Exome-wide analysis implicates rare protein-altering variants in human handedness

Abstract

AbstractHandedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examined whether left-handedness is also influenced by rare coding variants (frequencies ≤ 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals (UK Biobank). The beta-tubulin geneTUBB4Bshowed exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers (0.076%) than right-handers (0.028%). TheTUBB4Bvariants were mostly heterozygous missense changes, but included two frameshifts found only in left-handers. OtherTUBB4Bvariants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening,DSCAMandFOXP1showed evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study revealed a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.