Genome-wide screening for DNA variants associated with reading and language traits

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Publisher PDFPeer reviewe

The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation

Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia

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 x 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 x 10(-9)), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 x 10(-8)). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 x 10(-8)) and with all the cognitive traits tested (p = 3.07 x 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 similar to [10(-5)-10(-7)]) and negatively associated with ADHD PRS (p similar to [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.Peer reviewe

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

The genetics of handedness and dyslexia

The population level bias towards right-handedness in humans implies left-hemisphere dominance for fine motor control. Left-handedness and reduced cerebral asymmetry have been linked to neurodevelopmental disorders such as dyslexia. Understanding the biology of these traits at a genetic level is crucial for understanding the relationship between handedness and neurodevelopmental disorders. Here I present genome-wide association study (GWAS) meta-analyses for both relative hand skill (handedness, n = 728) and reading-related traits (n = 548) in individuals with dyslexia. I uncovered a genome-wide significant association in an intron of PCSK6 associated with relative hand skill. PCSK6 is a protease that cleaves NODAL proprotein into an active form, and NODAL determines the development of left/right (LR) asymmetry in bilaterians. I performed pathway analyses of the GWAS data that revealed handedness is determined in part by the mechanisms that establish left/right (LR) asymmetry early in development, such as NODAL signalling and ciliogenesis. This finding replicated in a general population cohort unaffected with neurodevelopmental disorders (n = 2,666). A key stage in LR asymmetry development is the rotation of cilia that creates a leftward flow of NODAL. Candidate genes for dyslexia are involved in both neuronal migration and ciliogenesis. Ciliopathies can cause not only LR body asymmetry phenotypes, but also cerebral midline phenotypes such as an absent corpus callosum. Furthermore, I identified a genome-wide significant association with non-word reading located in an intron of MAP1B, a gene involved in neuronal migration that causes an absent corpus callosum when disrupted in mice. However, this finding did not replicate in two independent cohorts with dyslexia (n = 156 &amp; 199), or in the general population cohort (n = 2,359). Though these cohorts had inadequate reading measures and poorly matched ascertainment for dyslexia. I also performed copy number variation (CNV) pathway and burden analyses of 920 individuals with dyslexia and 1,366 unselected controls, but did not find that rare CNVs play a major role in the etiology of dyslexia. Based on these results I propose that common variants in genes responsible for ciliogenesis and corpus callosum development influence traits such as handedness and reading ability.</p

The genetics of handedness and dyslexia

The population level bias towards right-handedness in humans implies left-hemisphere dominance for fine motor control. Left-handedness and reduced cerebral asymmetry have been linked to neurodevelopmental disorders such as dyslexia. Understanding the biology of these traits at a genetic level is crucial for understanding the relationship between handedness and neurodevelopmental disorders. Here I present genome-wide association study (GWAS) meta-analyses for both relative hand skill (handedness, n = 728) and reading-related traits (n = 548) in individuals with dyslexia. I uncovered a genome-wide significant association in an intron of PCSK6 associated with relative hand skill. PCSK6 is a protease that cleaves NODAL proprotein into an active form, and NODAL determines the development of left/right (LR) asymmetry in bilaterians. I performed pathway analyses of the GWAS data that revealed handedness is determined in part by the mechanisms that establish left/right (LR) asymmetry early in development, such as NODAL signalling and ciliogenesis. This finding replicated in a general population cohort unaffected with neurodevelopmental disorders (n = 2,666). A key stage in LR asymmetry development is the rotation of cilia that creates a leftward flow of NODAL. Candidate genes for dyslexia are involved in both neuronal migration and ciliogenesis. Ciliopathies can cause not only LR body asymmetry phenotypes, but also cerebral midline phenotypes such as an absent corpus callosum. Furthermore, I identified a genome-wide significant association with non-word reading located in an intron of MAP1B, a gene involved in neuronal migration that causes an absent corpus callosum when disrupted in mice. However, this finding did not replicate in two independent cohorts with dyslexia (n = 156 & 199), or in the general population cohort (n = 2,359). Though these cohorts had inadequate reading measures and poorly matched ascertainment for dyslexia. I also performed copy number variation (CNV) pathway and burden analyses of 920 individuals with dyslexia and 1,366 unselected controls, but did not find that rare CNVs play a major role in the etiology of dyslexia. Based on these results I propose that common variants in genes responsible for ciliogenesis and corpus callosum development influence traits such as handedness and reading ability.</p

The genetic relationship between handedness and neurodevelopmental disorders

Handedness and brain asymmetry have been linked to neurodevelopmental disorders such as dyslexia and schizophrenia. The genetic nature of this correlation is not understood. Recent discoveries have shown handedness is determined in part by the biological pathways that establish left/right (LR) body asymmetry during development. Cilia play a key role in this process, and candidate genes for dyslexia have also been recently shown to be involved in cilia formation. Defective cilia result not only in LR body asymmetry phenotypes but also brain midline phenotypes such as an absent corpus callosum. These findings suggest that the mechanisms for establishing LR asymmetry in the body are reused for brain midline development, which in turn influences traits such as handedness and reading ability.Publisher PDFPeer reviewe