Simon E. Fisher

Dyslexia is a common neurodevelopmental condition characterized by persistent difficulties in reading and spelling. Although social and emotional challenges have been reported in individuals with dyslexia, the genetic relationships between dyslexia, social functioning, and well-being remain poorly understood. We combined phenotypic and genetic data from the Lifelines cohort with publicly available genome-wide association study (GWAS) summary statistics. Associations between dyslexia and social traits were examined using a multi-layered approach encompassing complementary methods, including phenotypic correlation analyses, polygenic score (PGS) analyses, linkage disequilibrium score regression (LDSC), and bidirectional two-sample Mendelian randomization (MR). Correlation analyses revealed significant phenotypic and genetic correlations between dyslexia and several social traits, including lower levels of life satisfaction, higher levels of loneliness, and less collegial support on the work floor. PGS analyses demonstrated that genetic liability to dyslexia predicted lower life satisfaction and reduced support from colleagues in the workplace, whereas none of the social-based PGSs predicted dyslexia. Bidirectional MR analyses provided evidence that genetic liability to dyslexia contributes to increased loneliness and social isolation, while no evidence was found for causal effects of social-interaction or well-being traits on dyslexia. Together, our results consistently supported a directional relationship from dyslexia toward social and well-being outcomes. In conclusion, our findings demonstrate that dyslexia shares genetic influences with social interaction and well-being traits and suggest that genetic liability for dyslexia contributes to adverse (psycho)social outcomes. These results extend the impact of dyslexia beyond literacy-related difficulties and highlight the importance of providing social and structural support to individuals with dyslexia throughout the lifespan.

Cortical volume, a widely-used marker of brain aging, is the product of two genetically and developmentally dissociable morphometric features: thickness and area. However, it remains unclear whether these two features have dissociable consequences for cognitive aging. To address this, we analyze cross-sectional and longitudinal neuroimaging and cognitive data from one discovery cohort (Cam-CAN) and two independent, pre-registered replication cohorts (OASIS-3 and HABS-HD), leveraging wide age ranges across adulthood, different follow-up intervals and diverse population backgrounds. We show that thickness declines more steeply with age than does area, and shows stronger associations with longitudinal change in fluid cognitive abilities, fairly uniformly across the cortex. Cognitive change is also dependent on baseline thickness, independent of thickness change and independent of baseline cognitive ability. In contrast, area is comparatively stable across adulthood, at least until old age, and shows weaker and more heterogeneous associations with cognitive change. Together, these findings help to reconcile inconsistencies in the literature, and indicate that thickness provides a more sensitive marker of dynamic neurobiological processes underlying cognitive aging, whereas area seems to reflect primarily stable, trait-like variation in cognitive ability.

Social behaviour is a heritable trait linked to well-being and mental health, yet it varies across social context, including social domains, informants and development, which may shape its underlying genomic architecture. Here, we conducted a genome-wide meta-regression meta-analysis of social behaviour from infancy to early adulthood, studying ~500,000 repeated measures in European-ancestry cohorts ( N = 73,321). We modelled heterogeneity in single-variant associations across social domains (low prosocial behaviour and peer/social difficulties), multiple informants (parents, teachers and self-reports) and ages (2–29 years), identifying 6 associated loci, including variation within CADM2 ( P = 2.51 × 10 ⁻⁹ ). Single nucleotide polymorphism-based heritability ranged from 2% to 7%, and the genetic architecture comprised 4 factors reflecting differences in either social domains or informants. Polygenic scores ( N = 16,305) accurately predicted contextual variation in independent cohorts, with some cross-ancestry transferability. Context-specific patterns of genetic correlations, particularly when estimating the developmental onset of associations, offer opportunities to disentangle shared trajectories linking social behaviour with later-life and mental health outcomes.

A developmental language disorder (DLD) is a neurobiological condition characterized by impaired language development despite adequate linguistic input and normal intelligence. The role of monogenic causes in the pathogenesis of DLD is largely unknown and diagnostic genetic testing is rarely offered. This study assessed the diagnostic yield of genome sequencing in severe DLD and investigated the underlying genetic foundations. We designed a prospective cohort study involving trio-based genome sequencing in 25 individuals (aged 3–25 years) with severe DLD, no intellectual disability (non-verbal IQ ≥ 70), no autism spectrum disorder diagnosis and no first-degree family history of DLD or neurodevelopmental disorders. (Likely) pathogenic variants were found in nine of 25 individuals, reflecting a molecular diagnostic yield of 36%. The genetic causes were diverse and involved seven autosomal dominant disorders, one autosomal recessive disorder, and one sex chromosome aneuploidy. In seven individuals, the disease-causing variant occurred de novo. All identified (likely) pathogenic variants were located in genes or loci that have been previously implicated in neurodevelopmental disorders with variable clinical presentations. Importantly, the genetic diagnosis provided actionable insights for counselling and clinical follow-up for all nine individuals. This study reveals a high prevalence of rare (mainly de novo) genetic variants in individuals with severe and sporadic DLD, and demonstrates extensive molecular overlap with other neurodevelopmental disorders. Our results support the implementation of routine trio-based genetic testing in individuals with severe and sporadic DLD.

Cortical volume, a widely-used marker of brain ageing, is the product of two genetically and developmentally dissociable morphometric features: thickness and area. However, it remains unclear whether these two features have dissociable consequences for cognitive ageing. To address this, we analyse cross-sectional and longitudinal neuroimaging and cognitive data from one discovery cohort (Cam-CAN) and two independent, pre-registered replication cohorts (OASIS-3 and HABS-HD), leveraging wide age ranges across adulthood, different follow-up intervals and diverse population backgrounds. We show that thickness declines more steeply with age than does area, and shows stronger associations with longitudinal change in fluid cognitive abilities, fairly uniformly across the cortex. Cognitive change is also dependent on baseline thickness, independent of thickness change and independent of baseline cognitive ability. In contrast, area is comparatively stable across adulthood, at least until old age, and shows weaker and more heterogeneous associations with cognitive change. Together, these findings help to reconcile inconsistencies in the literature, and indicate that thickness provides a more sensitive marker of dynamic neurobiological processes underlying cognitive ageing, whereas area seems to reflect primarily stable, trait-like variation in cognitive ability.

The uniquely human capacity for language is supported by a distributed brain network with cerebral cortical hubs in the left inferior frontal gyrus (LIFG) and left superior temporal sulcus (LSTS). Individual differences in the graded spatial organization of function across these regions may provide sensitive phenotypes for behavioural and genetic association analyses, to better understand the biological underpinnings of language. In 41,437 UK Biobank participants we applied connectopic mapping to the LIFG and LSTS. This approach maps spatial changes across a region in terms of connectivity with the rest of the brain, based on resting state functional imaging. On average, we found that Brodmann Area (BA) 44, BA 45 and the posterior LSTS were strongly connected to the superior and inferior parietal lobe and the dorsal attention and frontoparietal networks, whereas BA 47 and the medial LSTS were strongly connected to superior frontal areas BA 8B and BA 9, and the default mode network more broadly. However, there was extensive population-wide variation in these graded connectopic patterns, which significantly mediated the effects of polygenic scores for reading ability and educational attainment on performance on a vocabulary task. Furthermore we identified 3 genomic loci displaying multivariate association patterns with these connectopic maps, one of which coincides with a long non-coding RNA, LINC01165 , with potential relevance in human evolution. Overall, connectopic mapping produced fewer significant genetic association findings and lower heritability (range from 0.3 to 9.4%) than previous parcel-based approaches for mapping language network connectivity. These observations suggest higher genetic complexity and/or prominent roles for environmental or random developmental effects on these connectopic maps.

Art can evoke strong emotional responses in humans. Here, we examine genetic contributions to chills, a marker of such responses. We gather self-reports from a genotyped sample of thousands of partly related individuals from the Netherlands ( n = 15,606). Using genomic relationships based on common single-nucleotide polymorphism (SNP) data, we find that up to 29% of the variation in proneness to aesthetic (visual art and poetry) and music chills can be explained by familial relatedness effects, one-fourth of which is attributed to SNP variation. Furthermore, we reveal a moderate genetic correlation of .58 between aesthetic and music chills, pointing to shared genetic variation affecting susceptibility to strong emotional responses across different art forms. Finally, we find that a polygenic index (PGI) for openness to experience ( n = 220,015) is associated with susceptibilities to both aesthetic and music chills. Our results show that additive genetic variation, but also familial relatedness beyond shared common SNPs, contributes to proneness to chills from artistic, poetic, and musical expressions. These results open up a promising path towards studying the human attitude towards art, via both state-of-the-art genomics and intergenerational models of transmission.

Sleep disturbances are among the most prevalent clinical features of FOXP1 syndrome, yet their nature and underlying mechanisms remain unclear. Here, we report that individuals with FOXP1 syndrome suffer from insomnia with sleep maintenance problems and early waking. Consistently, common variants in FOXP genes were associated with insomnia symptoms and short sleep. These sleep disturbances were recapitulated in Drosophila FoxP mutants, which exhibit severely fragmented and reduced sleep. FoxP loss also led to circadian arrhythmicity and impaired the plasticity of neuropeptide pigment dispersing factor–secreting (PDF-secreting) neurons in a non-cell-autonomous manner. FoxP was required during development for adult sleep integrity, particularly in peptidergic neurons. Transcriptomic analyses revealed a dysregulation of genes involved in peptidergic signaling, including hugin . FoxP was expressed in hugin ⁺ neurons (afferent to PDF-secreting neurons) during development, and its knockdown in these cells was sufficient to induce sleep fragmentation. Our findings establish an evolutionarily conserved role for FOXP proteins in the peptidergic regulation of sleep.

Brain structure and function have largely been studied separately in relation to the neurobiology and genetics of language. Here we used linked independent component analysis to integrate language network functional connectivity with brain volumetric and white matter structure in 32,677 UK Biobank participants, followed by analysis of behavioural, neurobiological and genetic correlates of the derived multimodal structure-function imaging components. Stronger functional connectivity between brain language areas was associated with increased volume of parts of the cerebellum and motor cortex, together with smaller ventricles and sensory parietal and occipital areas. The brain structure-function language components mediated an association between vocabulary level and polygenic scores for reading ability. We report 18 genomic loci associated with brain structure-function language components. Single-nucleotide polymorphism (SNP)-based heritability estimates for these components were 23-30%, and there was significant enrichment of heritability in primate-conserved genomic loci and fetal brain human-gained enhancer elements. This study revealed that structural correlates of functional language network connectivity extend well beyond previously defined language areas of the brain, and highlights the value of multimodal brain phenotyping for human neurogenetic discovery.

Advances in paleogenetics allowed the identification of protein-coding changes unique to Homo sapiens by comparing present-day and archaic hominin genomes. So far, experimental validation has been restricted to functional assays and model organisms. Large-scale biobanking now makes it possible to directly assess phenotypic consequences in living adults. Querying exomes of 455,000 UK Biobank participants at 37 sites with supposedly fixed human-specific changes, we identified 103 carriers at 17 positions, with variable allele counts across ancestries. We performed phenotypic evaluations for two example changes. Individuals carrying archaic SSH2 alleles showed no clear deviations in an array of health, neuropsychiatric, and cognitive traits. Carriers of a TKTL1 missense variant, previously linked to large effects on cortical neurogenesis, showed no obvious differences in brain anatomy, with many carriers holding college degrees. Our study demonstrates challenges associated with individual interrogation of key sites when seeking insights into the evolution of complex human traits and highlights the importance of including diverse ancestries in biobanking efforts.