Publications

Abstract

Linguistic diversity, now and in the past, is widely regarded to be independent of biological changes that took place after the emergence of Homo sapiens. We show converging evidence from paleoanthropology, speech biomechanics, ethnography, and historical linguistics that labiodental sounds (such as “f” and “v”) were innovated after the Neolithic. Changes in diet attributable to food-processing technologies modified the human bite from an edge-to-edge configuration to one that preserves adolescent overbite and overjet into adulthood. This change favored the emergence and maintenance of labiodentals. Our findings suggest that language is shaped not only by the contingencies of its history, but also by culturally induced changes in human biology.

Abstract

Most people have left‐hemisphere dominance for various aspects of language processing, but only roughly 1% of the adult population has atypically reversed, rightward hemispheric language dominance (RHLD). The genetic‐developmental program that underlies leftward language laterality is unknown, as are the causes of atypical variation. We performed an exploratory whole‐genome‐sequencing study, with the hypothesis that strongly penetrant, rare genetic mutations might sometimes be involved in RHLD. This was by analogy with situs inversus of the visceral organs (left‐right mirror reversal of the heart, lungs and so on), which is sometimes due to monogenic mutations. The genomes of 33 subjects with RHLD were sequenced and analyzed with reference to large population‐genetic data sets, as well as 34 subjects (14 left‐handed) with typical language laterality. The sample was powered to detect rare, highly penetrant, monogenic effects if they would be present in at least 10 of the 33 RHLD cases and no controls, but no individual genes had mutations in more than five RHLD cases while being un‐mutated in controls. A hypothesis derived from invertebrate mechanisms of left‐right axis formation led to the detection of an increased mutation load, in RHLD subjects, within genes involved with the actin cytoskeleton. The latter finding offers a first, tentative insight into molecular genetic influences on hemispheric language dominance.

Abstract

FOXP proteins form a subfamily of evolutionarily conserved transcription factors involved in the development and functioning of several tissues, including the central nervous system. In humans, mutations in FOXP1 and FOXP2 have been implicated in cognitive deficits including intellectual disability and speech disorders. Drosophila exhibits a single ortholog, called FoxP, but due to a lack of characterized mutants, our understanding of the gene remains poor. Here we show that the dimerization property required for mammalian FOXP function is conserved in Drosophila. In flies, FoxP is enriched in the adult brain, showing strong expression in ~1000 neurons of cholinergic, glutamatergic and GABAergic nature. We generate Drosophila loss-of-function mutants and UAS-FoxP transgenic lines for ectopic expression, and use them to characterize FoxP function in the nervous system. At the cellular level, we demonstrate that Drosophila FoxP is required in larvae for synaptic morphogenesis at axonal terminals of the neuromuscular junction and for dendrite development of dorsal multidendritic sensory neurons. In the developing brain, we find that FoxP plays important roles in α-lobe mushroom body formation. Finally, at a behavioral level, we show that Drosophila FoxP is important for locomotion, habituation learning and social space behavior of adult flies. Our work shows that Drosophila FoxP is important for regulating several neurodevelopmental processes and behaviors that are related to human disease or vertebrate disease model phenotypes. This suggests a high degree of functional conservation with vertebrate FOXP orthologues and established flies as a model system for understanding FOXP related pathologies.

Abstract

This paper argues that inter-individual and inter-group variation in language acquisition, perception, processing and production, rooted in our biology, may play a largely neglected role in sound change. We begin by discussing the patterning of these differences, highlighting those related to vocal tract anatomy with a foundation in genetics and development. We use our ArtiVarK database, a large multi-ethnic sample comprising 3D intraoral optical scans, as well as structural, static and real-time MRI scans of vocal tract anatomy and speech articulation, to quantify the articulatory strategies used to produce the North American English /r/ and to statistically show that anatomical factors seem to influence these articulatory strategies. Building on work showing that these alternative articulatory strategies may have indirect coarticulatory effects, we propose two models for how biases due to variation in vocal tract anatomy may affect sound change. The first involves direct overt acoustic effects of such biases that are then reinterpreted by the hearers, while the second is based on indirect coarticulatory phenomena generated by acoustically covert biases that produce overt “at-a-distance” acoustic effects. This view implies that speaker communities might be “poised” for change because they always contain pools of “standing variation” of such biased speakers, and when factors such as the frequency of the biased speakers in the community, their positions in the communicative network or the topology of the network itself change, sound change may rapidly follow as a self-reinforcing network-level phenomenon, akin to a phase transition. Thus, inter-speaker variation in structured and dynamic communicative networks may couple the initiation and actuation of sound change.

Abstract

Linguistic diversity is affected by multiple factors, but it is usually assumed that variation in the anatomy of our speech organs
plays no explanatory role. Here we use realistic computer models of the human speech organs to test whether inter-individual
and inter-group variation in the shape of the hard palate (the bony roof of the mouth) affects acoustics of speech sounds. Based
on 107 midsagittal MRI scans of the hard palate of human participants, we modelled with high accuracy the articulation of a set
of five cross-linguistically representative vowels by agents learning to produce speech sounds. We found that different hard
palate shapes result in subtle differences in the acoustics and articulatory strategies of the produced vowels, and that these
individual-level speech idiosyncrasies are amplified by the repeated transmission of language across generations. Therefore,
we suggest that, besides culture and environment, quantitative biological variation can be amplified, also influencing language.

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Abstract

This chapter discusses the genetic foundations of the human capacity for language. It reviews the molecular structure of the genome and the complex molecular mechanisms that allow genetic information to influence multiple levels of biology. It goes on to describe the active regulation of genes and their formation of complex genetic pathways that in turn control the cellular environment and function. At each of these levels, examples of genes and genetic variants that may influence the human capacity for language are given. Finally, it discusses the value of using animal models to understand the genetic underpinnings of speech and language. From this chapter will emerge the complexity of the genome in action and the multidisciplinary efforts that are currently made to bridge the gap between genetics and language.

Abstract

Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

Abstract

FOXP2 mutations cause a speech and language disorder, raising interest in potential roles of this gene in human evolution. A new study re-evaluates genomic variation at the human FOXP2 locus but finds no evidence of recent adaptive evolution.

Abstract

Disruptions of the FOXP2 gene cause a speech and language disorder involving difficulties in sequencing orofacial movements. FOXP2 is expressed in cortico-striatal and cortico-cerebellar circuits important for fine motor skills, and affected individuals show abnormalities in these brain regions. We selectively disrupted Foxp2 in the cerebellar Purkinje cells, striatum or cortex of mice and assessed the effects on skilled motor behaviour using an operant lever-pressing task. Foxp2 loss in each region impacted behaviour differently, with striatal and Purkinje cell disruptions affecting the variability and the speed of lever-press sequences, respectively. Mice lacking Foxp2 in Purkinje cells showed a prominent phenotype involving slowed lever pressing as well as deficits in skilled locomotion. In vivo recordings from Purkinje cells uncovered an increased simple spike firing rate and decreased modulation of firing during limb movements. This was caused by increased intrinsic excitability rather than changes in excitatory or inhibitory inputs. Our findings show that Foxp2 can modulate different aspects of motor behaviour in distinct brain regions, and uncover an unknown role for Foxp2 in the modulation of Purkinje cell activity that severely impacts skilled movements.

Abstract

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Abstract

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Abstract

One of the features that distinguishes modern humans from our extinct relatives
and ancestors is a globular shape of the braincase [1-4]. As the endocranium
closely mirrors the outer shape of the brain, these differences might reflect
altered neural architecture [4,5]. However, in the absence of fossil brain tissue the
underlying neuroanatomical changes as well as their genetic bases remain
elusive. To better understand the biological foundations of modern human
endocranial shape, we turn to our closest extinct relatives, the Neandertals.
Interbreeding between modern humans and Neandertals has resulted in
introgressed fragments of Neandertal DNA in the genomes of present-day non-
Africans [6,7]. Based on shape analyses of fossil skull endocasts, we derive a
measure of endocranial globularity from structural magnetic resonance imaging
(MRI) scans of thousands of modern humans, and study the effects of
introgressed fragments of Neandertal DNA on this phenotype. We find that
Neandertal alleles on chromosomes 1 and 18 are associated with reduced
endocranial globularity. These alleles influence expression of two nearby genes,
UBR4 and PHLPP1, which are involved in neurogenesis and myelination,
respectively. Our findings show how integration of fossil skull data with archaic
genomics and neuroimaging can suggest developmental mechanisms that may
contribute to the unique modern human endocranial shape.

Abstract

Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA‐L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico‐limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied healthy individuals and used multimodal neuroimaging (sample size range: 219–284 across modalities) and network‐based statistics (NBS) to probe the specificity of MAOA‐L‐related connectomic alterations to cortical‐limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed a distributed network of node links with a significantly increased connectivity in MAOA‐L carriers compared to the carriers of the high expression (H) variant. The hyperconnectivity phenotype primarily consisted of between‐lobe (“anisocoupled”) network links and showed a pronounced involvement of frontal‐temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = .037), resting‐state fMRI (pFWE = .022), and diffusion tensor imaging (pFWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (pFWE = .540). These observations are in line with prior research on the MAOA‐L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences affecting these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic influences and low-frequency genetic variation. To understand these influences, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Abstract

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual’s self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner’s self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual’s weekly alcohol consumption increases partner’s alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10−6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.

Abstract

Aim: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. Materials & methods: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. Results & conclusion: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.

Abstract

Mirror-sensory synaesthetes mirror the pain or touch that they observe in other people on their own bodies. This type of synaesthesia has been associated with enhanced empathy. We investigated whether the enhanced empathy of people with mirror-sensory synesthesia influences the experience of situations involving touch or pain and whether it affects their prosocial decision making. Mirror-sensory synaesthetes (N = 18, all female), verified with a touch-interference paradigm, were compared with a similar number of age-matched control individuals (all female). Participants viewed arousing images depicting pain or touch; we recorded subjective valence and arousal ratings, and physiological responses, hypothesizing more extreme reactions in synaesthetes. The subjective impact of positive and negative images was stronger in synaesthetes than in control participants; the stronger the reported synaesthesia, the more extreme the picture ratings. However, there was no evidence for differential physiological or hormonal responses to arousing pictures. Prosocial decision making was assessed with an economic game assessing altruism, in which participants had to divide money between themselves and a second player. Mirror-sensory synaesthetes donated more money than non-synaesthetes, showing enhanced prosocial behaviour, and also scored higher on the Interpersonal Reactivity Index as a measure of empathy. Our study demonstrates the subjective impact of mirror-sensory synaesthesia and its stimulating influence on prosocial behaviour.

Abstract

The influence of larynx position on vowel articulation is an important topic in understanding speech production, the present-day distribution of linguistic diversity and the evolution of speech and language in our lineage. We introduce here a realistic computer model of the vocal tract, constructed from actual human MRI data, which can learn, using machine learning techniques, to control the articulators in such a way as to produce speech sounds matching as closely as possible to a given set of target vowels. We systematically control the vertical position of the larynx and we quantify the differences between the target and produced vowels for each such position across multiple replications. We report that, indeed, larynx height does affect the accuracy of reproducing the target vowels and the distinctness of the produced vowel system, that there is a “sweet spot” of larynx positions that are optimal for vowel production, but that nevertheless, even extreme larynx positions do not result in a collapsed or heavily distorted vowel space that would make speech unintelligible. Together with other lines of evidence, our results support the view that the vowel space of human languages is influenced by our larynx position, but that other positions of the larynx may also be fully compatible with speech.

Abstract

Neurons of the neocortex are organized into six radial layers, which have appeared at different times during evolution, with the superficial layers representing a more recent acquisition. Input to the neocortex predominantly reaches superficial layers (SL, i.e., layers (L) 2-4), while output is generated in deep layers (DL, i.e., L5-6) [1]. Intracortical connections, which bridge input and output pathways, are key components of cortical circuits because they allow the propagation and processing of information within the neocortex. Two main types of intracortically projecting neurons (ICPN) can be distinguished by their axonal features: L4 spiny stellate neurons (SSN) with short axons projecting locally within cortical columns [2, 3, 4, 5], and SL and DL long-range projection neurons, including callosally projecting neurons (CPNSL and CPNDL) [5, 6]. Here, we investigate the molecular hallmarks that distinguish SSN, CPNSL, and CPNDL and relate their transcriptional signatures with their output connectivity. Specifically, taking advantage of the presence of CPN in both SL and DL, we identify lamina-independent genetic hallmarks of a constant projection motif (i.e., interhemispheric projection). By performing unbiased transcriptomic comparisons between CPNSL, CPNDL and SSN, we provide specific molecular profiles for each of these populations and show that target identity supersedes laminar position in defining ICPN transcriptional diversity. Together, these findings reveal a projection-based organization of transcriptional programs across cortical layers, which we propose reflects conserved strategy to protect canonical circuit structure (and hence function) across a diverse range of neuroanatomies.

Abstract

Hand preference is a conspicuous variation in human behaviour, with a worldwide proportion of around 90% of people preferring to use the right hand for many tasks, and 10% the left hand. We used the large cohort of the UK biobank (~500,000 participants) to study possible relations between early life factors and adult hand preference. The probability of being left-handed was affected by the year and location of birth, likely due to cultural effects. In addition, hand preference was affected by birthweight, being part of a multiple birth, season of birth, breastfeeding, and sex, with each effect remaining significant after accounting for all others. Analysis of genome-wide genotype data showed that left-handedness was very weakly heritable, but shared no genetic basis with birthweight. Although on average left-handers and right-handers differed for a number of early life factors, all together these factors had only a minimal predictive value for individual hand preference.

Abstract

Objective:

Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects.
Methods:

The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen’s d=0.1.
Results:

The largest effect size (Cohen’s d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset.
Conclusions:

Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Abstract

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.

Abstract

Schizophrenia is a common and complex mental disorder with neuroimaging alterations. Recent neuroanatomical pattern recognition studies attempted to distinguish individuals with schizophrenia by structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI). 1, 2 Applications of cutting-edge machine learning approaches in structural neuroimaging studies have revealed potential pathways to classification of schizophrenia based on regional gray matter volume (GMV) or density or cortical thickness. 3–5 Additionally, cortical folding may have high discriminatory value in correctly identifying symptom severity in schizophrenia. 6 Regional GMV and cortical thickness have also been combined in attempts to differentiate individuals with schizophrenia from healthy controls (HCs). 7 Applications of machine learning algorithms to diffusion imaging data analysis to predict individuals with first-episode schizophrenia (FES) have achieved encouraging accuracy. 8–10 White matter (WM) abnormalities in schizophrenia as estimated by DTI appear to be present in the early stage of the disorder, most likely reflecting the developmental stage of the sample of interest.

Abstract

Identifying data-driven biotypes of major depressive disorder (MDD) has promise for the clarification of diagnostic heterogeneity. However, few studies have focused on white-matter abnormalities for MDD subtyping. This study included 116 patients with MDD and 118 demographically-matched healthy controls assessed by diffusion tensor imaging and neurocognitive evaluation. Hierarchical clustering was applied to the major fiber tracts, in conjunction with tract-based spatial statistics, to reveal white-matter alterations associated with MDD. Clinical and neurocognitive differences were compared between identified subgroups and healthy controls. With fractional anisotropy extracted from 20 fiber tracts, cluster analysis revealed 3 subgroups based on the patterns of abnormalities. Patients in each subgroup versus healthy controls showed a stepwise pattern of white-matter alterations as follows: subgroup 1 (25.9% of patient sample), widespread white-matter disruption; subgroup 2 (43.1% of patient sample), intermediate and more localized abnormalities in aspects of the corpus callosum and left cingulate; and subgroup 3 (31.0% of patient sample), possible mild alterations, but no statistically significant tract disruption after controlling for family-wise error. The neurocognitive impairment in each subgroup accompanied the white-matter alterations: subgroup 1, deficits in sustained attention and delayed memory; subgroup 2, dysfunction in delayed memory; and subgroup 3, no significant deficits. Three subtypes of white-matter abnormality exist in individuals with major depression, those having widespread abnormalities suffering more neurocognitive impairments, which may provide evidence for parsing the heterogeneity of the disorder and help optimize type-specific treatment approaches.

Abstract

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.

Abstract

The anterior lordosis of the cervical spine is thought
to contribute to pitch (fo) production by influencing
cricoid rotation as a function of larynx height. This
study examines the matter of inter-individual
variation in cervical spine shape and whether this has
an influence on how fo is produced along increasing
or decreasing scales, using the ArtiVarK dataset,
which contains real-time MRI pitch production data.
We find that the cervical spine actively participates in
fo production, but the amount of displacement
depends on individual shape. In general, anterior
spine motion (tending toward cervical lordosis)
occurs for low fo, while posterior movement (tending
towards cervical kyphosis) occurs for high fo.

Abstract

Objective

Resting-state functional magnetic resonance imaging (fMRI) is promising for Alzheimer’s disease (AD). This study aimed to examine short-term reliability of the default-mode network (DMN), one of the main haemodynamic patterns of the brain.
Materials and methods

Using a 1.5 T Philips Achieva scanner, two consecutive resting-state fMRI runs were acquired on 69 healthy adults, 62 patients with mild cognitive impairment (MCI) due to AD, and 28 patients with AD dementia. The anterior and posterior DMN and, as control, the visual-processing network (VPN) were computed using two different methodologies: connectivity of predetermined seeds (theory-driven) and dual regression (data-driven). Divergence and convergence in network strength and topography were calculated with paired t tests, global correlation coefficients, voxel-based correlation maps, and indices of reliability.
Results

No topographical differences were found in any of the networks. High correlations and reliability were found in the posterior DMN of healthy adults and MCI patients. Lower reliability was found in the anterior DMN and in the VPN, and in the posterior DMN of dementia patients.
Discussion

Strength and topography of the posterior DMN appear relatively stable and reliable over a short-term period of acquisition but with some degree of variability across clinical samples.

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Abstract

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

Abstract

Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme–colour synaesthesia (n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index (R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging.

Abstract

Background Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms.

Objective To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach.

Methods We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African–American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted.

Results Genome-wide significant effects were observed at rs1555839 (p=4.03×10−8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer–promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule.

Conclusion This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene–brain–behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

Abstract

A commonly held assumption in cognitive neuroscience is that, because measures of human brain function are closer to underlying biology than distal indices of behavior/cognition, they hold more promise for uncovering genetic pathways. Supporting this view is an influential fMRI-based study of sentence reading/listening by Pinel et al. (2012), who reported that common DNA variants in specific candidate genes were associated with altered neural activation in language-related regions of healthy individuals that carried them. In particular, different single-nucleotide polymorphisms (SNPs) of FOXP2 correlated with variation in task-based activation in left inferior frontal and precentral gyri, whereas a SNP at the KIAA0319/TTRAP/THEM2 locus was associated with variable functional asymmetry of the superior temporal sulcus. Here, we directly test each claim using a closely matched neuroimaging genetics approach in independent cohorts comprising 427 participants, four times larger than the original study of 94 participants. Despite demonstrating power to detect associations with substantially smaller effect sizes than those of the original report, we do not replicate any of the reported associations. Moreover, formal Bayesian analyses reveal substantial to strong evidence in support of the null hypothesis (no effect). We highlight key aspects of the original investigation, common to functional neuroimaging genetics studies, which could have yielded elevated false-positive rates. Genetic accounts of individual differences in cognitive functional neuroimaging are likely to be as complex as behavioral/cognitive tests, involving many common genetic variants, each of tiny effect. Reliable identification of true biological signals requires large sample sizes, power calculations, and validation in independent cohorts with equivalent paradigms.

SIGNIFICANCE STATEMENT A pervasive idea in neuroscience is that neuroimaging-based measures of brain function, being closer to underlying neurobiology, are more amenable for uncovering links to genetics. This is a core assumption of prominent studies that associate common DNA variants with altered activations in task-based fMRI, despite using samples (10–100 people) that lack power for detecting the tiny effect sizes typical of genetically complex traits. Here, we test central findings from one of the most influential prior studies. Using matching paradigms and substantially larger samples, coupled to power calculations and formal Bayesian statistics, our data strongly refute the original findings. We demonstrate that neuroimaging genetics with task-based fMRI should be subject to the same rigorous standards as studies of other complex traits.

Abstract

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

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.