Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4)

Abstract

Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.

Figure 1

Multipoint LOD and heterogeneity LOD (HLOD) scores for CTS on chromosome 11: maximum HLOD=4.3 at D11S914 under a dominant mode of inheritance with 50% penetrance.

Figure 2

Cochrane–Armitage trend test of case–control association for CTS at the 11p13 locus in the discovery (New York) data set: Bonferroni critical value line displayed; significance criteria of 0.05/44 in discovery set corresponding to the 44 SNPs evaluated in the analysis.

Figure 3

(a and b) Pure likelihood plot of association evidence in discovery set (a, top) and in joint analysis of data sets (b, bottom). This pure likelihood analysis plots odds ratio (OR) on the y axis and base-pair position on the x axis. Each vertical line represents a likelihood interval (LI) for the OR at a given SNP. The OR=1 line is plotted as a solid black horizontal line, for reference. LIs in color are denoted as SNPs of interest, whereas a gray line indicates that the SNP is not of interest because the 1/32 LI for that SNP covers the OR=1 line. The small horizontal tick on each LI is the maximum likelihood estimator for the OR. The portion of the colored LI that covers the OR=1 horizontal line indicates the strength of the association information at that SNP. In particular, if the navy blue portion is above the OR=1 line while the yellow portion of the LI covers the OR=1 line, then the LOD evidence at that SNP is between 1.5 and 2 (ie, the 1/32 LI does not include the OR=1 value, but the 1/100 LI does); similarly, if both the yellow and navy blue portions are above the OR=1 line but the turquoise portion covers the line, then the LOD evidence is between 2 and 3 (ie, the 1/100 LI does not include OR=1 as a plausible value but the 1/1000 LI does). The further the colored line is above the OR=1 line, the stronger the association evidence. The max LR for each SNP in color is also provided as text in the plot, providing evidence not only of whether the LOD evidence is between 2 and 3, but also the exact value of the max LR.