The Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) Framework for Understanding Musicality-Language Links Across the Lifespan

Using individual differences approaches, a growing body of literature finds positive associations between musicality and language-related abilities, complementing prior findings of links between musical training and language skills. Despite these associations, musicality has been often overlooked in mainstream models of individual differences in language acquisition and development. To better understand the biological basis of these individual differences, we propose the Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) framework. This novel integrative framework posits that musical and language-related abilities likely share some common genetic architecture (i.e., genetic pleiotropy) in addition to some degree of overlapping neural endophenotypes, and genetic influences on musically and linguistically enriched environments. We review and discuss findings from over seventy studies in the literature demonstrating that individual differences in musical aptitude (i.e., rhythm and tonality skills) are robustly correlated with a wide range of speech-language skills that are foundational for effective communication, including speech perception, grammatical abilities, reading-related skills, and second/foreign language learning. From this body of work we conclude that musical abilities are intertwined with speech, language, and reading development over the lifespan. Drawing upon recent advances in genomic methodologies for unraveling pleiotropy, we outline testable predictions for future research on language development and how its underlying neurobiological substrates may be supported by genetic pleiotropy with musicality.

A New Functional F-Statistic for Gene-Based Inference Involving Multiple Phenotypes

Genetic pleiotropy is the phenomenon where a single gene or genetic variant influences multiple traits. Numerous statistical methods exist for testing for genetic pleiotropy at the variant level, but fewer methods are available for testing genetic pleiotropy at the gene-level. In the current study, we derive an exact alternative to the Shen and Faraway functional F-statistic for functional-on-scalar regression models. Through extensive simulation studies, we show that this exact alternative performs similarly to the Shen and Faraway F-statistic in gene-based, multi-phenotype analyses and both F-statistics perform better than existing methods in small sample, modest effect size situations. We then apply all methods to real-world, neurodegenerative disease data and identify novel associations.

Effects of Thyroid Status on Regional Brain Volumes: A Diagnostic and Genetic Imaging Study in UK Biobank

Background Thyroid hormone is essential for optimal human neurodevelopment and may modify the risk of attention-deficit/hyperactivity disorder (ADHD). However, the brain structures involved are unknown and it is unclear if the adult brain is also susceptible to changes in thyroid status. Methods We used International Classification of Disease-10 codes, polygenic thyroid scores at different thresholds of association with thyroid traits (PT-values), and image-derived phenotypes in UK Biobank (n = 18 825) to investigate the effects of a recorded diagnosis of thyroid disease and genetic risk for thyroid status on cerebellar and subcortical gray matter volume. Regional genetic pleiotropy between thyroid status and ADHD was explored using the GWAS-pairwise method. Results A recorded diagnosis of hypothyroidism (n = 419) was associated with significant reductions in total cerebellar and pallidum gray matter volumes (β [95% CI] = −0.14[−0.23, −0.06], P = 0.0005 and β [95%CI] = −0.12 [−0.20, −0.04], P = 0.0042, respectively), mediated in part by increases in body mass index. While we found no evidence for total cerebellar volume alterations with increased polygenic scores for any thyroid trait, opposing influences of increased polygenic scores for hypo- and hyperthyroidism were found in the pallidum (PT < 1e−3: β [95% CI] = −0.02 [−0.03, −0.01], P = 0.0003 and PT < 1e−7: β [95% CI] = 0.02 [0.01, 0.03], P = 0.0003, respectively). Neither hypo- nor hyperthyroidism showed evidence of regional genetic pleiotropy with ADHD. Conclusions Thyroid status affects gray matter volume in adults, particularly at the level of the cerebellum and pallidum, with potential implications for the regulation of motor, cognitive, and affective function.