J Schmitz, M Zheng, K Lui, C McBride, C Ho and S Paracchini

Quantitative multidimensional phenotypes improve genetic analysis of laterality traits

Translational Psychiatry

The heritability of handedness, the most commonly investigated lateralised phenotype, has been consistently estimated to be ~25%. Handedness is linked to brain asymmetries such as hemispheric dominance for language and it has been associated to psychiatric and neurodevelopmental disorders. Here, we investigated the genetics of handedness as well as foot and eye preference and their relationship with neurodevelopmental phenotypes. Parental left-side preference increased the chance of an individual to be left-sided for the same trait, with stronger maternal than paternal effects ( n  ≤ 4,042 family trios from the Avon Longitudinal Study of Parents and Children (ALSPAC)). By regressing out effects of sex, age, and the first two ancestry-informative principal components, we transformed categorical phenotypes (right, mixed, left) into quantitative measures for single nucleotide polymorphism (SNP) based heritability (SNP-h 2 ). We found moderate SNP-h 2  for transformed measures of hand (.21) and foot (.28) but negligible SNP-h 2  for eye preference (.02) or the untransformed categorical measures ( n  ≤ 5,931). Genomic and behavioural structural equation modelling (SEM) in ALSPAC and a twin cohort from Hong Kong ( n  = 366) identified a shared genetic factor contributing to hand, foot, and eye preference, but no independent effects on individual phenotypes. Higher polygenic risk scores (PRS) for ADHD and genetic predisposition towards lower IQ and educational attainment (EA) were associated with left hand preference. This finding supports the idea of a right-handedness advantage on neurodevelopmental outcomes. This is the largest study conducted to date for multiple lateralised measures in the same individuals. Our analysis demonstrates how quantitative multidimensional laterality phenotypes are better suited to capture the underlying genetic component than simple left/right binary traits.

The preprint is available on https://www.biorxiv.org/content/10.1101/2021.04.28.441754v1.