The genetic architecture of language functional connectivity

Abstract

Language is a unique trait of the human species, of which the genetic architecture remains largely unknown. Through language disorders studies, many candidate genes were identified. However, such complex and multifactorial trait is unlikely to be driven by only few genes and case-control studies, suffering from a lack of power, struggle to uncover significant variants. In parallel, neuroimaging has significantly contributed to the understanding of structural and functional aspects of language in the human brain and the recent availability of large scale cohorts like UK Biobank have made possible to study language via image-derived endophenotypes in the general population. Because of its strong relationship with task-based fMRI activations and its easiness of acquisition, resting-state functional MRI have been more popularised, making it a good surrogate of functional neuronal processes. Taking advantage of such a synergistic system by aggregating effects across spatially distributed traits, we performed a multivariate genome-wide association study (mvGWAS) between genetic variations and resting-state functional connectivity (FC) of classical brain language areas in the inferior frontal (pars opercularis, triangularis and orbitalis), temporal and inferior parietal lobes (angular and supramarginal gyri), in 32,186 participants from UK Biobank. Twenty genomic loci were found associated with language FCs, out of which three were replicated in an independent replication sample. A locus in 3p11.1, regulating EPHA3 gene expression, is found associated with FCs of the semantic component of the language network, while a locus in 15q14, regulating THBS1 gene expression is found associated with FCs of the perceptual motor language processing, bringing novel insights into the neurobiology of language.

Unraveling the functional attributes of the language connectome: crucial subnetworks, flexibility and variability

“…The functional selectivity of Net1 regions is likely to be inherited from our ancestors and to be part of a language-ready brain (Boeckx & Benítez-Burraco, 2014). They are also supported by a specific brain architecture already present in children (Friederici, 2017) whose functional connectivity is genetically encoded (Mekki et al 2022, for the genetic regulation specifically involved in the perceptual-motor and semantic pathways of language).…”

Genetic architecture of the white matter connectome of the human brain

“…Of the 231 lead SNPs from our brain-wide mvGWAS of tract-wise connectivity, 26 were significantly associated with at least one of these six tracts according to the tract-specific z-scores derived from MOSTest (Bonferroni correction at 0.05; Supplementary Table 23). For example, rs12636275 on 3p11.1 is located within an intron of EPHA3 , a gene that encodes an ephrin receptor subunit that regulates the formation of axon projection maps( 68 ), and has also been associated with functional connectivity between language-related regions( 69 ). Another example: rs7580864 on 2q33.1 is an eQTL of PLCL1 that is implicated in autism( 70, 71 ), a neurodevelopmental disorder that often affects language and social skills.…”

“…We illustrated this by querying the results with respect to six tracts linking four core regions of the left-hemisphere language network – together approximating to Broca’s and Wernicke’s classically defined functional areas( 112 ). Twenty-six implicated loci included the EPHA3 locus, encoding an ephrin receptor subunit that acts a positional guidance cue for the formation of axon projection maps, and has also been associated with functional connectivity between regional components of the language network that are especially involved in semantics( 69 ). This is therefore a concordant genetic finding with respect to both structural and functional connectivity of the human brain’s language network.…”

Atypical language network lateralization is reflected throughout the macroscale functional organization of cortex

“…The genetic origin of language capacities 93 and other properties of hemispheric specialization reflect a fundamental question in cognitive neuroscience with clear relevance for the study of both health and disease 12 . Prior work indicates that intrinsic connectivity between language related regions 94 , as well as evoked brain activations during language tasks 95 , are heritable. Our present analyses indicate a clear genetic basis for population-level patterns of language lateralization and corresponding features of cortical organization.…”