white matter segmented images. The colour-bar shows the z-scores of the statistical analysis. (B–D) Structural connectivity. (B) A sample of fiber tracking from one individual passing through the region associated with rs917235. Different colours show the direction of pathways (red for left-right, blue for superior-inferior, and green for anterior-posterior). (C) Overlay of tract tracing from 30 randomly selected individuals. The colour-bar is a count for the number of subjects; yellow shows the most probable pathways. (D) Cortical end-points of the white matter pathways showing that the fibers connect right postcentral gyrus, superior parietal lobule, precuneous, occipital cortex and temporal fusiform gyrus to the analogous left regions.</p

P-values from single-SNP analyses for VIQ and PIQ in replication samples.

<p>p-values statistically significant are in bold.</p><p>RA = Risk alleles are given only for results showing trend of association (p<0.1); NT = not tested.</p><p>Risk allele was G for all SNPs in all samples.</p

Summary results for rs917235/rs714939 haplotype associations with VIQ in the ALSPAC cohort.

<p>p-values statistically significant are in bold.</p

Details of phenotypic measures.

<p>VIQ (verbal IQ); PIQ (performance (non-verbal) IQ); SD (standard deviation); WISC (Wechsler Intelligence Scale for Children); BAS (British Abilities Scales); WAIS (Wechsler Adult Intelligence Scale); PPVT (Peabody Picture Vocabulary Test); RCPM (Raven's Coloured Progressive Matrices).</p