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&thinsp;=&thinsp;2562&ndash;3468). We observed a genome-wide significant effect (p&thinsp;&lt;&thinsp;1&thinsp;&times;&thinsp;10&minus;8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p&thinsp;=&thinsp;4.73&thinsp;&times;&thinsp;10&minus;9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p&thinsp;=&thinsp;2.25&thinsp;&times;&thinsp;10&minus;8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p&thinsp;=&thinsp;1.15&thinsp;&times;&thinsp;10&minus;8) and with all the cognitive traits tested (p&thinsp;=&thinsp;3.07&thinsp;&times;&thinsp;10&minus;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&thinsp;~&thinsp;[10&minus;5&ndash;10&minus;7]) and negatively associated with ADHD PRS (p&thinsp;~&thinsp;[10&minus;8&minus;10&minus;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. </div

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

Response to early literacy instruction in the United States, Australia, and Scandinavia A behavioral-genetic analysis

Abstract Genetic and environmental influences on early reading and spelling at the end of kindergarten and Grade 1 were compared across three twin samples tested in the United States, Australia, and Scandinavia. Proportions of variance due to genetic influences on kindergarten reading were estimated at .84 in Australia, .68 in the U.S., and .33 in Scandinavia. The effects of shared environment on kindergarten reading were estimated at .09 in Australia, .25 in the U.S., and .52 in Scandinavia. A similar pattern of genetic and environmental influences was obtained for kindergarten spelling. One year later when twins in all three samples had received formal literacy instruction for at least one full school year, heritability was similarly high across country, with estimated genetic influences varying between .79 and .83 for reading and between .62 and .79 for spelling. These findings indicate that the pattern of genetic and environmental influences on early reading and spelling development varies according to educational context, with genetic influence increasing as a function of increasing intensity of early instruction. Longitudinal analyses revealed genetic continuity for both reading and spelling between kindergarten and Grade 1 across country. However, a new genetic factor comes into play accounting for independent variance in reading at Grade 1 in the U.S. and Scandinavia, suggesting a change in genetic influences on reading. Implications for responseto-instruction are discussed. 4 Historically, and as late as 1800, more than 50% of the population in most western countries was illiterate. The opportunity to learn to read and write was a privilege, to a large extent determined by social-cultural conditions In this article, we continue to report on our International Longitudinal Twin Study (ILTS) of early language and literacy development The main purpose here was to compare genetic and environmental influences on early reading and spelling skills across three twin samples tested in the United States, Australia, and Scandinavia (i.e., Sweden and Norway) and across time of testing (i.e., kindergarten and Grade 1). Two questions are addressed: First, are there any differences in the pattern of genetic and environmental influences on early reading and spelling skills across country? Second, what are the changes in the pattern of genetic and environmental influences on reading and spelling from kindergarten to Grade 1? The general expectation is that the effects of environment on literacy skills should decrease and the genetic contribution increase as a function of intensity and consistency of instruction, across countries and time. This approach should also inform recent interest in response-to-intervention, or RTI, as a method to ascertain, define, and remediate 5 reading difficulties The ILTS has previously documented substantial effects of genes and relatively minor However, in a recent ILTS study of data collected near the end of kindergarten ), individual differences in reading and spelling skills were mainly 6 accounted for by genetic factors in a sample of Australian twins, with estimates of .91 and .84, respectively. In contrast, in a sample of U.S. twins from the state of Colorado, only approximately half of the variance in reading and spelling was accounted for by genetic influences, with the other half attributed to shared and non-shared environment. Although these country differences in genetic and environmental influences on individual differences in reading and spelling were not statistically significant with the available sample sizes, we hypothesized that the trends might be explained by country differences in educational practice. Compulsory school starts at around age five in both Australia and Colorado, but in New South Wales, Australian children enter a school system regulated by a state-wide curriculum mandating that at least 35% of a full school week (9 am to 3 pm, five days a week) should be devoted to language and literacy instruction. In contrast, in Colorado children attend kindergarten school for only 3-4 hours each day, and there is no state-mandated curriculum for teaching reading and spelling. One plausible explanation for the different pattern of genetic and environmental influences on reading and spelling in Australia and U.S. is that a state-wide curriculum emphasizing intense literacy instruction reduces the environmental range in the population, and thus, the amount of variance in reading and spelling skills that can be accounted for by environmental factors. Another explanation is that the greater intensity of instruction in NSW engages genetically-influenced learning processes earlier than in the US, resulting in a higher genetic contribution to overall variability. To further explore these hypotheses, the present study includes a sample of Scandinavian twins. In Scandinavia, compulsory school starts when the child is seven years old, that is, one to two years later compared to Australia and the U.S. Nevertheless, almost all children do attend kindergarten prior to compulsory attendance in Grade 1, but kindergarten curriculum in Sweden and Norway emphasizes social, emotional, and aesthetic development rather than early literacy acquisition. In this way, Scandinavia represents a population where environmental 7 variation outside of school might have a substantial impact on individual differences in kindergarten reading and spelling skills because there is no formal reading instruction in kindergarten. Instead, literacy socialization is mainly given informally at home. However, at seven years of age, in Grade 1, teaching reading and spelling is the target activity in school, and literacy instruction is guided by a master plan common to all schools in Sweden and Norway. This change from informal literacy teaching taking place at the children&apos;s home to a countrywide curriculum emphasizing formal reading and spelling instruction should reduce environmental range and increase the intensity of engagement. From kindergarten to Grade 1, we hypothesize, therefore, that the heritability of literacy skills increases and the importance of shared environment decreases in Scandinavia. To summarize, we hypothesize different contributions from genes and environment to kindergarten literacy skills across countries. We also hypothesize an increase in genetic effects on literacy from kindergarten to Grade 1, especially in Scandinavia where formal reading instruction is introduced one year later than in Australia and the U.S. These questions are addressed in the present study through univariate behavior-genetic analyses of data from identical and same-sex fraternal twins tested near the end of kindergarten and first grade. In addition to comparing the magnitudes of genetic and environmental influences between countries and grades in univariate analyses, with a multivariate approach we also address the question whether the same or different sources of genetic and environmental influences account for individual differences in literacy at kindergarten and Grade 1. Based on the differences in the curriculum for literacy instruction across countries summarized above, we hypothesize continuity in the pattern of genetic and environmental influences on reading and spelling from kindergarten to Grade 1 in Australia, but a possible change in genetic and environmental effects on literacy skills in Scandinavia, with the US representing an intermediate case. Method Participants The kindergarten sample comprised a total of 812 same-sex twin pairs recruited from the Colorado Twin Registry in the U.S., the National Heath and Medical Research Council&apos;s Australian Twin Registry, and from the Medical Birth Registries in Norway and Sweden (see Actual attrition because of families leaving the project is virtually zero. Only participants for whom the predominant language of their country (i.e., English, Swedish, or Norwegian) was the first language spoken at home were selected. There were no significant differences in parents&apos; mean years of education across twin samples. Also, the means were around 14 years suggesting that level of education is representative for each country. Zygosity was determined by DNA analysis from cheek swab collection, or, in a minority of cases, by selected items from the questionnaire by Literacy skills Reading. Reading skills in kindergarten and Grade 1 were measured by both the word and nonword subtests from the Test of Word Reading Efficiency (TOWRE; Torgesen, Wagner, &amp; Rashotte, 1999), with both Forms A and B administered and averaged to increase reliability (test-retest reliability for children aged 6-9 years, .97 for word and .90 for nonword standard scores). In each Form, children read a list of words and a list of nonwords as quickly as possible in 45 sec. A composite measure of reading skill was created for phenotypic analyses, justified by high correlations, .83 and .86 on average, between word and nonword reading at both kindergarten and at the end of Grade 1. For the behavior genetic analyses, we modelled the four subtests of word and nonword reading as latent traits. Spelling. At kindergarten, spelling was measured by a test developed by Byrne and Fielding- Procedure Children were assessed individually by trained examiners in their homes and/or schools at the end of kindergarten and Grade 1. To foster fidelity of assessment between testers and sites, we have adopted the practice of videotaping samples of test sessions and having each tester inspect the tapes of other testers. In this study, we only report on reading and spelling measures performed at each age. However, in single one-hour sessions at each of kindergarten and Grade 1, several other measures such as phonological awareness, RAN, and verbal abilities were included (for details, see Analysis One-way analyses of variance (ANOVA) and Tukey HSD post hoc tests were performed to test differences between country samples for reading and spelling at kindergarten and Grade 1. The magnitude of the mean differences was calculated using Cohen&apos;s d. Genetic and environmental influences on reading and spelling skills across country and within country 11 across time were analyzed using monozygotic (MZ) and dizygotic (DZ) twin correlations, and models were fitted from raw data using maximum likelihood estimation in Mx Results Reading and spelling skills across country Means and standard deviations for reading and spelling at kindergarten and Grade 1 across country and effect size estimations for mean differences are presented in Behavior-genetic analyses Standardized raw data adjusted for age and gender effects within each twin sample were used as input for all behavior-genetic analyses. To estimate the relative influence on individual differences from additive genetic effects (a 2 ), shared-environment effects (c 2 ), and nonsharedenvironment effects (e 2 ), the data for reading and spelling skills were subjected to structural equation modelling by use of the Mx statistical modelling package (Neale, Boker, Xie, &amp; Maes, 2002). In this section, we start by presenting correlations between MZ and DZ twins

Discovery of 42 genome-wide significant loci associated with dyslexia

Funding: EE, GA, BM, BSP, CF and SEF are supported by the Max Planck Society (Germany). The Chinese Reading Study was supported by grants from the National Natural Science Foundation of China Youth Project (Grant No. 61807023), the Youth Fund for Humanities and Social Sciences Research of the Ministry of Education (Grant No. 19YJC190023 and 17XJC190010), and the Natural Science Basic Research Plan in Shaanxi Province of China (Grant No. 2021JQ-309). SP is funded by the Royal Society.Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.Publisher PDFPeer reviewe

Identification of Candidate Genes for Dyslexia Susceptibility on Chromosome 18

Background: Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis. Methodology/Principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L). Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.Publisher PDFPeer reviewe

Monitoring the world's agriculture

Agriculture must be transformed. Although global food production is increasing, today's farming systems undermine the well-being of communities in many ways. For instance, farming has destroyed huge regions of natural habitat and caused an untold loss of ecosystem services, and it is responsible for about 30% of greenhouse-gas emissions. Already, about 1 billion people are undernourished. Yet to feed the global population expected by 2050, more than 1 billion hectares of wild land will need to be converted to farmland if current approaches continue to be used

Effective monitoring of agriculture: a response

The development of effective agricultural monitoring networks is essential to track, anticipate and manage changes in the social, economic and environmental aspects of agriculture. We welcome the perspective of Lindenmayer and Likens (J. Environ. Monit., 2011, 13, 1559) as published in the Journal of Environmental Monitoring on our earlier paper, “Monitoring the World's Agriculture” (Sachs et al., Nature, 2010, 466, 558–560). In this response, we address their three main critiques labeled as ‘the passive approach’, ‘the problem with uniform metrics’ and ‘the problem with composite metrics’. We expand on specific research questions at the core of the network design, on the distinction between key universal and site-specific metrics to detect change over time and across scales, and on the need for composite metrics in decision-making. We believe that simultaneously measuring indicators of the three pillars of sustainability (environmentally sound, social responsible and economically viable) in an effectively integrated monitoring system will ultimately allow scientists and land managers alike to find solutions to the most pressing problems facing global food security