Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

Peer reviewe

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 x 10(-8)) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.Peer reviewe

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, in samples of 13,633 to 33,959 participants aged 5-26 years. We identified genome-wide significant association with word reading (rs11208009, p=1.098 x 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP-heritability, accounting for 13-26% of trait variability. Genomic structural equation modelling revealed a shared genetic factor explaining most variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain, and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of uniquely human traits

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Prevalence and Correlates of Autism Spectrum Disorders in Quebec

To estimate the prevalence, comorbidities, and service use of people with autism spectrum disorders (ASDs) based on data from Quebec Integrated Chronic Diseases Surveillance System (QICDSS).We included all residents up to age 24 eligible for health plan coverage who were in Quebec for at least 1 day from January 1, 1996, to March 31, 2015. To be considered as having an ASD, an individual had to have had at least 1 physician claim or hospital discharge abstract from 2000 to 2015 indicating one of the following ASD diagnosis codes: ICD-9 codes 299.0 to 299.9 or their ICD-10 equivalents.The QICDSS shows that the prevalence of ASD has risen steadily over the past decade to approximately 1.2% ( n = 16,940) of children and youths aged 1 to 17 years in 2014 to 2015. The same prevalence was obtained using Ministry of Education data. Common medical comorbidities included congenital abnormalities of the nervous system, particularly in the first year of life. Psychiatric comorbidity was much more highly prevalent, especially common mental disorders like anxiety and attention-deficit/hyperactivity disorder. Children and youths with ASDs made on average 2.3 medical visits per year compared with 0.2 in the general population. Between 18 and 24 years old, the mental health needs of individuals with ASDs were met less by medical specialists and more by general practitioners.Information derived from this database could support and monitor development of better medical services coordination and shared care to meet the continuous and changing needs of patients and families over time

Estimation de la prévalence et du taux d’incidence du trouble du spectre de l’autisme (TSA). Comparaison interprovinciale

L’objectif de cet article est d’estimer la prévalence et le taux d’incidence du trouble du spectre de l’autisme (TSA) diagnostiqué chez les enfants et les adolescents à partir de données médico-administratives jumelées de quatre provinces canadiennes. Un objectif secondaire est de comparer les résultats obtenus afin d’établir si les fichiers administratifs peuvent servir de système d’information pour la surveillance du TSA au Canada.Les estimations ont été produites à partir des données provenant des provinces du Manitoba, de l’Ontario, du Québec et de la Nouvelle-Écosse. La population à l’étude est composée de tous les résidents âgés de 24 ans et moins admissibles au régime d’assurance maladie en vertu de la loi provinciale entre 1999 à 2012. Pour être considéré comme ayant un TSA, l’individu devra avoir eu au moins une visite médicale ou une hospitalisation avec un diagnostic principal de TSA (codes 299 de la CIM-9 ou leurs équivalents CIM-10-CA). La prévalence annuelle et le taux d’incidence sont mesurés pour la période allant de 1999-2000 à 2011-2012, et présentés selon le sexe et par groupes d’âge.La prévalence du TSA entre 1999 et 2012 a connu une forte progression dans toutes les provinces et pour tous les groupes d’âge. Le taux d’incidence a suivi la même tendance d’accroissement dans le temps. La prévalence et le taux d’incidence du TSA n’ont pas augmenté de façon similaire dans toutes les provinces du Canada. L’Ontario semble afficher les plus fortes proportions, suivi de la Nouvelle-Écosse.Nos résultats permettent non seulement de dresser un portrait du TSA dans quatre provinces canadiennes, mais soulèvent aussi de nombreuses pistes pour de futures recherches. Cette étude discute également de l’utilité, de la fiabilité et du potentiel des fichiers médico-administratifs en matière de recherche.Objective The prevalence of diagnosed autism spectrum disorders (ASD) has risen steadily over time. There is therefore a need for the monitoring of treated ASD for timely policy making. The objective of this study is to report and compare over a 10-year period the prevalence and incidence rate of diagnosed ASD in four Canadian provinces.Methods This study utilized data from the provinces of Manitoba, Ontario, Quebec and Nova Scotia with access to linked administrative database sources used in the Canadian Chronic Diseases Surveillance Systems to assess the prevalence and incidence rate of a physician diagnosis of ASD. Estimates were produced using health datasets for outpatient and inpatient care (Med-Echo in Quebec, the Canadian Institute of Health Information Discharge Abstract Database in the three other provinces, plus the Ontario Mental Health Reporting System). Dates of service, diagnosis, and physician specialty were extracted. The target population consisted of all residents aged 24 and under eligible for healthcare coverage under provincial law between 1999 and 2012. To be considered as having ASD, an individual had to have at least one physician claim or hospital discharge abstract indicating one of the following: ICD-9 codes 299.0 to 299.9 or their ICD-10 equivalents, F84.0 to F84.9. The estimates were presented in yearly brackets between 1999-2000 and 2011-2012 by sex and age groups. The main analyses focused on those aged 17 years or less, with the 18 to 24 years group added to show the subsequent progression of the disorder.Results Our findings show that the annual prevalence of ASD rose steadily between 1999 and 2012 in all provinces and for all age groups although this increase varied across Canadian provinces. There were higher annual prevalence estimates in Ontario (4.8 per 1,000) and Nova Scotia (4.2 per 1,000) compared to Quebec (3.0 per 1,000) and Manitoba (2.5 per 1,000), among persons aged 17 years and younger in 2011. As compared to 1999, Quebec and Ontario reported a fivefold and fourfold increase in 2010-2012, the highest among provinces. The prevalence was four times higher in boys than in girls. By age group, the highest prevalence was observed in those aged between 1 to 4 and 5 to 9 years depending on the province. ASD was generally diagnosed before age 10. Incident cases were more frequently diagnosed by pediatricians followed by either psychiatrists or general practitioners depending on the province.Conclusion Our research confirms that ASD has risen steadily in terms of prevalence and incidence rate and that it varies considerably across provinces. It also demonstrates that health administrative databases can be used as registers for ASD. Information derived from these databases could support and monitor development of improved coordination and shared care to meet the continuous and changing needs of patients and families over time. Implication for future research include exploring the etiology of ASD in more recent cohorts as well as investigating the association between variations in health service availability and the prevalence of ASD

Modulating the activity of human nociceptors with a SCN10A promoter-specific viral vector tool

Despite the high prevalence of chronic pain as a disease in our society, there is a lack of effective treatment options for patients living with this condition. Gene therapies using recombinant AAVs are a direct method to selectively express genes of interest in target cells with the potential of, in the case of nociceptors, reducing neuronal firing in pain conditions. We designed a recombinant AAV vector expressing cargos whose expression was driven by a portion of the SCN10A (NaV1.8) promoter, which is predominantly active in nociceptors. We validated its specificity for nociceptors in mouse and human dorsal root ganglia and showed that it can drive the expression of functional proteins. Our viral vector and promoter package drove the expression of both excitatory or inhibitory DREADDs in primary human DRG cultures and in whole cell electrophysiology experiments, increased or decreased neuronal firing, respectively. Taken together, we present a novel viral tool that drives expression of cargo specifically in human nociceptors. This will allow for future specific studies of human nociceptor properties as well as pave the way for potential future gene therapies for chronic pain

Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis

International audienceNeurons have an important role in retinal vascular development. Here we show that the G protein-coupled receptor (GPCR) coagulation factor II receptor-like 1 (F2rl1, previously known as Par2) is abundant in retinal ganglion cells and is associated with new blood vessel formation during retinal development and in ischemic retinopathy. After stimulation, F2rl1 in retinal ganglion cells translocates from the plasma membrane to the cell nucleus using a microtubule-dependent shuttle that requires sorting nexin 11 (Snx11). At the nucleus, F2rl1 facilitates recruitment of the transcription factor Sp1 to trigger Vegfa expression and, in turn, neovascularization. In contrast, classical plasma membrane activation of F2rl1 leads to the expression of distinct genes, including Ang1, that are involved in vessel maturation. Mutant versions of F2rl1 that prevent nuclear relocalization but not plasma membrane activation interfere with Vegfa but not Ang1 expression. Complementary angiogenic factors are therefore regulated by the subcellular localization of a receptor (F2rl1) that governs angiogenesis. These findings may have implications for the selectivity of drug actions based on the subcellular distribution of their targets