Publications

Abstract

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6–19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06–1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Abstract

Pairwise maximum likelihood (PML) estimation is a promising method for multilevel models with discrete responses. Multilevel models take into account that units within a cluster tend to be more alike than units from different clusters. The pairwise likelihood is then obtained as the product of bivariate likelihoods for all within-cluster pairs of units and items. In this study, we investigate the PML estimation method with computationally intensive multilevel random intercept and random slope structural equation models (SEM) in discrete data. In pursuing this, we first reconsidered the general ‘wide format’ (WF) approach for SEM models and then extend the WF approach with random slopes. In a small simulation study we the determine accuracy and efficiency of the PML estimation method by varying the sample size (250, 500, 1000, 2000), response scales (two-point, four-point), and data-generating model (mediation model with three random slopes, factor model with one and two random slopes). Overall, results show that the PML estimation method is capable of estimating computationally intensive random intercept and random slopes multilevel models in the SEM framework with discrete data and many (six or more) latent variables with satisfactory accuracy and efficiency. However, the condition with 250 clusters combined with a two-point response scale shows more bias.

Abstract

The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrophy probands. A total of 858 probands were collected from 26 centers, of whom 722 carried no or one pathogenic ABCA4 variant while 136 cases carried two ABCA4 alleles, one of which was a frequent mild variant, suggesting that deep-intronic variants (DIVs) or other cis-modifiers might have been missed. After single molecule molecular inversion probes (smMIPs)-based sequencing of the complete 128-kb ABCA4 locus, the effect of putative splice variants was assessed in vitro by midigene splice assays in HEK293T cells. The breakpoints of copy number variants (CNVs) were determined by junction PCR and Sanger sequencing. ABCA4 sequence analysis solved 207/520 (39.8%) naïve or unsolved cases and 70/202 (34.7%) monoallelic cases, while additional causal variants were identified in 54/136 (39.7%) of probands carrying two variants. Seven novel DIVs and six novel non-canonical splice site variants were detected in a total of 35 alleles and characterized, including the c.6283-321C>G variant leading to a complex splicing defect. Additionally, four novel CNVs were identified and characterized in five alleles. These results confirm that smMIPs-based sequencing of the complete ABCA4 gene provides a cost-effective method to genetically solve retinopathy cases and that several rare structural and splice altering defects remain undiscovered in STGD1 cases.

Abstract

Several molecular and phenotypic algorithms exist that establish genotype–phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore’s ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype–phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally.

Abstract

Lifelong graph learning deals with the problem of continually adapting graph neural network (GNN) models to changes in evolving graphs. We address two critical challenges of lifelong graph learning in this work: dealing with new classes and tackling imbalanced class distributions. The combination of these two challenges is particularly relevant since newly emerging classes typically resemble only a tiny fraction of the data, adding to the already skewed class distribution. We make several contributions: First, we show that the amount of unlabeled data does not influence the results, which is an essential prerequisite for lifelong learning on a sequence of tasks. Second, we experiment with different label rates and show that our methods can perform well with only a tiny fraction of annotated nodes. Third, we propose the gDOC method to detect new classes under the constraint of having an imbalanced class distribution. The critical ingredient is a weighted binary cross-entropy loss function to account for the class imbalance. Moreover, we demonstrate combinations of gDOC with various base GNN models such as GraphSAGE, Simplified Graph Convolution, and Graph Attention Networks. Lastly, our k-neighborhood time difference measure provably normalizes the temporal changes across different graph datasets. With extensive experimentation, we find that the proposed gDOC method is consistently better than a naive adaption of DOC to graphs. Specifically, in experiments using the smallest history size, the out-of-distribution detection score of gDOC is 0.09 compared to 0.01 for DOC. Furthermore, gDOC achieves an Open-F1 score, a combined measure of in-distribution classification and out-of-distribution detection, of 0.33 compared to 0.25 of DOC (32% increase).

Abstract

Schizophrenia is a debilitating psychiatric disorder associated with a reduced fertility and decreased life expectancy, yet common predisposing variation substantially contributes to the onset of the disorder, which poses an evolutionary paradox. Previous research has suggested balanced selection, a mechanism by which schizophrenia risk alleles could also provide advantages under certain environments, as a reliable explanation. However, recent studies have shown strong evidence against a positive selection of predisposing loci. Furthermore, evolutionary pressures on schizophrenia risk alleles could have changed throughout human history as new environments emerged. Here in this study, we used 1000 Genomes Project data to explore the relationship between schizophrenia predisposing loci and recent natural selection (RNS) signatures after the human diaspora out of Africa around 100,000 years ago on a genome-wide scale. We found evidence for significant enrichment of RNS markers in derived alleles arisen during human evolution conferring protection to schizophrenia. Moreover, both partitioned heritability and gene set enrichment analyses of mapped genes from schizophrenia predisposing loci subject to RNS revealed a lower involvement in brain and neuronal related functions compared to those not subject to RNS. Taken together, our results suggest non-antagonistic pleiotropy as a likely mechanism behind RNS that could explain the persistence of schizophrenia common predisposing variation in human populations due to its association to other non-psychiatric phenotypes.

Abstract

The search for molecular underpinnings of human vocal communication has focused on genes encoding forkhead-box transcription factors, as rare disruptions of FOXP1, FOXP2, and FOXP4 have been linked to disorders involving speech and language deficits. In male songbirds, an animal model for vocal learning, experimentally altered expression levels of these transcription factors impair song production learning. The relative contributions of auditory processing, motor function or auditory-motor integration to the deficits observed after different FoxP manipulations in songbirds are unknown. To examine the potential effects on auditory learning and development, we focused on female zebra finches (Taeniopygia guttata) that do not sing but develop song memories, which can be assayed in operant preference tests. We tested whether the relatively high levels of FoxP1 expression in forebrain areas implicated in female song preference learning are crucial for the development and/or maintenance of this behavior. Juvenile and adult female zebra finches received FoxP1 knockdowns targeted to HVC (proper name) or to the caudomedial mesopallium (CMM). Irrespective of target site and whether the knockdown took place before (juveniles) or after (adults) the sensitive phase for song memorization, all groups preferred their tutor’s song. However, adult females with FoxP1 knockdowns targeted at HVC showed weaker motivation to hear song and weaker song preferences than sham-treated controls, while no such differences were observed after knockdowns in CMM or in juveniles. In summary, FoxP1 knockdowns in the cortical song nucleus HVC were not associated with impaired tutor song memory but reduced motivation to actively request tutor songs.

Abstract

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials.

Abstract

The expansion of the cerebral cortex is one of the most distinctive changes in the evolution of the human brain. Cortical expansion and related increases in cortical folding may have contributed to emergence of our capacities for high-order cognitive abilities. Molecular analysis of humans, archaic hominins, and non-human primates has allowed identification of chromosomal regions showing evolutionary changes at different points of our phylogenetic history. In this study, we assessed the contributions of genomic annotations spanning 30 million years to human sulcal morphology measured via MRI in more than 18,000 participants from the UK Biobank. We found that variation within brain-expressed human gained enhancers, regulatory genetic elements that emerged since our last common ancestor with Old World monkeys, explained more trait heritability than expected for the left and right calloso-marginal posterior fissures and the right central sulcus. Intriguingly, these are sulci that have been previously linked to the evolution of locomotion in primates and later on bipedalism in our hominin ancestors.

Abstract

Background
Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition.

Methods
Here we phenotyped 29 individuals from 18 families with pathogenic FOXP2-only variants (13 loss-of-function, 5 missense variants; 14 males; aged 2 years to 62 years). Health and development (cognitive, motor, social domains) was examined, including speech and language outcomes with the first cross-linguistic analysis of English and German.

Results
Speech disorders were prevalent (24/26, 92%) and CAS was most common (23/26, 89%), with similar speech presentations across English and German. Speech was still impaired in adulthood and some speech sounds (e.g. ‘th’, ‘r’, ‘ch’, ‘j’) were never acquired. Language impairments (22/26, 85%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (14/27, 52%) and gross (14/27, 52%) motor impairment, anxiety (6/28, 21%), depression (7/28, 25%), and sleep disturbance (11/15, 44%). Physical features were common (23/28, 82%) but with no consistent pattern. Cognition ranged from average to mildly impaired, and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition.

Conclusions
Although we identify increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared to other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entrypoint for examining the neurobiological bases of speech disorder.

Abstract

Mice display a wide repertoire of vocalizations that varies with sex, strain, and context. Especially during social interaction, including sexually motivated dyadic interaction, mice emit sequences of ultrasonic vocalizations (USVs) of high complexity. As animals of both sexes vocalize, a reliable attribution of USVs to their emitter is essential. The state-of-the-art in sound localization for USVs in 2D allows spatial localization at a resolution of multiple centimeters. However, animals interact at closer ranges, e.g. snout-to-snout. Hence, improved algorithms are required to reliably assign USVs. We present a novel algorithm, SLIM (Sound Localization via Intersecting Manifolds), that achieves a 2–3-fold improvement in accuracy (13.1–14.3 mm) using only 4 microphones and extends to many microphones and localization in 3D. This accuracy allows reliable assignment of 84.3% of all USVs in our dataset. We apply SLIM to courtship interactions between adult C57Bl/6J wildtype mice and those carrying a heterozygous Foxp2 variant (R552H). The improved spatial accuracy reveals that vocalization behavior is dependent on the spatial relation between the interacting mice. Female mice vocalized more in close snout-to-snout interaction while male mice vocalized more when the male snout was in close proximity to the female's ano-genital region. Further, we find that the acoustic properties of the ultrasonic vocalizations (duration, Wiener Entropy, and sound level) are dependent on the spatial relation between the interacting mice as well as on the genotype. In conclusion, the improved attribution of vocalizations to their emitters provides a foundation for better understanding social vocal behaviors.

Abstract

Background

Autistic people show diverse trajectories of autistic traits over time, a phenomenon labelled ‘chronogeneity’. For example, some show a decrease in symptoms, whilst others experience an intensification of difficulties. Autism spectrum disorder (ASD) is a dimensional condition, representing one end of a trait continuum that extends throughout the population. To date, no studies have investigated chronogeneity across the full range of autistic traits. We investigated the nature and clinical significance of autism trait chronogeneity in a large, general population sample.
Methods

Autistic social/communication traits (ASTs) were measured in the Avon Longitudinal Study of Parents and Children using the Social and Communication Disorders Checklist (SCDC) at ages 7, 10, 13 and 16 (N = 9744). We used Growth Mixture Modelling (GMM) to identify groups defined by their AST trajectories. Measures of ASD diagnosis, sex, IQ and mental health (internalising and externalising) were used to investigate external validity of the derived trajectory groups.
Results

The selected GMM model identified four AST trajectory groups: (i) Persistent High (2.3% of sample), (ii) Persistent Low (83.5%), (iii) Increasing (7.3%) and (iv) Decreasing (6.9%) trajectories. The Increasing group, in which females were a slight majority (53.2%), showed dramatic increases in SCDC scores during adolescence, accompanied by escalating internalising and externalising difficulties. Two-thirds (63.6%) of the Decreasing group were male.
Conclusions

Clinicians should note that for some young people autism-trait-like social difficulties first emerge during adolescence accompanied by problems with mood, anxiety, conduct and attention. A converse, majority-male group shows decreasing social difficulties during adolescence.

Abstract

Human communication involves the process of translating intentions into communicative actions. But how exactly do our intentions surface in the visible communicative behavior we display? Here we focus on pointing gestures, a fundamental building block of everyday communication, and investigate whether and how different types of underlying intent modulate the kinematics of the pointing hand and the brain activity preceding the gestural movement. In a dynamic virtual reality environment, participants pointed at a referent to either share attention with their addressee, inform their addressee, or get their addressee to perform an action. Behaviorally, it was observed that these different underlying intentions modulated how long participants kept their arm and finger still, both prior to starting the movement and when keeping their pointing hand in apex position. In early planning stages, a neurophysiological distinction was observed between a gesture that is used to share attitudes and knowledge with another person versus a gesture that mainly uses that person as a means to perform an action. Together, these findings suggest that our intentions influence our actions from the earliest neurophysiological planning stages to the kinematic endpoint of the movement itself.

Abstract

The structural design features of human language emerge in the process of cultural evolution, shaping languages over the course of communication, learning, and transmission. What role does this leave biological evolution? This chapter highlights the biological bases and preconditions that underlie the particular type of prosocial behaviours and cognitive inference abilities that are required for languages to emerge via cultural evolution to begin with.

Abstract

Humans are unique in their sophisticated culture and societal structures, their complex languages, and their extensive tool use. According to the human self-domestication hypothesis, this unique set of traits may be the result of an evolutionary process of self-induced domestication, in which humans evolved to be less aggressive and more cooperative. However, the only other species that has been argued to be self-domesticated besides humans so far is bonobos, resulting in a narrow scope for investigating this theory limited to the primate order. Here, we propose an animal model for studying self-domestication: the elephant. First, we support our hypothesis with an extensive cross-species comparison, which suggests that elephants indeed exhibit many of the features associated with self-domestication (e.g., reduced aggression, increased prosociality, extended juvenile period, increased playfulness, socially regulated cortisol levels, and complex vocal behavior). Next, we present genetic evidence to reinforce our proposal, showing that genes positively selected in elephants are enriched in pathways associated with domestication traits and include several candidate genes previously associated with domestication. We also discuss several explanations for what may have triggered a self-domestication process in the elephant lineage. Our findings support the idea that elephants, like humans and bonobos, may be self-domesticated. Since the most recent common ancestor of humans and elephants is likely the most recent common ancestor of all placental mammals, our findings have important implications for convergent evolution beyond the primate taxa, and constitute an important advance toward understanding how and why self-domestication shaped humans’ unique cultural niche.

Abstract

Cortical asymmetry is a ubiquitous feature of brain organization that is altered in neurodevelopmental disorders and aging. Achieving consensus on cortical asymmetries in humans is necessary to uncover the genetic-developmental mechanisms that shape them and factors moderating cortical lateralization. Here, we delineate population-level asymmetry in cortical thickness and surface area vertex-wise in 7 datasets and chart asymmetry trajectories across life (4-89 years; observations = 3937; 70% longitudinal). We reveal asymmetry interrelationships, heritability, and test associations in UK Biobank (N=∼37,500). Cortical asymmetry was robust across datasets. Whereas areal asymmetry is predominantly stable across life, thickness asymmetry grows in development and declines in aging. Areal asymmetry correlates in specific regions, whereas thickness asymmetry is globally interrelated across cortex and suggests high directional variability in global thickness lateralization. Areal asymmetry is moderately heritable (max h2SNP ∼19%), and phenotypic correlations are reflected by high genetic correlations, whereas heritability of thickness asymmetry is low. Finally, we detected an asymmetry association with cognition and confirm recently-reported handedness links. Results suggest areal asymmetry is developmentally stable and arises in early life, whereas developmental changes in thickness asymmetry may lead to directional variability of global thickness lateralization. Our results bear enough reproducibility to serve as a standard for future brain asymmetry studies.

Abstract

Purpose: To determine the disease pathogenesis associated with the frequent ABCA4 variant c.5714+5G>A (p.[=,Glu1863Leufs*33]).

Methods: Patient-derived photoreceptor precursor cells were generated to analyze the effect of c.5714+5G>A on splicing and perform a quantitative analysis of c.5714+5G>A products. Patients with c.5714+5G>A in trans with a null allele (i.e., c.5714+5G>A patients; n = 7) were compared with patients with two null alleles (i.e., double null patients; n = 11); with a special attention to the degree of RPE atrophy (area of definitely decreased autofluorescence and the degree of photoreceptor impairment (outer nuclear layer thickness and pattern electroretinography amplitude).

Results: RT-PCR of mRNA from patient-derived photoreceptor precursor cells showed exon 40 and exon 39/40 deletion products, as well as the normal transcript. Quantification of products showed 52.4% normal and 47.6% mutant ABCA4 mRNA. Clinically, c.5714+5G>A patients displayed significantly better structural and functional preservation of photoreceptors (thicker outer nuclear layer, presence of tubulations, higher pattern electroretinography amplitude) than double null patients with similar degrees of RPE loss, whereas double null patients exhibited signs of extensive photoreceptor ,damage even in the areas with preserved RPE.

Conclusions: The prototypical STGD1 sequence of events of primary RPE and secondary photoreceptor damage is congruous with c.5714+5G>A, but not the double null genotype, which implies different and genotype-dependent disease mechanisms. We hypothesize that the relative photoreceptor sparing in c.5714+5G>A patients results from the remaining function of the ABCA4 transporter originating from the normally spliced product, possibly by decreasing the direct bisretinoid toxicity on photoreceptor membranes.

Abstract

Left–right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case–control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case–control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case–control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case–control status. Subtle case–control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Abstract

White matter tracts form the structural basis of large-scale brain networks. We applied brain-wide tractography to diffusion images from 30,810 adults (U.K. Biobank) and found significant heritability for 90 node-level and 851 edge-level network connectivity measures. Multivariate genome-wide association analyses identified 325 genetic loci, of which 80% had not been previously associated with brain metrics. Enrichment analyses implicated neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes, microglia, and neurons. The multivariate association profiles implicated 31 loci in connectivity between core regions of the left-hemisphere language network. Polygenic scores for psychiatric, neurological, and behavioral traits also showed significant multivariate associations with structural connectivity, each implicating distinct sets of brain regions with trait-relevant functional profiles. This large-scale mapping study revealed common genetic contributions to variation in the structural connectome of the human brain.

Abstract

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals, and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (N=11), intellectual disability (N=9), epilepsy (N=7) and autism spectrum disorder (N=4). Additional phenotypic features included abnormal growth parameters (N=7), heart anomalies (N=2) and hearing loss (N=2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

Abstract

Background: The hypothalamus-pituitary-thyroid axis coordinates brain development and postdevelopmental function. Thyroid hormone (TH) variations, even within the normal range, have been associated with the risk of developing common psychiatric disorders, although the underlying mechanisms remain poorly understood.

Methods: To get new insight into the potentially shared mechanisms underlying thyroid dysfunction and psychiatric disorders, we performed a comprehensive analysis of multiple phenotypic and genotypic databases. We investigated the relationship of thyroid disorders with depression, bipolar disorder (BIP), and anxiety disorders (ANXs) in 497,726 subjects from U.K. Biobank. We subsequently investigated genetic correlations between thyroid disorders, thyrotropin (TSH), and free thyroxine (fT4) levels, with the genome-wide factors that predispose to psychiatric disorders. Finally, the observed global genetic correlations were furthermore pinpointed to specific local genomic regions.

Results: Hypothyroidism was positively associated with an increased risk of major depressive disorder (MDD; OR = 1.31, p = 5.29 × 10−89), BIP (OR = 1.55, p = 0.0038), and ANX (OR = 1.16, p = 6.22 × 10−8). Hyperthyroidism was associated with MDD (OR = 1.11, p = 0.0034) and ANX (OR = 1.34, p = 5.99 × 10−⁶). Genetically, strong coheritability was observed between thyroid disease and both major depressive (rg = 0.17, p = 2.7 × 10−⁴) and ANXs (rg = 0.17, p = 6.7 × 10−⁶). This genetic correlation was particularly strong at the major histocompatibility complex locus on chromosome 6 (p < 10−⁵), but further analysis showed that other parts of the genome also contributed to this global effect. Importantly, neither TSH nor fT4 levels were genetically correlated with mood disorders.

Conclusions: Our findings highlight an underlying association between autoimmune hypothyroidism and mood disorders, which is not mediated through THs and in which autoimmunity plays a prominent role. While these findings could shed new light on the potential ineffectiveness of treating (minor) variations in thyroid function in psychiatric disorders, further research is needed to identify the exact underlying molecular mechanisms.

Abstract

TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein–protein interaction.

Abstract

When experienced in-person, engagement with art has been associated with positive outcomes in well-being and mental health. However, especially in the last decade, art viewing, cultural engagement, and even ‘trips’ to museums have begun to take place online, via computers, smartphones, tablets, or in virtual reality. Similarly, to what has been reported for in-person visits, online art engagements—easily accessible from personal devices—have also been associated to well-being impacts. However, a broader understanding of for whom and how online-delivered art might have well-being impacts is still lacking. In the present study, we used a Monet interactive art exhibition from Google Arts and Culture to deepen our understanding of the role of pleasure, meaning, and individual differences in the responsiveness to art. Beyond replicating the previous group-level effects, we confirmed our pre-registered hypothesis that trait-level inter-individual differences in aesthetic responsiveness predict some of the benefits that online art viewing has on well-being and further that such inter-individual differences at the trait level were mediated by subjective experiences of pleasure and especially meaningfulness felt during the online-art intervention. The role that participants' experiences play as a possible mechanism during art interventions is discussed in light of recent theoretical models.

Abstract

What determines the aesthetic appeal of artworks? Recent work suggests that aesthetic appeal can, to some extent, be predicted from a visual artwork’s image features. Yet a large fraction of variance in aesthetic ratings remains unexplained and may relate to individual preferences. We hypothesized that an artwork’s aesthetic appeal depends strongly on self-relevance. In a first study (N = 33 adults, online replication N = 208), rated aesthetic appeal for real artworks was positively predicted by rated self-relevance. In a second experiment (N = 45 online), we created synthetic, self-relevant artworks using deep neural networks that transferred the style of existing artworks to photographs. Style transfer was applied to self-relevant photographs selected to reflect participant-specific attributes such as autobiographical memories. Self-relevant, synthetic artworks were rated as more aesthetically appealing than matched control images, at a level similar to human-made artworks. Thus, self-relevance is a key determinant of aesthetic appeal, independent of artistic skill and image features.

Abstract

Laterality indices (LIs) quantify the left-right asymmetry of brain and behavioural variables and provide a measure that is statistically convenient and seemingly easy to interpret. Substantial variability in how structural and functional asymmetries are recorded, calculated, and reported, however, suggest little agreement on the conditions required for its valid assessment. The present study aimed for consensus on general aspects in this context of laterality research, and more specifically within a particular method or technique (i.e., dichotic listening, visual half-field technique, performance asymmetries, preference bias reports, electrophysiological recording, functional MRI, structural MRI, and functional transcranial Doppler sonography). Experts in laterality research were invited to participate in an online Delphi survey to evaluate consensus and stimulate discussion. In Round 0, 106 experts generated 453 statements on what they considered good practice in their field of expertise. Statements were organised into a 295-statement survey that the experts then were asked, in Round 1, to independently assess for importance and support, which further reduced the survey to 241 statements that were presented again to the experts in Round 2. Based on the Round 2 input, we present a set of critically reviewed key recommendations to record, assess, and report laterality research for various methods.

Abstract

Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.

Abstract

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Abstract

Q fever, caused by Coxiella burnetii, is a zoonosis with a worldwide distribution. A large rural area in the southeast of the Netherlands was heavily affected by Q fever between 2007 and 2009. This initiated the development of a robust and internally controlled multiplex quantitative PCR (qPCR) assay for the detection of C. burnetii DNA in veterinary and environmental matrices on suspected Q fever-affected farms. The qPCR detects three C. burnetii targets (icd, com1, and IS1111) and one Bacillus thuringiensis internal control target (cry1b). Bacillus thuringiensis spores were added to samples to control both DNA extraction and PCR amplification. The performance of the qPCR assay was investigated and showed a high efficiency; a limit of detection of 13.0, 10.6, and 10.4 copies per reaction for the targets icd, com1, and IS1111, respectively; and no crossreactivity with the nontarget organisms tested. Screening for C. burnetii DNA on 29 suspected Q fever-affected farms during the Q fever epidemic in 2008 showed that swabs from dust-accumulating surfaces contained higher levels of C. burnetii DNA than vaginal swabs from goats or sheep. PCR inhibition by coextracted substances was observed in some environmental samples, and 10- or 100-fold dilutions of samples were sufficient to obtain interpretable signals for both the C. burnetii targets and the internal control. The inclusion of an internal control target and three C. burnetii targets in one multiplex qPCR assay showed that complex veterinary and environmental matrices can be screened reliably for the presence of C. burnetii DNA during an outbreak. © 2011, American Society for Microbiology.

Abstract

Use of peripheral blood- or bone marrow-derived progenitors for ischemic heart repair is a feasible option to induce neo-vascularization in ischemic tissues. These cells, named Endothelial Progenitors Cells (EPCs), have been extensively characterized phenotypically and functionally. The clinical efficacy of cardiac repair by EPCs cells remains, however, limited, due to cell autonomous defects as a consequence of risk factors. The devise of “enhancement” strategies has been therefore sought to improve repair ability of these cells and increase the clinical benefit

Abstract

It is generally accepted that the relationship between human genes
and language is very complex and multifaceted. This has its roots in the
“regular” complexity governing the interplay among genes and between genes
and environment for most phenotypes, but with the added layer of supraontogenetic
and supra-individual processes defining culture. At the coarsest
level, focusing on the species, it is clear that human-specific—but not necessarily
faculty-specific—genetic factors subtend our capacity for language and a
currently very productive research program is aiming at uncovering them. At the
other end of the spectrum, it is uncontroversial that individual-level variations in
different aspects related to speech and language have an important genetic
component and their discovery and detailed characterization have already started
to revolutionize the way we think about human nature. However, at the
intermediate, glossogenetic/population level, the relationship becomes controversial,
partly due to deeply ingrained beliefs about language acquisition and
universality and partly because of confusions with a different type of genelanguages
correlation due to shared history. Nevertheless, conceptual, mathematical
and computational models—and, recently, experimental evidence from
artificial languages and songbirds—have repeatedly shown that genetic biases
affecting the acquisition or processing of aspects of language and speech can be
amplified by population-level intergenerational cultural processes and made
manifest either as fixed “universal” properties of language or as structured
linguistic diversity. Here, I review several such models as well as the recently
proposed case of a causal relationship between the distribution of tone languages
and two genes related to brain growth and development, ASPM and Microcephalin,
and I discuss the relevance of such genetic biasing for language
evolution, change, and diversity.

Abstract

Language is a hallmark of our species and understanding linguistic diversity is an area of major interest. Genetic factors influencing the cultural transmission of language provide a powerful and elegant explanation for aspects of the present day linguistic diversity and a window into the emergence and evolution of language. In particular, it has recently been proposed that linguistic tone—the usage of voice pitch to convey lexical and grammatical meaning—is biased by two genes involved in brain growth and development, ASPM and Microcephalin. This hypothesis predicts that tone is a stable characteristic of language because of its ‘genetic anchoring’. The present paper tests this prediction using a Bayesian phylogenetic framework applied to a large set of linguistic features and language families, using multiple software implementations, data codings, stability estimations, linguistic classifications and outgroup choices. The results of these different methods and datasets show a large agreement, suggesting that this approach produces reliable estimates of the stability of linguistic data. Moreover, linguistic tone is found to be stable across methods and datasets, providing suggestive support for the hypothesis of genetic influences on its distribution.

Abstract

* Deriziotis, P., André, R., and Smith. D.M. contributed equally to this work * - Prion diseases are associated with the conversion of cellular prion protein (PrP(C)) to toxic β-sheet isoforms (PrP(Sc)), which are reported to inhibit the ubiquitin-proteasome system (UPS). Accordingly, UPS substrates accumulate in prion-infected mouse brains, suggesting impairment of the 26S proteasome. A direct interaction between its 20S core particle and PrP isoforms was demonstrated by immunoprecipitation. β-PrP aggregates associated with the 20S particle, but did not impede binding of the PA26 complex, suggesting that the aggregates do not bind to its ends. Aggregated β-PrP reduced the 20S proteasome's basal peptidase activity, and the enhanced activity induced by C-terminal peptides from the 19S ATPases or by the 19S regulator itself, including when stimulated by polyubiquitin conjugates. However, the 20S proteasome was not inhibited when the gate in the α-ring was open due to a truncation mutation or by association with PA26/PA28. These PrP aggregates inhibit by stabilising the closed conformation of the substrate entry channel. A similar inhibition of substrate entry into the proteasome may occur in other neurodegenerative diseases where misfolded β-sheet-rich proteins accumulate.

Abstract

The scavenger receptor C-type lectin (SRCL) is a glycan-binding receptor that has the capacity to mediate endocytosis of glycoproteins carrying terminal Lewis(x) groups (Galβ1-4(Fucα1-3)GlcNAc). A screen for glycoprotein ligands for SRCL using affinity chromatography on immobilized SRCL followed by mass spectrometry-based proteomic analysis revealed that soluble glycoproteins from secondary granules of neutrophils, including lactoferrin and matrix metalloproteinases 8 and 9, are major ligands. Binding competition and surface plasmon resonance analysis showed affinities in the low micromolar range. Comparison of SRCL binding to neutrophil and milk lactoferrin indicates that the binding is dependent on cell-specific glycosylation in the neutrophils, as the milk form of the glycoprotein is a much poorer ligand. Binding to neutrophil glycoproteins is fucose dependent and mass spectrometry-based glycomic analysis of neutrophil and milk lactoferrin was used to establish a correlation between high affinity binding to SRCL and the presence of multiple, clustered terminal Lewis(x) groups on a heterogeneous mixture of branched glycans, some with poly N-acetyllactosamine extensions. The ability of SRCL to mediate uptake of neutrophil lactoferrin was confirmed using fibroblasts transfected with SRCL. The common presence of Lewis(x) groups in granule protein glycans can thus target granule proteins for clearance by SRCL. PCR and immunohistochemical analysis confirms that SRCL is widely expressed on endothelial cells and thus represents a distributed system which could scavenge released neutrophil glycoproteins both locally at sites of inflammation or systemically when they are released in the circulation.

Abstract

The impact of the Neolithic dispersal on the western European populations is subject to continuing debate. To trace and date genetic lineages potentially brought during this transition and so understand the origin of the gene pool of current populations, we studied DNA extracted from human remains excavated in a Spanish funeral cave dating from the beginning of the fifth millennium B.C. Thanks to a “multimarkers” approach based on the analysis of mitochondrial and nuclear DNA (autosomes and Y-chromosome), we obtained information on the early Neolithic funeral practices and on the biogeographical origin of the inhumed individuals. No close kinship was detected. Maternal haplogroups found are consistent with pre-Neolithic settlement, whereas the Y-chromosomal analyses permitted confirmation of the existence in Spain approximately 7,000 y ago of two haplogroups previously associated with the Neolithic transition: G2a and E1b1b1a1b. These results are highly consistent with those previously found in Neolithic individuals from French Late Neolithic individuals, indicating a surprising temporal genetic homogeneity in these groups. The high frequency of G2a in Neolithic samples in western Europe could suggest, furthermore, that the role of men during Neolithic dispersal could be greater than currently estimated.

Abstract

Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity1, 2. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk3. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.

Abstract

The present study explored whether language-nonselective access in bilinguals occurs across word classes in a sentence context. Dutch–English bilinguals were auditorily presented with English (L2) sentences while looking at a visual world. The sentences contained interlingual homophones from distinct lexical categories (e.g., the English verb spoke, which overlaps phonologically with the Dutch noun for ghost, spook). Eye movement recordings showed that depictions of referents of the Dutch (L1) nouns attracted more visual attention than unrelated distractor pictures in sentences containing homophones. This finding shows that native language objects are activated during second language verb processing despite the structural information provided by the sentence context. Research highlights We show that native language words are activated during second language sentence processing. We tested this in a visual world setting on homophones with a different word class across languages. Fixations show that processing second language verbs activated native language nouns.

Abstract

Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (Foxp2) causes deficient cortico-striatal synaptic plasticity and impairs motor-skill learning. Moreover, the songbird orthologue appears critically important for vocal learning. Across diverse vertebrate species, this well-conserved transcription factor is highly expressed in the developing and adult central nervous system. Very little is known about the mechanisms regulated by Foxp2 during brain development. We used an integrated functional genomics strategy to robustly define Foxp2-dependent pathways, both direct and indirect targets, in the embryonic brain. Specifically, we performed genome-wide in vivo ChIP–chip screens for Foxp2-binding and thereby identified a set of 264 high-confidence neural targets under strict, empirically derived significance thresholds. The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections

Abstract

Mutations of the human FOXP2 gene have been shown to cause severe difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech (developmental verbal dyspraxia or DVD). Affected individuals are impaired in multiple aspects of expressive and receptive linguistic processing and ­display abnormal grey matter volume and functional activation patterns in cortical and subcortical brain regions. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerization. This chapter describes the successful use of FOXP2 as a unique molecular window into neurogenetic pathways that are important for speech and language development, adopting several complementary strategies. These include direct functional investigations of FOXP2 splice variants and the effects of etiological mutations. FOXP2’s role as a transcription factor also enabled the development of functional genomic routes for dissecting neurogenetic mechanisms that may be relevant for speech and language. By identifying downstream target genes regulated by FOXP2, it was possible to identify common regulatory themes in modulating synaptic plasticity, neurodevelopment, and axon guidance. These targets represent novel entrypoints into in vivo pathways that may be disturbed in speech and language disorders. The identification of FOXP2 target genes has also led to the discovery of a shared neurogenetic pathway between clinically distinct language disorders; the rare Mendelian form of DVD and a complex and more common form of language ­disorder known as Specific Language Impairment.

Abstract

Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males, 543 emales) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers, and with a consistent direction of effect (rs2710102, p = .0239; rs759178, p = .0248). Based on these findings we performed analyses of four-marker haplotypes of rs2710102- s759178-rs17236239-rs2538976, and identified significant association (haplotype TTAA, p = .049; haplotype GCAG, p = .0014). Our study suggests that common variants in the exon 13-15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors.