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.
Migraine is a disabling common brain disorder typically characterized by attacks of severe headache and associated with autonomic and neurological symptoms. Its etiology is far from resolved. This ...review will focus on evidence that epigenetic mechanisms play an important role in disease etiology. Epigenetics comprise both DNA methylation and post-translational modifications of the tails of histone proteins, affecting chromatin structure and gene expression. Besides playing a role in establishing cellular and developmental stage-specific regulation of gene expression, epigenetic processes are also important for programming lasting cellular responses to environmental signals. Epigenetic mechanisms may explain how non-genetic endogenous and exogenous factors such as female sex hormones, stress hormones and inflammation trigger may modulate attack frequency. Developing drugs that specifically target epigenetic mechanisms may open up exciting new avenues for the prophylactic treatment of migraine.
An aberrant interaction between hematopoietic stem cells and mesenchymal stromal cells has been linked to disease and shown to contribute to the pathophysiology of hematologic malignancies in murine ...models. Juvenile myelomonocytic leukemia is an aggressive malignant disease affecting young infants. Here we investigated the impact of juvenile myelomonocytic leukemia on mesenchymal stromal cells. Mesenchymal stromal cells were expanded from bone marrow samples of patients at diagnosis (n=9) and after hematopoietic stem cell transplantation (n=7; from 5 patients) and from healthy children (n=10). Cells were characterized by phenotyping, differentiation, gene expression analysis (of controls and samples obtained at diagnosis) and in vitro functional studies assessing immunomodulation and hematopoietic support. Mesenchymal stromal cells from patients did not differ from controls in differentiation capacity nor did they differ in their capacity to support in vitro hematopoiesis. Deep-SAGE sequencing revealed differential mRNA expression in patient-derived samples, including genes encoding proteins involved in immunomodulation and cell-cell interaction. Selected gene expression normalized during remission after successful hematopoietic stem cell transplantation. Whereas natural killer cell activation and peripheral blood mononuclear cell proliferation were not differentially affected, the suppressive effect on monocyte to dendritic cell differentiation was increased by mesenchymal stromal cells obtained at diagnosis, but not at time of remission. This study shows that active juvenile myelomonocytic leukemia affects the immune response-related gene expression and function of mesenchymal stromal cells. In contrast, the differential gene expression of hematopoiesis-related genes could not be supported by functional data. Decreased immune surveillance might contribute to the therapy resistance and progression in juvenile myelomonocytic leukemia.
Background: Generalized Structured Component Analysis (GSCA) is a component-based alternative to traditional covariance-based structural equation modelling. This method has previously been applied to ...test for association between candidate genes and clinical phenotypes, contrasting with traditional genetic association analyses that adopt univariate testing of many individual single nucleotide polymorphisms (SNPs) with correction for multiple testing. Methods: We first evaluate the ability of the GSCA method to replicate two previous findings from a genetics association study of developmental language disorders. We then present the results of a simulation study to test the validity of the GSCA method under more restrictive data conditions, using smaller sample sizes and larger numbers of SNPs than have previously been investigated. Finally, we compare GSCA performance against univariate association analysis conducted using PLINK v1.9. Results: Results from simulations show that power to detect effects depends not just on sample size, but also on the ratio of SNPs with effect to number of SNPs tested within a gene. Inclusion of many SNPs in a model dilutes true effects. Conclusions: We propose that GSCA is a useful method for replication studies, when candidate SNPs have been identified, but should not be used for exploratory analysis.
Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated ...with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the ‘antagonistic pleiotropy’ hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report – https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18–88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.
Rhythm-related skills such as beat synchronization are phenotypically correlated with language traits, with implications for shared neural and genetic architectures. In particular, individuals with ...rhythm impairment may be predisposed towards disorders such as dyslexia and developmental language disorder. Shared risk is thought to be rooted biologically, given that the evolution of rhythm synchrony has been theoretically linked to multiple aspects of human communication. Genomic approaches bring a new dimension to explore theories on the co-evolution of language and rhythm. We hypothesize that identifying shared genetic architecture of rhythm and language and probing the evolutionary past of the common genetic factor, can reveal neural and biological underpinnings of rhythm and language traits.
We used summary statistics from two large-scale genome-wide-association studies (GWAS) in samples of European ancestry from our collaborations with 23 and Me, inc.: 1) GWAS of a musical rhythm phenotype (beat synchronization) in N=606,825 individuals, and 2) GWAS of dyslexia in N=1,138,870. In line with phenotypic evidence, we found significant genetic correlations between beat synchronization and a set of language-related traits including dyslexia (rg(SE)=-0.28(0.02), PFDR=2.05 × 10-31) and language resting-state functional connectivity (rg(SE)=0.28(0.05), PFDR=8.72 × 10-32).
We then performed a multivariate GWAS (mvGWAS) using Genomic Structural Equation Modelling in a bivariate common factor framework to capture the shared genetic factor associated with rhythm impairment and dyslexia, which we call D-RI. Our mvGWAS identified 18 genome-wide significant loci, with the strongest signal coming from the SNP rs28576629 (P=3.79 × 10-14) on chromosome 3, an intronic SNP located on PPP2R3A (implicated in calcium ion binding and protein phosphatase regulator activity). Next, we used S-PrediXcan to integrate gene expression information with D-RI summary statistics, and to identify genes whose predicted expression levels are associated with D-RI. We used the whole-blood and 13 brain joint-tissue imputation phenotype weights, yielding 342 unique genes significantly associated (PFDR < 0.05) with D-RI, including AC072039.2 expression in brain nucleus (Z-score=-7.74, PFDR=1.17 × 10-9). LDSC partitioned heritability analysis yielded significant SNP-heritability enrichments in various cell type-specific regulatory regions, including neuronal promoters (Enrichment(SE)=8.14(1.55), PFDR=3.38 × 10-5) and enhancers (Enrichment(SE)=4.43(0.35), PFDR=7.96 × 10-18). We investigated the associations between D-RI and white-matter tracts of evolutionary significance using LAVA, and identified a significant local genetic correlation between D-RI and the left hemisphere superior longitudinal fasciculus I (rg=1, PFDR=0.02), a white-matter tract implicated in auditory-motor connectivity.
Overall, our results reveal the complexity of shared genetic and neural foundations of rhythm and language, and groundwork towards co-evolution debates.
Genetic investigations of people with speech and language disorders can provide windows into key aspects of human biology. Most genomic research into impaired speech development has so far focused on ...childhood apraxia of speech (CAS), a rare neurodevelopmental disorder characterized by difficulties with coordinating rapid fine motor sequences that underlie proficient speech. In 2001, pathogenic variants of FOXP2 provided the first molecular genetic accounts of CAS aetiology. Since then, disruptions in several other genes have been implicated in CAS, with a substantial proportion of cases being explained by high-penetrance variants. However, the genetic architecture underlying other speech-related disorders remains less well understood. Thus, in the present study, we used systematic DNA sequencing methods to investigate idiopathic speech delay, as characterized by delayed speech development in the absence of a motor speech diagnosis (such as CAS), a language/reading disorder, or intellectual disability. We performed genome sequencing in a cohort of 23 children with a rigorous diagnosis of idiopathic speech delay. For roughly half of the sample (ten probands), sufficient DNA was also available for genome sequencing in both parents, allowing discovery of de novo variants. In the thirteen singleton probands, we focused on identifying loss-of-function and likely damaging missense variants in genes intolerant to such mutations. We found that one speech delay proband carried a pathogenic frameshift deletion in SETD1A, a gene previously implicated in a broader variable monogenic syndrome characterized by global developmental problems including delayed speech and/or language development, mild intellectual disability, facial dysmorphisms, and behavioural and psychiatric symptoms. Of note, pathogenic SETD1A variants have been independently reported in children with CAS in two separate studies. In other probands in our speech delay cohort, likely pathogenic missense variants were identified affecting highly conserved amino acids in key functional domains of SPTBN1 and ARF3. Overall, this study expands the phenotype spectrum associated with pathogenic SETD1A variants, to also include idiopathic speech delay without CAS or intellectual disability, and suggests additional novel potential candidate genes that may harbour high-penetrance variants that can disrupt speech development.
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