Publications

Abstract

Researchers are beginning to uncover the neurogenetic pathways that underlie our unparalleled capacity for spoken language. Initial clues come from identification of genetic risk factors implicated in developmental language disorders. The underlying genetic architecture is complex, involving a range of molecular mechanisms. For example, rare protein-coding mutations of the FOXP2 transcription factor cause severe problems with sequencing of speech sounds, while common genetic risk variants of small effect size in genes like CNTNAP2, ATP2C2 and CMIP are associated with typical forms of language impairment. In this article, we describe how investigations of these and other candidate genes, in humans, animals and cellular models, are unravelling the connections between genes and cognition. This depends on interdisciplinary research at multiple levels, from determining molecular interactions and functional roles in neural cell-biology all the way through to effects on brain structure and activity.

Abstract

Absolute pitch and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in a same individual. Here we systematically evaluate the occurrence of syesthesia in a population of 768 subjects with documented absolute pitch. Out of these 768 subjects, 151(20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with absolute pitch and 36 multiplex families with synesthesia. We observed a peak NPL LOD=4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2 using a dominant model. These data establish the close phenotypic and genetic relationship between absolute pitch and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region.

Abstract

It is usually assumed that the language spoken by a human community is independent of the community's genetic makeup, an assumption supported by an overwhelming amount of evidence. However, the possibility that language is influenced by its speakers' genes cannot be ruled out a priori, and a recently discovered correlation between the geographic distribution of tone languages and two human genes seems to point to a genetically influenced bias affecting language. This entry describes this specific correlation and highlights its major implications. Voice pitch has a variety of communicative functions. Some of these are probably universal, such as conveying information about the speaker's sex, age, and emotional state. In many languages, including the European languages, voice pitch also conveys certain sentence-level meanings such as signaling that an utterance is a question or an exclamation; these uses of pitch are known as intonation. Some languages, however, known as tone languages, nian ...

Abstract

Recent experimental findings suggest stable individual differences in the perception of auditory stimuli lacking energy at the fundamental frequency (F0), here called missing fundamental (MF) tones. Specifically, some individuals readily identify the pitch of such tones with the missing F0 ("F0 listeners"), and some base their judgment on the frequency of the partials that make up the tones ("spectral listeners"). However, the diversity of goals and methods in recent research makes it difficult to draw clear conclusions about individual differences. The first purpose of this article is to discuss the influence of methodological choices on listeners' responses. The second goal is to report findings on individual differences in our own studies of the MF phenomenon. In several experiments, participants judged the direction of pitch change in stimuli composed of two MF tones, constructed so as to reveal whether the pitch percept was based on the MF or the partials. The reported difference between F0 listeners and spectral listeners was replicated, but other stable patterns of responses were also observed. Test-retest reliability is high. We conclude that there are genuine, stable individual differences underlying the diverse findings, but also that there are more than two general types of listeners, and that stimulus variables strongly affect some listeners' responses. This suggests that it is generally misleading to classify individuals as "F0 listeners" or "spectral listeners." It may be more accurate to speak of two modes of perception ("F0 listening" and "spectral listening"), both of which are available to many listeners. The individual differences lie in what conditions the choice between the two modes.

Abstract

In this issue, Raca et al1 present two cases of childhood apraxia of speech (CAS) arising from microdeletions of chromosome 16p11.2. They propose that comprehensive phenotypic profiling may assist in the delineation and classification of such cases. To complement this study, we would like to report on a third, unrelated, child who presents with CAS and a chromosome 16p11.2 heterozygous deletion. We use genetic data from this child and his family to illustrate how comprehensive genetic profiling may also assist in the characterisation of 16p11.2 microdeletion syndrome.

Abstract

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype

Abstract

Disorders of speech and language are highly heritable, providing strong
support for a genetic basis. However, the underlying genetic architecture is complex,
involving multiple risk factors. This chapter begins by discussing genetic loci associated
with common multifactorial language-related impairments and goes on to
detail the only gene (known as FOXP2) to be directly implicated in a rare monogenic
speech and language disorder. Although FOXP2 was initially uncovered in
humans, model systems have been invaluable in progressing our understanding of
the function of this gene and its associated pathways in language-related areas of the
brain. Research in species from mouse to songbird has revealed effects of this gene
on relevant behaviours including acquisition of motor skills and learned vocalisations
and demonstrated a role for Foxp2 in neuronal connectivity and signalling,
particularly in the striatum. Animal models have also facilitated the identification of
wider neurogenetic networks thought to be involved in language development and
disorder and allowed the investigation of new candidate genes for disorders involving
language, such as CNTNAP2 and FOXP1. Ongoing work in animal models promises
to yield new insights into the genetic and neural mechanisms underlying human
speech and language

Abstract

Objective The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. Method A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. Results Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. Conclusions The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.

Abstract

The Hmong Diaspora is one of the widest modern human migrations. Mainly localised in South-East Asia, the United States of America, and metropolitan France, a small community has also settled the Amazonian forest of French Guiana. We have biologically analysed 62 individuals of this unique Guianese population through three complementary genetic markers: mitochondrial DNA (HVS-I/II and coding region SNPs), Y-chromosome (SNPs and STRs), and the Gm allotypic system. All genetic systems showed a high conservation of the Asian gene pool (Asian ancestry: mtDNA = 100.0%; NRY = 99.1%; Gm = 96.6%), without a trace of founder effect. When compared across various Asian populations, the highest correlations were observed with Hmong-Mien groups still living in South-East Asia (Fst < 0.05; P-value < 0.05). Despite a long history punctuated by exodus, the French Guianese Hmong have maintained their original genetic diversity.

Abstract

We show that Atkinson’s (Reports, 15 April 2011, p. 346) intriguing proposal—that global
linguistic diversity supports a single language origin in Africa—is an artifact of using suboptimal
data, biased methodology, and unjustified assumptions. We criticize his approach using more
suitable data, and we additionally provide new results suggesting a more complex scenario for the
emergence of global linguistic diversity.

Abstract

Language is the best example of a cultural evolutionary system, able to retain a phylogenetic signal over many thousands of years. The temporal stability (conservatism) of basic vocabulary is relatively well understood, but the stability of the structural properties of language (phonology, morphology, syntax) is still unclear. Here we report an extensive Bayesian phylogenetic investigation of the structural stability of numerous features across many language families and we introduce a novel method for analyzing the relationships between the “stability profiles” of language families. We found that there is a strong universal component across language families, suggesting the existence of universal linguistic, cognitive and genetic constraints. Against this background, however, each language family has a distinct stability profile, and these profiles cluster by geographic area and likely deep genealogical relationships. These stability profiles reveal, for example, the ancient historical relationships between the Siberian and American language families, presumed to be separated by at least 12,000 years. Thus, such higher-level properties of language seen as an evolutionary system might allow the investigation of ancient connections between languages and shed light on the peopling of the world.

Abstract

Commentary on Cohen, E. (2012). The evolution of tag-based cooperation in humans: The case for accent. Current Anthropology, 53, 588-616. doi:10.1086/667654.

Abstract

Approach and avoidance are two behavioral responses that make people tend to approach positive and avoid negative situations. This study examines whether postural behavior is influenced by the affective state of pictures. While standing on the Wii™ Balance Board, participants viewed pleasant, neutral, and unpleasant pictures (passively viewing phase). Then they had to move their body to the left or the right (lateral movement phase) to make the next picture appear. We recorded movements in the anterior-posterior direction to examine approach and avoidant behavior. During passively viewing, people approached pleasant pictures. They avoided unpleasant ones while they made a lateral movement. These findings provide support for the idea that we tend to approach positive and avoid negative situations.

Abstract

Mutations in the human FOXP2 gene cause impaired speech development and linguistic deficits, which have been best characterised in a large pedigree called the KE family. The encoded protein is highly conserved in many vertebrates and is expressed in homologous brain regions required for sensorimotor integration and motor-skill learning, in particular corticostriatal circuits. Independent studies in multiple species suggest that the striatum is a key site of FOXP2 action. Here, we used in vivo recordings in awake-behaving mice to investigate the effects of the KE-family mutation on the function of striatal circuits during motor-skill learning. We uncovered abnormally high ongoing striatal activity in mice carrying an identical mutation to that of the KE family. Furthermore, there were dramatic alterations in striatal plasticity during the acquisition of a motor skill, with most neurons in mutants showing negative modulation of firing rate, starkly contrasting with the predominantly positive modulation seen in control animals. We also observed striking changes in the temporal coordination of striatal firing during motor-skill learning in mutants. Our results indicate that FOXP2 is critical for the function of striatal circuits in vivo, which are important not only for speech but also for other striatal-dependent skills.

Abstract

In principle mutational records make it possible to estimate frequencies of disease alleles (q) for autosomal recessive disorders using a novel approach based on the calculation of the Homozygosity Index (HI), i.e., the proportion of homozygous patients, which is complementary to the proportion of compound heterozygous patients P(CH). In other words, the rarer the disorder, the higher will be the HI and the lower will be the P(CH). To test this hypothesis we used mutational records of individuals affected with Familial Mediterranean Fever (FMF) and Phenylketonuria (PKU), born to either consanguineous or apparently unrelated parents from six population samples of the Mediterranean region. Despite the unavailability of precise values of the inbreeding coefficient for the general population, which are needed in the case of apparently unrelated parents, our estimates of q are very similar to those of previous descriptive epidemiological studies. Finally, we inferred from simulation studies that the minimum sample size needed to use this approach is 25 patients either with unrelated or first cousin parents. These results show that the HI can be used to produce a ranking order of allele frequencies of autosomal recessive disorders, especially in populations with high rates of consanguineous marriages.

Abstract

Many learners of a foreign language (L2) struggle to correctly pronounce newly-learned speech sounds, yet many others achieve this with apparent ease. Here we explored how a training study of learning complex consonant clusters at the very onset of the L2 acquisition can inform us about L2 learning in general and individual differences in particular. To this end, adult Dutch native speakers were trained on Slovak words with complex consonant clusters (e.g., pstruh /pstrux/‘trout’, štvrť /ʃtvrc/ ‘quarter’) using auditory and orthographic input. In the same session following training, participants were tested on a battery of L2 perception and production tasks. The battery of L2 tests was repeated twice more with one week between each session. In the first session, an additional battery of control tests was used to test participants’ native language (L1) skills. Overall, in line with some previous research, participants showed only weak learning effects across the L2 perception tasks. However, there were considerable individual differences across all L2 tasks, which remained stable across sessions. Only two participants showed overall high L2 production performance that fell within 2 standard deviations of the mean ratings obtained for an L1 speaker. The mispronunciation detection task was the only perception task which significantly predicted production performance in the final session. We conclude by discussing several recommendations for future L2 learning studies.

Abstract

CONTEXT Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES Primary data. STUDY SELECTION Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19 505) (P = .01). CONCLUSION These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Abstract

Background Reduced total brain volume is a consistent finding in children with Attention Deficit/Hyperactivity Disorder (ADHD). In order to get a better understanding of the neurobiology of ADHD, we take the first step in studying the dimensionality of current self-reported adult ADHD symptoms, by looking at its relation with total brain volume. Methodology/Principal Findings In a sample of 652 highly educated adults, the association between total brain volume, assessed with magnetic resonance imaging, and current number of self-reported ADHD symptoms was studied. The results showed an association between these self-reported ADHD symptoms and total brain volume. Post-hoc analysis revealed that the symptom domain of inattention had the strongest association with total brain volume. In addition, the threshold for impairment coincides with the threshold for brain volume reduction. Conclusions/Significance This finding improves our understanding of the biological substrates of self-reported ADHD symptoms, and suggests total brain volume as a target intermediate phenotype for future gene-finding in ADHD.

Abstract

Infectious diseases exert a constant evolutionary pressure on the innate immunity genes. TLR4, an important member of the Toll-like receptors family, specifically recognizes conserved structures of various infectious pathogens. Two functional TLR4 polymorphisms, Asp299Gly and Thr399Ile, modulate innate host defense against infections, and their prevalence between various populations has been proposed to be influenced by local infectious pressures. If this assumption is true, strong local infectious pressures would lead to a homogeneous pattern of these ancient TLR4 polymorphisms in geographically close populations, while a weak selection or genetic drift may result in a diverse pattern. We evaluated TLR4 polymorphisms in 15 ethnic groups of Iran, to assess whether infections exerted selective pressures on different haplotypes containing these variants. The Iranian subpopulations displayed a heterogeneous pattern of TLR4 polymorphisms, comprising various percentages of Asp299Gly and Thr399Ile alone or in combination. The Iranian sample as a whole showed an intermediate mixed pattern when compared with commonly found patterns in Africa, Europe, Eastern Asia and Americas. These findings suggest a weak or absent selection pressure on TLR4 polymorphisms in the Middle-East, that does not support the assumption of an important role of these polymorphisms in the host defence against local pathogens.

Abstract

Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Here, we use genetic mapping, copy-number analysis, exclusion of mutations by high-throughput sequencing, gene expression analysis and functional assays to show that HMPS is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This unusual mutation is associated with increased allele-specific GREM1 expression. Whereas GREM1 is expressed in intestinal subepithelial myofibroblasts in controls, GREM1 is predominantly expressed in the epithelium of the large bowel in individuals with HMPS. The HMPS duplication contains predicted enhancer elements; some of these interact with the GREM1 promoter and can drive gene expression in vitro. Increased GREM1 expression is predicted to cause reduced bone morphogenetic protein (BMP) pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel.

Abstract

Microarrays provide a powerful analytical tool for the simultaneous detection of multiple pathogens. We developed diagnostic suspension microarrays for sensitive and specific detection of the biothreat pathogens Bacillus anthracis, Yersinia pestis, Francisella tularensis and Coxiella burnetii. Two assay chemistries for amplification and labeling were developed, one method using direct hybridization and the other using target-specific primer extension, combined with hybridization to universal arrays. Asymmetric PCR products for both assay chemistries were produced by using a multiplex asymmetric PCR amplifying 16 DNA signatures (16-plex). The performances of both assay chemistries were compared and their advantages and disadvantages are discussed. The developed microarrays detected multiple signature sequences and an internal control which made it possible to confidently identify the targeted pathogens and assess their virulence potential. The microarrays were highly specific and detected various strains of the targeted pathogens. Detection limits for the different pathogen signatures were similar or slightly higher compared to real-time PCR. Probit analysis showed that even a few genomic copies could be detected with 95% confidence. The microarrays detected DNA from different pathogens mixed in different ratios and from spiked or naturally contaminated samples. The assays that were developed have a potential for application in surveillance and diagnostics. © 2012 Janse et al.

Abstract

Widespread minority language shift in Early Modern Europe is often ascribed to restrictive language policies and the migration of both majority- and minority-language speakers. However, without a sociohistorically credible account of the mechanisms through which these events caused a language shift, these policies lack explanatory power. Inspired by research on 'language histories from below,' we present an integrated sociohistorical and linguistic account that can shed light on the procresses taking place during a case of language shift in the 17th and 18th centuries. We present and analyze demographic data on the immigration and integration of French speakers in previously Dutch-speaking Dunkirk in this period, showing how moderate intermarriage of immigrants and locals could have represented a motive and a mechanism for language shift against a backdrop of larger language-political processes. We then discuss the modern language-shift dialect of Dunkirk in comparison with different dialects of French. The linguistic data suggests a large influence from the dialects of migrants, underlining their role in the language shift process. The combination of sociohistorical and linguistic evidence gives us a better understanding of language shift in this period, showing the value of an integrated 'from below' approach.

Abstract

Heterozygous mutations of the human FOXP2 transcription factor gene cause the best-described examples of monogenic speech and language disorders. Acquisition of proficient spoken language involves auditory-guided vocal learning, a specialized form of sensory-motor association learning. The impact of etiological Foxp2 mutations on learning of auditory-motor associations in mammals has not been determined yet. Here, we directly assess this type of learning using a newly developed conditioned avoidance paradigm in a shuttle-box for mice. We show striking deficits in mice heterozygous for either of two different Foxp2 mutations previously implicated in human speech disorders. Both mutations cause delays in acquiring new motor skills. The magnitude of impairments in association learning, however, depends on the nature of the mutation. Mice with a missense mutation in the DNA-binding domain are able to learn, but at a much slower rate than wild type animals, while mice carrying an early nonsense mutation learn very little. These results are consistent with expression of Foxp2 in distributed circuits of the cortex, striatum and cerebellum that are known to play key roles in acquisition of motor skills and sensory-motor association learning, and suggest differing in vivo effects for distinct variants of the Foxp2 protein. Given the importance of such networks for the acquisition of human spoken language, and the fact that similar mutations in human FOXP2 cause problems with speech development, this work opens up a new perspective on the use of mouse models for understanding pathways underlying speech and language disorders.

Abstract

Purpose: Classical studies of consanguinity have taken advantage of the relationship between the gene frequency for a rare autosomal recessive disorder (q) and the proportion of offspring of consanguineous couples who are affected with the same disorder. The Swedish geneticist Gunnar Dahlberg provided the first theoretical formulation of the inverse correlation between q and the increase in frequency of consanguineous marriages among parents of affected children with respect to marriages of the same degree in the general population. Today it is possible to develop a new approach for estimating q using mutation analysis of affected offspring of consanguineous couples. The rationale of this new approach is based on the possibility that the child born of consanguineous parents carries the same mutation in double copy (true homozygosity) or alternatively carries two different mutations in the same gene (compound heterozygosity). In the latter case the two mutations must have been inherited through two different ancestors of the consanguineous parents (in this case the two mutated alleles are not ‘identical by descent’). Patients and methods: Data from the offspring of consanguineous marriages affected with different autosomal recessive disorders were collected by different molecular diagnostic laboratories in Mediterranean countries and in particular in Arab countries, where the frequencies of consanguineous marriages is high, show the validity of this approach. Results: The proportion of compound heterozygotes among children affected with a given autosomal recessive disorder, born of consanguineous parents, can be taken as an indirect indicator of the frequency of the same disorder in the general population. Identification of the responsible gene (and mutations) is the necessary condition to apply this method. Conclusion: The following paper from our group relevant for the present review is being published: Alessandro Gialluisi, Tommaso Pippucci, Yair Anikster, Ugur Ozbek, Myrna Medlej-Hashim, Andre Megarbane and Giovanni Romeo: Estimating the allele frequency of autosomal recessive disorders through mutational records and consanguinity: the homozygosity index (HI) annals of human genetics (in press; acceptance date 1 November 2011) In addition, our experimental data show that the causative mutation for a rare autosomal recessive disorder can be identified by whole exome sequencing of only two affected children of first cousins parents, as described in the following recent paper: Pippucci T, Benelli M, Magi A, Martelli PL, Magini P, Torricelli F, Casadio R, Seri M, Romeo G EX-HOM (EXome HOMozygosity): A Proof of Principle. Hum Hered 2011; 72:45-53.

Abstract

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

Abstract

Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder, and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterisation of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300bp to -177bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, whilst a region -982bp to -301bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by FOXP2, a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia (DVD). Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.

Abstract

Corrigendum to CNTNAP2 variants affect early language development in the general population A. J. O. Whitehouse, D. V. M. Bishop, Q. W. Ang, C. E. Pennell and S. E. Fisher Genes Brain Behav (2011) doi: 10.1111/j.1601-183X.2011.00684.x. The authors have detected a typographical error in the Abstract of this paper. The error is in the fifth sentence, which reads: ‘‘On the basis of these findings, we performed analyses of four-marker haplotypes of rs2710102–rs759178–rs17236239–rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype GCAG,P = .0014).’’ Rather than ‘‘GCAG’’, the final haplotype should read ‘‘CGAG’’. This typographical error was made in the Abstract only and this has no bearing on the results or conclusions of the study, which remain unchanged. Reference Whitehouse, A. J. O., Bishop, D. V. M., Ang, Q. W., Pennell, C. E. & Fisher, S. E. (2011) CNTNAP2 variants affect early language development in the general population. Genes Brain Behav 10, 451–456. doi: 10.1111/j.1601-183X.2011.00684.x.

Abstract

We carried out the first study on the relationship between individual language aptitude and structural connectivity of language pathways in the adult brain. We measured four components of language aptitude (vocabulary learning, VocL; sound recognition, SndRec; sound-symbol correspondence, SndSym; and grammatical inferencing, GrInf) using the LLAMA language aptitude test (Meara, 2005). Spatial working memory (SWM), verbal working memory (VWM) and IQ were also measured as control factors. Diffusion Tensor Imaging (DTI) was employed to investigate the structural connectivity of language pathways in the perisylvian language network. Principal Component Analysis (PCA) on behavioural measures suggests that a general ability might be important to the first stages of L2 acquisition. It also suggested that VocL, SndSy and SWM are more closely related to general IQ than SndRec and VocL, and distinguished the tasks specifically designed to tap into L2 acquisition (VocL, SndRec,SndSym and GrInf) from more generic measures (IQ, SWM and VWM). Regression analysis suggested significant correlations between most of these behavioural measures and the structural connectivity of certain language pathways, i.e., VocL and BA47-Parietal pathway, SndSym and inter-hemispheric BA45 pathway, GrInf and BA45-Temporal pathway and BA6-Temporal pathway, IQ and BA44-Parietal pathway, BA47-Parietal pathway, BA47-Temporal pathway and inter-hemispheric BA45 pathway, SWM and inter-hemispheric BA6 pathway and BA47-Parietal pathway, and VWM and BA47-Temporal pathway. These results are discussed in relation to relevant findings in the literature.

Abstract

How does language comprehension interact with motor activity? We investigated the conditions under which comprehending an action sentence affects people's balance. We performed two experiments to assess whether sentences describing forward or backward movement modulate the lateral movements made by subjects who made sensibility judgments about the sentences. In one experiment subjects were standing on a balance board and in the other they were seated on a balance board that was mounted on a chair. This allowed us to investigate whether the action compatibility effect (ACE) is robust and persists in the face of salient incompatibilities between sentence content and subject movement. Growth-curve analysis of the movement trajectories produced by the subjects in response to the sentences suggests that the ACE is indeed robust. Sentence content influenced movement trajectory despite salient inconsistencies between implied and actual movement. These results are interpreted in the context of the current discussion of embodied, or grounded, language comprehension and meaning representation.

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.

Abstract

Background Retracing the genetic histories of the descendant populations of the Slave Trade (16th-19th centuries) is particularly challenging due to the diversity of African ethnic groups involved and the different hybridisation processes with Europeans and Amerindians, which have blurred their original genetic inheritances. The Noir Marron in French Guiana are the direct descendants of maroons who escaped from Dutch plantations in the current day Surinam. They represent an original ethnic group with a highly blended culture. Uniparental markers (mtDNA and NRY) coupled with HTLV-1 sequences (env and LTR) were studied to establish the genetic relationships linking them to African American and African populations. Results All genetic systems presented a high conservation of the African gene pool (African ancestry: mtDNA = 99.3%; NRY = 97.6%; HTLV-1 env = 20/23; HTLV-1 LTR = 6/8). Neither founder effect nor genetic drift was detected and the genetic diversity is within a range commonly observed in Africa. Higher genetic similarities were observed with the populations inhabiting the Bight of Benin (from Ivory Coast to Benin). Other ancestries were identified but they presented an interesting sex-bias. Whilst male origins spread throughout the north of the bight (from Benin to Senegal), female origins were spread throughout the south (from the Ivory Coast to Angola). Conclusions The Noir Marron are unique in having conserved their African genetic ancestry, despite major cultural exchanges with Amerindians and Europeans through inhabiting the same region for four centuries. Their maroon identity and the important number of slaves deported in this region have maintained the original African diversity. All these characteristics permit to identify a major origin located in the former region of the Gold Coast and the Bight of Benin; regions highly impacted by slavery, from which goes a sex-biased longitudinal gradient of ancestry.

Abstract

There are some 6000 languages spoken today, classfied in approximately 90 linguistic families and many isolates, and also differing across structural, typological, dimensions. Genetically, the human species is remarkably homogeneous, with the existant genetic diversity mostly explain by intra-population differences between individuals, but the remaining inter-population differences have a non-trivial structure. Populations splits and contacts influence both languages and genes, in principle allowing them to evolve in parallel ways. The farming/language co-dispersal hypothesis is a well-known such theory, whereby farmers spreading agriculture from its places of origin also spread their genes and languages. A different type of relationship was recently proposed, involving a genetic bias which influences the structural properties of language as it is transmitted across generations. Such a bias was proposed to explain the correlations between the distribution of tone languages and two brain development-related human genes and, if confirmed by experimental studies, it could represent a new factor explaining the distrbution of diversity. The present chapter overviews these related topics in the hope that a truly interdisciplinary approach could allow a better understanding of our complex (recent as well as evolutionary) history.

Abstract

Population-based linkage analysis is a new method for analysing genomewide single nucleotide polymorphism (SNP) genotype data in case-control samples, which does not assume a common disease, common variant model. The genome is scanned for extended segments that show increased identity-by-descent sharing within case-case pairs, relative to case-control or control-control pairs. The method is robust to allelic heterogeneity and is suited to mapping genes which contain multiple, rare susceptibility variants of relatively high penetrance. We analysed genomewide SNP datasets for two schizophrenia case-control cohorts, collected in Aberdeen (461 cases, 459 controls) and Munich (429 cases, 428 controls). Population-based linkage testing must be performed within homogeneous samples and it was therefore necessary to analyse the cohorts separately. Each cohort was first subjected to several procedures to improve genetic homogeneity, including identity-by-state outlier detection and multidimensional scaling analysis. When testing only cases who reported a positive family history of major psychiatric disease, consistent with a model of strongly penetrant susceptibility alleles, we saw a distinct peak on chromosome 19q in both cohorts that appeared in meta-analysis (P=0.000016) to surpass the traditional level for genomewide significance for complex trait linkage. The linkage signal was also present in a third case-control sample for familial bipolar disorder, such that meta-analysing all three datasets together yielded a linkage P=0.0000026. A model of rare but highly penetrant disease alleles may be more applicable to some instances of major psychiatric diseases than the common disease common variant model, and we therefore suggest that other genome scan datasets are analysed with this new, complementary method.

Abstract

Heterozygous mutations of the human FOXP2 gene are implicated in a severe speech and language disorder. Aetiological mutations of murine Foxp2 yield abnormal synaptic plasticity and impaired motor-skill learning in mutant mice, while knockdown of the avian orthologue in songbirds interferes with auditory-guided vocal learning. Here, we investigate influences of two distinct Foxp2 point mutations on vocalizations of 4-day-old mouse pups (Mus musculus). The R552H missense mutation is identical to that causing speech and language deficits in a large well-studied human family, while the S321X nonsense mutation represents a null allele that does not produce Foxp2 protein. We ask whether vocalizations, based solely on innate mechanisms of production, are affected by these alternative Foxp2 mutations. Sound recordings were taken in two different situations: isolation and distress, eliciting a range of call types, including broadband vocalizations of varying noise content, ultrasonic whistles and clicks. Sound production rates and several acoustic parameters showed that, despite absence of functional Foxp2, homozygous mutants could vocalize all types of sounds in a normal temporal pattern, but only at comparably low intensities. We suggest that altered vocal output of these homozygotes may be secondary to developmental delays and somatic weakness. Heterozygous mutants did not differ from wild-types in any of the measures that we studied (R552H ) or in only a few (S321X ), which were in the range of differences routinely observed for different mouse strains. Thus, Foxp2 is not essential for the innate production of emotional vocalizations with largely normal acoustic properties by mouse pups.

Abstract

The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18,920 controls. Both the replication study of new samples and the meta-analysis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P = 8.2 x 10(-5)-1.7 x 10(-3), common OR = 1.09-1.11). The region contains two genes, AHI1 and C6orf217, and both genes-as well as the neighbouring phosphodiesterase 7B (PDE7B)-may be considered candidates for involvement in the genetic aetiology of schizophrenia.

Abstract

Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Abstract

This article reports on research which seeks to compare and measure the similarities between phonetic transcriptions in the analysis of relationships between varieties of English. It addresses the question of whether these varieties have been converging, diverging, or maintaining equilibrium as a result of endogenous and exogenous phonetic and phonological changes. We argue that it is only possible to identify such patterns of change by the simultaneous comparison of a wide range of varieties of a language across a data set that has not been specifically selected to highlight those changes that are believed to be important. Our analysis suggests that although there has been an obvious reduction in regional variation with the loss of traditional dialects of English and Scots, there has not been any significant convergence (or divergence) of regional accents of English in recent decades, despite the rapid spread of a number of features such as TH-fronting.

Abstract

Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.

Abstract

Specific language impairment (SLI) is defined as an unexpected and persistent impairment in language ability despite adequate opportunity and intelligence and in the absence of any explanatory medical conditions. This condition is highly heritable and affects between 5% and 8% of pre-school children. Over the past few years, investigations have begun to uncover genetic factors that may contribute to susceptibility to language impairment. So far, variants in four specific genes have been associated with spoken language disorders - forkhead box P2 (FOXP2) and contactin-associated protein-like 2 (CNTNAP2) on chromosome7 and calcium-transporting ATPase 2C2 (ATP2C2) and c-MAF inducing protein (CMIP) on chromosome 16. Here, we describe the different ways in which these genes were identified as candidates for language impairment. We discuss how characterization of these genes, and the pathways in which they are involved, may enhance our understanding of language disorders and improve our understanding of the biological foundations of language acquisition.

Abstract

It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), while mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2 binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites, and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired FOXP2 regulation of SRPX2 promoter activity, while that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNPA2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.

Abstract

Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (F(st)) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.