Left-handedness is a uniquely human trait, with 90% human populations globally being right-handed since the Paleolithic (extending from 3.3 million years ago to the end of the Pleistocene). A feature of motor control, the prevailing theory is that handedness is a consequence of language being "lateralized to the left hemisphere"; "lefties" are known to have more bilateral or language activation in the right hemisphere. It is also known that left-handedness is associated with several neurological disorders, including schizophrenia. But up to now no good neuroanatomical localization of the trait were known. Also unknown was the genetic basis (if any) for left-handedness (although it is known to "run in families").
The first steps to rectifying this knowledge dearth were published in Brain in September, in a paper entitled "Handedness, language areas and neuropsychatric diseases" insights from brain imaging and genetics." The paper described the use of imaging, genotype, and handedness data from UK Biobank, "a prospective cohort study of ∼500 000 participants who have allowed linkage of their physical data, including genetics, with their medical records, lifestyle questionnaires, and cognitive measures." In this study, the researchers assessed gene expression in 356,567 right-handed participants, 38,332 left-handed participants, and 6,299 ambidextrous participants. They then developed 547,011 genotyped SNPs and ~11 million imputed SNPs and utilized a set of 3144 "image-derived phenotypes" (IDP) of human brain from participants, selected to "summarize[] the information across all brain structural and functional modalities," consisting of:
[R]egional volumetric, area and thickness measures; subcortical measures of MRI modalities sensitive to e.g. venous vasculature or microbleeds and white matter lesions, white matter tract measures of physical connection ('structural connectivity') between brain regions using diffusion indices, and measures of spontaneous temporal synchronization ('functional connectivity') between pairs of brain regions.
The authors then performed genome-wide association studies (GWAS) using 547,011 mapped SNPs and ~11 million "imputed" SNPs, with the interrelationships between handedness, genetics, and brain regions illustrated by this diagram:
The results of these studies were set forth as follows. Association between handedness and brain regions showed "(i) a stronger connectivity between right and left (homologous) language networks . . . ; and (ii) a weaker connectivity between the right homologous language network and the default-mode network (DMN) and salience network ([]'stronger connectivity' corresponds to higher absolute values of partial correlation between the time courses of the two resting-state networks involved)."
Genetic studies showed three GWAS significant loci comparing handedness differences, identified as rs199512 (located at 17q21.31); rs45608532 (located at 22q11.22); and rs13017199 (located at 2q34); there was also a locus (rs3094128 located at 6p21.33) discovered by comparing the broader group of "non-right-handers" with individuals who are exclusively right-handers. These loci are correlated with expression quantitative trait loci (eQTL) for MAP2 (microtubule-associated protein 2, at rs13017199 on chromosome 2), TUBB/MICB (tubulin beta class 1, at rs3094128 on chromosome 6; and WNT3/MAPT (microtubule associated protein tau, at rs199512 on chromosome 17).
Assessing the association of these loci with neuronal development and neurodegenerative phenotypes, SNP-based enrichment analysis showed the top 2 enrichments were for Parkinson's disease and neurodegenerative disease, with the remaining 8 for other neurological disorder phenotypes. Supporting these correlations was positional gene mapping of left- and right-handers identified a set of genes highly expressed in brain tissue. Linkage disequilibrium studies showed statistically significant correlations with schizophrenia, Parkinson's disease, a tendency towards anorexia nervosa, and bipolar disorder. Specifically, the rs199512 locus (associated with MAPT) "yielded many highly significant associations with measures of white matter structural connectivity," "most strongly in tracts linking Broca's and temporoparietal junction areas (arcuate/superior longitudinal fasciculus III), i.e. specifically the same brain regions found differentially functionally-connected in our direct handedness and imaging analysis."
The strongest correlation between handedness and genotype reported from these studies were found at rs199512, relating handedness with Parkinson's disease and other "mental health phenotypes." IDP images correlated language-related tracts in brain with schizophrenia and auditory hallucinations. A correlation was found with lack of lateralization of white matter consistent with other studies showing lack of correlation with gray matter asymmetries and handedness. And these "language-related white matter tracts specifically make up the functional (homologous) language networks that differ between left- and right-handers." They further note that:
[T]hree of the four loci correlating with handedness in our GWAS are indeed associated with genes strongly involved in brain development and patterning (MAP2, TUBB/MICB, WNT3/MAPT). In particular, microtubules (MAP2, TUBB, MAPT)—as integral components of the neuronal cytoskeleton—play a key role in neuronal morphogenesis and migration. WNT3 has also been shown to act as an axon guidance molecule and, strikingly, as a gradient for retinotopic mapping along the medial-lateral axis . . . . Of note, rs3094128 is an eQTL of MICB, which is crucial to brain development and plasticity and may mediate both genetic and environmental involvements in schizophrenia.
And these authors "found a statistically significant positive correlation between left-handedness and schizophrenia using LD score regression."
The paper concludes by saying that "[t]his study thus represents an important advance in our understanding of human handedness and offers mechanistic insights into the observed correlations between chirality and microtubules in the brain, and suggests an overlap of genetic architecture between handedness and certain neurodegenerative and psychiatric phenotypes."
