A genomewide linkage screen for relative hand skill in sibling pairs

Abstract

Genomewide quantitative-trait locus (QTL) linkage analysis was performed using a continuous measure of relative hand skill (PegQ) in a sample of 195 reading-disabled sibling pairs from the United Kingdom. This was the first genomewide screen for any measure related to handedness. The mean PegQ in the sample was equivalent to that of normative data, and PegQ was not correlated with tests of reading ability (correlations between minus sign0.13 and 0.05). Relative hand skill could therefore be considered normal within the sample. A QTL on chromosome 2p11.2-12 yielded strong evidence for linkage to PegQ (empirical P=.00007), and another suggestive QTL on 17p11-q23 was also identified (empirical P=.002). The 2p11.2-12 locus was further analyzed in an independent sample of 143 reading-disabled sibling pairs, and this analysis yielded an empirical P=.13. Relative hand skill therefore is probably a complex multifactorial phenotype with a heterogeneous background, but nevertheless is amenable to QTL-based gene-mapping approaches.

Figure 1

Distribution of PegQ, a quantitative measure of relative hand skill, in the genome-screen sample (222 siblings). Mean = 0.072; SD = 0.104; range −0.24 to 0.42; skewness = 0.154; kurtosis = 0.876. The distribution is unimodal, continuous, and roughly normal, suggesting that linkage analysis can be performed within a classical oligogenic framework (see text). A positive mean (i.e., superior right-hand skill) is characteristic of unselected populations. The Pearson correlation of PegQ with self-reported “writing hand,” a dichotomous variable, was 0.51 (one-tailed P=6.3×10^-17). Twenty-two (9.9%) of the siblings wrote with their left hands; all 22 left-handed writers had negative PegQ scores, as did 27 right-handed writers.

Figure 2

Genomewide multipoint linkage analysis of PegQ, a measure of relative hand skill. Cumulative distance (in Haldane centimorgans) is shown along the X-axis, with chromosome identities along the top. Evidence for linkage (Y-axis) is given as pointwise empirically derived significance, calculated under a VC framework (see text). The QTL on chromosome 2p11.2-12 yields a pointwise peak P=.00007, suggesting a positive relationship between sibling phenotypic and genetic similarity at this locus.