Publications

Abstract

Rhythm and language-related traits are phenotypically correlated, but their genetic overlap is largely unknown. Here, we leveraged two large-scale genome-wide association studies performed to shed light on the shared genetics of rhythm (N=606,825) and dyslexia (N=1,138,870). Our results reveal an intricate shared genetic and neurobiological architecture, and lay groundwork for resolving longstanding debates about the potential co-evolution of human language and musical traits.

Abstract

Humans engage with music for various reasons that range from emotional regulation and relaxation to social bonding. While there are large inter-individual differences in how much humans enjoy music, little is known about the origins of those differences. Here, we disentangle the genetic factors underlying such variation. We collect data on several facets of music reward sensitivity, as measured by the Barcelona Music Reward Questionnaire, plus music perceptual abilities and general reward sensitivity from a large sample of Swedish twins (N = 9169; 2305 complete pairs). We estimate that genetic effects contribute up to 54% of the variability in music reward sensitivity, with 70% of these effects being independent of music perceptual abilities and general reward sensitivity. Furthermore, multivariate analyses show that genetic and environmental influences on the different facets of music reward sensitivity are partly distinct, uncovering distinct pathways to music enjoyment and different patterns of genetic associations with objectively assessed music perceptual abilities. These results paint a complex picture in which partially distinct sources of variation contribute to different aspects of musical enjoyment.

Abstract

Dyslexia is a learning difficulty with neurodevelopmental origins, manifesting as reduced accuracy and speed in reading and spelling. It is substantially heritable and frequently co-occurs with other neurodevelopmental conditions, particularly attention deficit-hyperactivity disorder (ADHD). Here, we investigate the genetic structure underlying dyslexia and a range of psychiatric traits using results from genome-wide association studies of dyslexia, ADHD, autism, anorexia nervosa, anxiety, bipolar disorder, major depressive disorder, obsessive compulsive disorder,
schizophrenia, and Tourette syndrome. Genomic Structural Equation Modelling (GenomicSEM) showed heightened support for a model consisting of five correlated latent genomic factors described as: F1) compulsive disorders (including obsessive-compulsive disorder, anorexia nervosa, Tourette syndrome), F2) psychotic disorder (including bipolar disorder, schizophrenia), F3) internalising disorders (including anxiety disorder, major depressive disorder), F4) neurodevelopmental traits (including autism, ADHD), and F5) attention and learning difficulties (including ADHD, dyslexia). ADHD loaded more strongly on the attention and learning difficulties latent factor (F5) than on the neurodevelopmental traits latent factor (F4). The attention and learning difficulties latent factor (F5) was positively correlated with internalising disorders (.40), neurodevelopmental traits (.25) and psychotic disorders (.17) latent factors, and negatively correlated with the compulsive disorders (–.16) latent factor. These factor correlations are mirrored in genetic correlations observed between the attention and learning difficulties latent factor and other cognitive, psychological and wellbeing traits. We further investigated genetic variants underlying both dyslexia and ADHD, which implicated 49 loci (40 not previously found in GWAS of the individual traits) mapping to 174 genes (121 not found in GWAS of individual traits) as potential pleiotropic variants. Our study confirms the increased genetic relation between dyslexia and ADHD versus other psychiatric traits and uncovers novel pleiotropic variants affecting both traits. In future, analyses including additional co-occurring traits such as dyscalculia and dyspraxia will allow a clearer definition of the attention and learning difficulties latent factor, yielding further insights into factor structure and pleiotropic effects.

Abstract

Apolipoprotein E ε4 is a major genetic risk factor for Alzheimer’s disease, and some apolipoprotein E ε4 carriers show Alzheimer’s disease–related neuropathology many years before cognitive changes are apparent. Therefore, studying healthy apolipoprotein E genotyped individuals offers an opportunity to investigate the earliest changes in brain measures that may signal the presence of disease-related processes. For example, subtle changes in functional magnetic resonance imaging functional connectivity, particularly within the default mode network, have been described when comparing healthy ε4 carriers to ε3 carriers. Similarly, very mild impairments of episodic memory have also been documented in healthy apolipoprotein E ε4 carriers. Here, we use a naturalistic activity (movie watching), and a marker of episodic memory encoding (transient changes in functional magnetic resonance imaging activity and functional connectivity around so-called ‘event boundaries’), to investigate potential phenotype differences associated with the apolipoprotein E ε4 genotype in a large sample of healthy adults. Using Bayes factor analyses, we found strong evidence against existence of differences associated with apolipoprotein E allelic status. Similarly, we did not find apolipoprotein E-associated differences when we ran exploratory analyses examining: functional system segregation across the whole brain, and connectivity within the default mode network. We conclude that apolipoprotein E genotype has little or no effect on how ongoing experiences are processed in healthy adults. The mild phenotype differences observed in some studies may reflect early effects of Alzheimer’s disease–related pathology in apolipoprotein E ε4 carriers.

Abstract

Studies of dyslexia provide vital insights into the cognitive architecture underpinning both disordered and normal reading. It is well established that inherited factors contribute to dyslexia susceptibility, but only very recently has evidence emerged to implicate specific candidate genes. In this article, we provide an accessible overview of four prominent examples--DYX1C1, KIAA0319, DCDC2 and ROBO1--and discuss their relevance for cognition. In each case correlations have been found between genetic variation and reading impairments, but precise risk variants remain elusive. Although none of these genes is specific to reading-related neuronal circuits, or even to the human brain, they have intriguing roles in neuronal migration or connectivity. Dissection of cognitive mechanisms that subserve reading will ultimately depend on an integrated approach, uniting data from genetic investigations, behavioural studies and neuroimaging.

Abstract

The mysterious human propensity for acquiring speech and language has fascinated scientists for decades. A substantial body of evidence suggests that this capacity is rooted in aspects of neurodevelopment that are specified at the genomic level. Researchers have begun to identify genetic factors that increase susceptibility to developmental disorders of speech and language, thereby offering the first molecular entry points into neuronal mechanisms underlying human vocal communication. The identification of genetic variants influencing language acquisition facilitates the analysis of animal models in which the corresponding orthologs are disrupted. At face value, the situation raises aperplexing question: if speech and language are uniquely human, can any relevant insights be gained from investigations of gene function in other species? This chapter addresses the question using the example of FOXP2, a gene implicated in a severe monogenic speech and language disorder. FOXP2 encodes a transcription factor that is highly conserved in vertebrate species, both in terms of protein sequence and expression patterns. Current data suggest that an earlier version of this gene, present in the common ancestor of humans, rodents, and birds, was already involved in establishing neuronal circuits underlying sensory-motor integration and learning of complex motor sequences. This may have represented one of the factors providing a permissive neural environment for subsequent evolution of vocal learning. Thus, dissection of neuromolecular pathways regulated by Foxp2 in nonlinguistic species is a necessary prerequisite for understanding the role of the human version of the gene in speech and language.

Abstract

The rise of molecular genetics is having a pervasive influence in a wide variety of fields, including research into neurodevelopmental disorders like dyslexia, speech and language impairments, and autism. There are many studies underway which are attempting to determine the roles of genetic factors in the aetiology of these disorders. Beyond the obvious implications for diagnosis, treatment and understanding, success in these efforts promises to shed light on the links between genes and aspects of cognition and behaviour. However, the deceptive simplicity of finding correlations between genetic and phenotypic variation has led to a common misconception that there exist straightforward linear relationships between specific genes and particular behavioural and/or cognitive outputs. The problem is exacerbated by the adoption of an abstract view of the nature of the gene, without consideration of molecular, developmental or ontogenetic frameworks. To illustrate the limitations of this perspective, I select two cases from recent research into the genetic underpinnings of neurodevelopmental disorders. First, I discuss the proposal that dyslexia can be dissected into distinct components specified by different genes. Second, I review the story of the FOXP2 gene and its role in human speech and language. In both cases, adoption of an abstract concept of the gene can lead to erroneous conclusions, which are incompatible with current knowledge of molecular and developmental systems. Genes do not specify behaviours or cognitive processes; they make regulatory factors, signalling molecules, receptors, enzymes, and so on, that interact in highly complex networks, modulated by environmental influences, in order to build and maintain the brain. I propose that it is necessary for us to fully embrace the complexity of biological systems, if we are ever to untangle the webs that link genes to cognition.

Abstract

The human capacity to acquire complex language seems to be without parallel in the natural world. The origins of this remarkable trait have long resisted adequate explanation, but advances in fields that range from molecular genetics to cognitive neuroscience offer new promise. Here we synthesize recent developments in linguistics, psychology and neuroimaging with progress in comparative genomics, gene-expression profiling and studies of developmental disorders. We argue that language should be viewed not as a wholesale innovation, but as a complex reconfiguration of ancestral systems that have been adapted in evolutionarily novel ways.

Abstract

Mutations in the FOXP2 gene cause a severe communication disorder involving speech deficits (developmental verbal dyspraxia), accompanied by wide-ranging impairments in expressive and receptive language. 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. Here we report the first direct functional genetic investigation of missense and nonsense mutations in FOXP2 using human cell-lines, including a well-established neuronal model system. We focused on three unusual FOXP2 coding variants, uniquely identified in cases of verbal dyspraxia, assessing expression, subcellular localization, DNA-binding and transactivation properties. Analysis of the R553H forkhead-box substitution, found in all affected members of a large three-generation family, indicated that it severely affects FOXP2 function, chiefly by disrupting nuclear localization and DNA-binding properties. The R328X truncation mutation, segregating with speech/language disorder in a second family, yields an unstable, predominantly cytoplasmic product that lacks transactivation capacity. A third coding variant (Q17L) observed in a single affected child did not have any detectable functional effect in the present study. In addition, we used the same systems to explore the properties of different isoforms of FOXP2, resulting from alternative splicing in human brain. Notably, one such isoform, FOXP2.10+, contains dimerization domains, but no DNA-binding domain, and displayed increased cytoplasmic localization, coupled with aggresome formation. We hypothesize that expression of alternative isoforms of FOXP2 may provide mechanisms for post-translational regulation of transcription factor function.

Abstract

In 2001, a point mutation in the forkhead box P2 (FOXP2) coding sequence was identified as the basis of an inherited speech and language disorder suffered by members of the family known as "KE." This mini-symposium review focuses on recent findings and research-in-progress, primarily from five laboratories. Each aims at capitalizing on the FOXP2 discovery to build a neurobiological bridge between molecule and phenotype. Below, we describe genetic through behavioral techniques used currently to investigate FoxP2 in birds, rodents, and humans for discovery of the neural bases of vocal learning and language.

Abstract

Family and twin studies of developmental dyslexia have consistently shown that there is a significant heritable component for this disorder. However, any genetic basis for the trait is likely to be complex, involving reduced penetrance, phenocopy, heterogeneity and oligogenic inheritance. This complexity results in reduced power for traditional parametric linkage analysis, where specification of the correct genetic model is important. One strategy is to focus on large multigenerational pedigrees with severe phenotypes and/or apparent simple Mendelian inheritance, as has been successfully demonstrated for speech and language impairment. This approach is limited by the scarcity of such families. An alternative which has recently become feasible due to the development of high-throughput genotyping techniques is the analysis of large numbers of sib-pairs using allele-sharing methodology. This paper outlines our strategy for conducting a systematic genome-wide search for genes involved in dyslexia in a large number of affected sib-pair familites from the UK. We use a series of psychometric tests to obtain different quantitative measures of reading deficit, which should correlate with different components of the dyslexia phenotype, such as phonological awareness and orthographic coding ability. This enable us to use QTL (quantitative trait locus) mapping as a powerful tool for localising genes which may contribute to reading and spelling disability.

Abstract

Recent application of nonparametric-linkage analysis to reading disability has implicated a putative quantitative-trait locus (QTL) on the short arm of chromosome 6. In the present study, we use QTL methods to evaluate linkage to the 6p25-21.3 region in a sample of 181 sib pairs from 82 nuclear families that were selected on the basis of a dyslexic proband. We have assessed linkage directly for several quantitative measures that should correlate with different components of the phenotype, rather than using a single composite measure or employing categorical definitions of subtypes. Our measures include the traditional IQ/reading discrepancy score, as well as tests of word recognition, irregular-word reading, and nonword reading. Pointwise analysis by means of sib-pair trait differences suggests the presence, in 6p21.3, of a QTL influencing multiple components of dyslexia, in particular the reading of irregular words (P=.0016) and nonwords (P=.0024). A complementary statistical approach involving estimation of variance components supports these findings (irregular words, P=.007; nonwords, P=.0004). Multipoint analyses place the QTL within the D6S422-D6S291 interval, with a peak around markers D6S276 and D6S105 consistently identified by approaches based on trait differences (irregular words, P=.00035; nonwords, P=.0035) and variance components (irregular words, P=.007; nonwords, P=.0038). Our findings indicate that the QTL affects both phonological and orthographic skills and is not specific to phoneme awareness, as has been previously suggested. Further studies will be necessary to obtain a more precise localization of this QTL, which may lead to the isolation of one of the genes involved in developmental dyslexia.

Abstract

The murine homologue of the human chloride channel gene, CLCN5, defects in which are responsible for Dent disease, has been cloned and characterized. We isolated the entire coding region of mouse Clcn5 cDNA and approximately 45 kb of genomic sequence embracing the gene. To study its transcriptional control, the 5' upstream sequences of the mouse Clcn5 gene were cloned into a luciferase reporter vector. Deletion analysis of 1.5 kb of the 5' flanking sequence defined an active promoter region within 128 bp of the putative transcription start site, which is associated with a TATA motif but lacks a CAAT consensus. Within this sequence, there is a motif with homology to a purine-rich sequence responsible for the kidney-specific promoter activity of the rat CLC-K1 gene, another member of the chloride-channel gene family expressed in kidney. An enhancer element that confers a 10- to 20-fold increase in the promoter activity of the mouse Clcn5 gene was found within the first intron. The organization of the human CLCN5 and mouse Clcn5 gene structures is highly conserved, and the sequence of the murine protein is 98% similar to that of human, with its highest expression seen in the kidney. This study thus provides the first identification of the transcriptional control region of, and the basis for an understanding of the regulatory mechanism that controls, this kidney-specific, chloride-channel gene.