Quantitative multidimensional phenotypes improve genetic analysis of laterality traits

Abstract

Handedness is the most commonly investigated lateralised phenotype and is usually measured as a binary left/right category. Its links with psychiatric and neurodevelopmental disorders prompted studies aimed at understanding the underlying genetics, while other measures and side preferences have been less studied. We investigated the heritability of hand, as well as foot, and eye preference by assessing parental effects (n ≤ 5028 family trios) and SNP-based heritability (SNP-h2, n ≤ 5931 children) in the Avon Longitudinal Study of Parents and Children (ALSPAC). An independent twin cohort from Hong Kong (n = 358) was used to replicate results from structural equation modelling (SEM). Parental left-side preference increased the chance of an individual to be left-sided for the same trait, with stronger maternal than paternal effects for footedness. By regressing out the effects of sex, age, and ancestry, we transformed laterality categories into quantitative measures. The SNP-h2 for quantitative handedness and footedness was 0.21 and 0.23, respectively, which is higher than the SNP-h2 reported in larger genetic studies using binary handedness measures. The heritability of the quantitative measure of handedness increased (0.45) compared to a binary measure for writing hand (0.27) in the Hong Kong twins. Genomic and behavioural SEM identified a shared genetic factor contributing to handedness, footedness, and eyedness, but no independent effects on individual phenotypes. Our analysis demonstrates how quantitative multidimensional laterality phenotypes are better suited to capture the underlying genetics than binary traits.

The influence of vestibular system and fetal presentation on handedness, cognitive and motor development: A comparison between cephalic and breech presentation

“…Nonetheless, this assessment appeared to provide useful information about handedness. For instance, Schmitz et al (2022) successfully identified a heritability estimate of handedness using the same 6-item questionnaire of ALSPAC, finding a similar heritability estimate to what was previously reported in twin studies (Medland et al, 2006(Medland et al, , 2009. Thus, we believe that the questionnaire has scientific validity and can inform the relationship between hand preference and fetal presentation.…”

“…Genetics are undoubtedly involved in handedness (Cuellar-Partida et al, 2021;McManus, 2021;Medland et al, 2006Medland et al, , 2009. Recently, using the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort, Schmitz et al (2022) conducted a large study investigating the heritability of lateral preferences (i.e., handedness, footedness, eyedness). The authors found that individuals with parental left-sidedness are more likely to present the same trait.…”

Cognitive and Neurophysiological Models of Brain Asymmetry

“…Moreover, the model is further extended to include cerebral polymorphisms that are based on a multitude of functional modules for different lateralized cognitive systems, such as language, praxis, and visuo-spatial functioning. This idea is in line with recent findings showing that multidimensional phenotypes improve the genetic analysis of laterality traits [23]. It is very encouraging to observe how a leading model in the field is adjusted to fit with recent empirical findings, even decades after it was first published.…”

Language and reading impairments are associated with increased prevalence of non‐right‐handedness

“…Annett's Right-Shift theory also predicted a link between NRH and dyslexia determined by an "asymmetry gene" which would affect the typical left hemisphere lateralization for both language and handedness. This, and other single-gene theories (McManus, 1985) are not supported by recent genomic studies which show that in most cases, handedness is influenced by the combined effects of variants in a large number of genes (Armour et al, 2014;Cuellar-Partida et al, 2021;Schmitz et al, 2022). Genome-wide association studies (GWAS) for handedness have identified some of these genes, some of which have also been implicated in neurodevelopmental conditions, including schizophrenia and dyslexia (Brandler et al, 2013;Brandler & Paracchini, 2014;Cuellar-Partida et al, 2021;Wiberg et al, 2019).…”