Genetic neurodevelopmental clustering and dyslexia.

Dyslexia is a learning difficulty with neurodevelopmental origins, manifesting as reduced accuracy and speed in reading and spelling. It is substantially heritable and frequently co-occurs with other neurodevelopmental conditions, particularly attention deficit-hyperactivity disorder (ADHD). Here, we investigate the genetic structure underlying dyslexia and a range of psychiatric traits using results from genome-wide association studies of dyslexia, ADHD, autism, anorexia nervosa, anxiety, bipolar disorder, major depressive disorder, obsessive compulsive disorder, schizophrenia, and Tourette syndrome. Genomic Structural Equation Modelling (GenomicSEM) showed heightened support for a model consisting of five correlated latent genomic factors described as: F1) compulsive disorders (including obsessive-compulsive disorder, anorexia nervosa, Tourette syndrome), F2) psychotic disorders (including bipolar disorder, schizophrenia), F3) internalising disorders (including anxiety disorder, major depressive disorder), F4) neurodevelopmental traits (including autism, ADHD), and F5) attention and learning difficulties (including ADHD, dyslexia). ADHD loaded more strongly on the attention and learning difficulties latent factor (F5) than on the neurodevelopmental traits latent factor (F4). The attention and learning difficulties latent factor (F5) was positively correlated with internalising disorders (.40), neurodevelopmental traits (.25) and psychotic disorders (.17) latent factors, and negatively correlated with the compulsive disorders (-.16) latent factor. These factor correlations are mirrored in genetic correlations observed between the attention and learning difficulties latent factor and other cognitive, psychological and wellbeing traits. We further investigated genetic variants underlying both dyslexia and ADHD, which implicated 49 loci (40 not previously found in GWAS of the individual traits) mapping to 174 genes (121 not found in GWAS of individual traits) as potential pleiotropic variants. Our study confirms the increased genetic relation between dyslexia and ADHD versus other psychiatric traits and uncovers novel pleiotropic variants affecting both traits. In future, analyses including additional co-occurring traits such as dyscalculia and dyspraxia will allow a clearer definition of the attention and learning difficulties latent factor, yielding further insights into factor structure and pleiotropic effects.

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 × 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.

Diverging Maternal and Cord Antibody Functions From SARS-CoV-2 Infection and Vaccination in Pregnancy.

Maternal immunity impacts the infant, but how is unclear. To understand the implications of the immune exposures of vaccination and infection in pregnancy for neonatal immunity, we evaluated antibody functions in paired peripheral maternal and cord blood. We compared those who in pregnancy received mRNA coronavirus disease 2019 (COVID-19) vaccine, were infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the combination. We found that vaccination enriched a subset of neutralizing activities and Fc effector functions that was driven by IgG1 and was minimally impacted by antibody glycosylation in maternal blood. In paired cord blood, maternal vaccination also enhanced IgG1. However, Fc effector functions compared to neutralizing activities were preferentially transferred. Moreover, changes in IgG posttranslational glycosylation contributed more to cord than peripheral maternal blood antibody functional potency. These differences were enhanced with the combination of vaccination and infection as compared to either alone. Thus, Fc effector functions and antibody glycosylation highlight underexplored maternal opportunities to safeguard newborns.

Evaluating Humoral Immunity Elicited by XBB.1.5 Monovalent COVID-19 Vaccine.

Because novel SARS-CoV-2 variants continue to emerge, immunogenicity of XBB.1.5 monovalent vaccines against live clinical isolates needs to be evaluated. We report boosting of IgG (2.1×), IgA (1.5×), and total IgG/A/M (1.7×) targeting the spike receptor-binding domain and neutralizing titers against WA1 (2.2×), XBB.1.5 (7.4×), EG.5.1 (10.5×), and JN.1 (4.7×) variants.

Longitudinal Reading Measures and Genome Imputation in the National Child Development Study: Prospects for Future Reading Research.

Reading difficulties are prevalent worldwide, including in economically developed countries, and are associated with low academic achievement and unemployment. Longitudinal studies have identified several early childhood predictors of reading ability, but studies frequently lack genotype data that would enable testing of predictors with heritable influences. The National Child Development Study (NCDS) is a UK birth cohort study containing direct reading skill variables at every data collection wave from age 7 years through to adulthood with a subsample (final n = 6431) for whom modern genotype data are available. It is one of the longest running UK cohort studies for which genotyped data are currently available and is a rich dataset with excellent potential for future phenotypic and gene-by-environment interaction studies in reading. Here, we carry out imputation of the genotype data to the Haplotype Reference Panel, an updated reference panel that offers greater imputation quality. Guiding phenotype choice, we report a principal components analysis of nine reading variables, yielding a composite measure of reading ability in the genotyped sample. We include recommendations for use of composite scores and the most reliable variables for use during childhood when conducting longitudinal, genetically sensitive analyses of reading ability.

Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.

Developmental defects affecting the heart and aortic arch arteries are a significant phenotype observed in individuals with 22q11 deletion syndrome and are caused by a microdeletion on chromosome 22q11. TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key gene, when mutated, for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9-deficient mice are born with complex cardiovascular malformations that affect the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared with Tbx1 heterozygous mice. Using a novel Pax9Cre allele, we demonstrated that the site of this Tbx1-Pax9 genetic interaction is the pharyngeal endoderm, therefore revealing that a Tbx1-Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for crucial tissue interactions during normal morphogenesis of the pharyngeal arch artery system.

High seroprevalence of anti-SARS-CoV-2 antibodies among Ethiopian healthcare workers.

BACKGROUND: COVID-19 pandemic has a devastating impact on the economies and health care system of sub-Saharan Africa. Healthcare workers (HWs), the main actors of the health system, are at higher risk because of their occupation. Serology-based estimates of SARS-CoV-2 infection among HWs represent a measure of HWs' exposure to the virus and could be used as a guide to the prevalence of SARS-CoV-2 in the community and valuable in combating COVID-19. This information is currently lacking in Ethiopia and other African countries. This study aimed to develop an in-house antibody testing assay, assess the prevalence of SARS-CoV-2 antibodies among Ethiopian high-risk frontline HWs. METHODS: We developed and validated an in-house Enzyme-Linked Immunosorbent Assay (ELISA) for specific detection of anti-SARS-CoV-2 receptor binding domain immunoglobin G (IgG) antibodies. We then used this assay to assess the seroprevalence among HWs in five public hospitals located in different geographic regions of Ethiopia. From consenting HWs, blood samples were collected between December 2020 and February 2021, the period between the two peaks of COVID-19 in Ethiopia. Socio-demographic and clinical data were collected using questionnaire-based interviews. Descriptive statistics and bivariate and multivariate logistic regression were used to determine the overall and post-stratified seroprevalence and the association between seropositivity and potential risk factors. RESULTS: Our successfully developed in-house assay sensitivity was 100% in serum samples collected 2- weeks after the first onset of symptoms whereas its specificity in pre-COVID-19 pandemic sera was 97.7%. Using this assay, we analyzed a total of 1997 sera collected from HWs. Of 1997 HWs who provided a blood sample, and demographic and clinical data, 51.7% were females, 74.0% had no symptoms compatible with COVID-19, and 29.0% had a history of contact with suspected or confirmed patients with SARS-CoV-2 infection. The overall seroprevalence was 39.6%. The lowest (24.5%) and the highest (48.0%) seroprevalence rates were found in Hiwot Fana Specialized Hospital in Harar and ALERT Hospital in Addis Ababa, respectively. Of the 821 seropositive HWs, 224(27.3%) of them had a history of symptoms consistent with COVID-19 while 436 (> 53%) of them had no contact with COVID-19 cases as well as no history of COVID-19 like symptoms. A history of close contact with suspected/confirmed COVID-19 cases is associated with seropositivity (Adjusted Odds Ratio (AOR) = 1.4, 95% CI 1.1-1.8; p = 0.015). CONCLUSION: High SARS-CoV-2 seroprevalence levels were observed in the five Ethiopian hospitals. These findings highlight the significant burden of asymptomatic infection in Ethiopia and may reflect the scale of transmission in the general population.

Cannabinoids Block Cellular Entry of SARS-CoV-2 and the Emerging Variants.

As a complement to vaccines, small-molecule therapeutic agents are needed to treat or prevent infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its variants, which cause COVID-19. Affinity selection-mass spectrometry was used for the discovery of botanical ligands to the SARS-CoV-2 spike protein. Cannabinoid acids from hemp (Cannabis sativa) were found to be allosteric as well as orthosteric ligands with micromolar affinity for the spike protein. In follow-up virus neutralization assays, cannabigerolic acid and cannabidiolic acid prevented infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells. Importantly, cannabigerolic acid and cannabidiolic acid were equally effective against the SARS-CoV-2 alpha variant B.1.1.7 and the beta variant B.1.351. Orally bioavailable and with a long history of safe human use, these cannabinoids, isolated or in hemp extracts, have the potential to prevent as well as treat infection by SARS-CoV-2.

Who Believes in the Species? Three-Factor Structure and Heritability of Generativity.

Erikson asked what makes some people care for the future of the species and others not, calling this 'generativity vs. stagnation'. In three studies, we addressed structure of this trait and its heritability. Study 1 (N = 1570), using structural models of the Loyola Generativity Scale , revealed three correlated factors consisting of (1) Establishing and aiding the next generation; (2) Maintaining the world; and (3) Symbolic immortality through a positive legacy. Study 2 (N = 311) successfully replicated this structure in an independent UK sample. Study 3 tested genetic and environmental influences on generativity. All three factors showed significant and substantial heritable influence. A general factor was required, which was also heritable. In resolving previous uncertainty over the transmission of generativity across generations, shared environmental transmission models fit poorly. Substantial unique environmental effects suggest strong cultural impacts on concern for the species. Generativity researchers may usefully adopt this three-factor scoring system, allowing research on the predictive power of each component of generativity as well as molecular genetic or biological studies.

Factors driving the seasonal and hourly variability of sea-spray aerosol number in the North Atlantic.

Four North Atlantic Aerosol and Marine Ecosystems Study (NAAMES) field campaigns from winter 2015 through spring 2018 sampled an extensive set of oceanographic and atmospheric parameters during the annual phytoplankton bloom cycle. This unique dataset provides four seasons of open-ocean observations of wind speed, sea surface temperature (SST), seawater particle attenuation at 660 nm (cp,660, a measure of ocean particulate organic carbon), bacterial production rates, and sea-spray aerosol size distributions and number concentrations (NSSA). The NAAMES measurements show moderate to strong correlations (0.56 < R < 0.70) between NSSA and local wind speeds in the marine boundary layer on hourly timescales, but this relationship weakens in the campaign averages that represent each season, in part because of the reduction in range of wind speed by multiday averaging. NSSA correlates weakly with seawater cp,660 (R = 0.36, P << 0.01), but the correlation with cp,660, is improved (R = 0.51, P < 0.05) for periods of low wind speeds. In addition, NAAMES measurements provide observational dependence of SSA mode diameter (dm) on SST, with dm increasing to larger sizes at higher SST (R = 0.60, P << 0.01) on hourly timescales. These results imply that climate models using bimodal SSA parameterizations to wind speed rather than a single SSA mode that varies with SST may overestimate SSA number concentrations (hence cloud condensation nuclei) by a factor of 4 to 7 and may underestimate SSA scattering (hence direct radiative effects) by a factor of 2 to 5, in addition to overpredicting variability in SSA scattering from wind speed by a factor of 5.

Evolving the blank slate.

We support Uchiyama et al. in the value of genetics, sample diversification, and context measurement. Against the example of vitamins, we highlight the intransigence of many phenotypes. We caution that while culture can mask genetic differences, the dependence of behaviour on genetics is reinvented and unmasked by novel challenges across generations.

The Association of Race, Ethnicity, and Wages Among Registered Nurses in Long-term Care.

OBJECTIVE: This study seeks to measure wage differences between registered nurses (RNs) working in long-term care (LTC) (eg, nursing homes, home health) and non-LTC settings (eg, hospitals, ambulatory care) and whether differences are associated with the characteristics of the RN workforce between and within settings. STUDY DESIGN: This was a cross-sectional design. This study used the 2018 National Sample Survey of Registered Nurses (NSSRN) public-use file to examine RN employment and earnings. METHODS: Our study population included a sample of 15,373 RNs who were employed at least 1000 hours in nursing in the past year and active in patient care. Characteristics such as race/ethnicity, type of RN degree completed, census region, and union status were included. Multiple regression analyses examined the effect of these characteristics on wages. Logistic regression was used to predict RN employment in LTC settings. RESULTS: RNs in LTC experienced lower wages compared with those in non-LTC settings, yet this difference was not associated with racial/ethnic or international educational differences. Among RNs working in LTC, lower wages were associated with part-time work, less experience, lack of union representation, and regional wage differences. CONCLUSION: Because RNs in LTC earn lower wages than RNs in other settings, policies to minimize pay inequities are needed to support the RN workforce caring for frail older adults.

Gene expression changes associated with malignant transformation of oral potentially malignant disorders.

BACKGROUND: A large number of oral squamous cell carcinomas (OSCCs) are believed to be preceded by oral potentially malignant disorders (OPMD) that have an increased likelihood of malignant transformation compared to clinically normal mucosa. This study was performed to identify differentially expressed genes between OPMDs that underwent malignant transformation (MT) and those that did not, termed "non-transforming" (NT) cases. METHODS: Total RNA was extracted from formalin-fixed paraffin-embedded tissue biopsies of 20 OPMD cases with known clinical outcomes (10 MT vs. 10 NT). Samples were assessed for quantity, quality and integrity of RNA prior to sequencing. Analysis for differential gene expression between MT and NT was performed using statistical packages in R. Genes were considered to be significantly differentially expressed if the False Discovery Rate corrected P-value was < 0.05. RESULTS: RNA yield was variable but RNA purity was good (A260/A280 > 1.90). Analysis of RNA-Sequencing outputs revealed 41 genes (34 protein-coding; 7 non-coding) that were significantly differentially expressed between MT and NT cases. The log2 fold change for the statistically significant differentially expressed genes ranged from -2.63 to 2.48, with 23 protein-coding genes being downregulated and 11 protein-coding genes being upregulated in MT cases compared to NT cases. CONCLUSION: Several candidate genes that may play a role in malignant transformation of OPMD have been identified. Experiments to validate these candidates are underway. It is anticipated that this work will contribute to better understanding of the etiopathogenesis of OPMD and development of novel biomarkers.

Gaps in the Care of Familial Hypercholesterolaemia in Australia: First Report From the National Registry.

BACKGROUND: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients. METHODS: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics. RESULTS: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD. CONCLUSION: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.

The Genetics of Reading and Language.

Recounts how our collaboration with Nick Martin was shaped over two decades, leading to the first studies of predictions from the 'Dual Route Cascaded' computational model of reading in twins, and extending into the molecular work, first linkage, fine mapping of genes identified in pedigree studies, into now the genomewide association study era and the first polygenic risk scores for reading and their potential in early clarifying causality and validating interventions, as well as for future global collaborations in improving these predictors and identifying causal variants. We highlight Nick's warm, future-focused optimism, support and inclusive approach without which none of this would have been possible. The circle of Nick asking, over half a century ago, 'What genes do you think make some kids get better grades?' has built a diverse scientific legacy involving thousands of papers and collaborations. The (heritable) traits of curiosity, boldness, warmth, interest in societally important questions, openness to new methods, ambition and collaborative skill to bring into being the infrastructure and samples needed for this research are rare, and we are grateful.

The Association of Dyslexia and Developmental Speech and Language Disorder Candidate Genes with Reading and Language Abilities in Adults.

Reading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7-73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.

Physical and Cultural Inheritance Enhance Agency, but What are the Origins of this Concern to Establish a Legacy? A Nationally-Representative Twin Study of Erikson's Concept of Generativity.

Generativity-showing concern to establish and guide future generations-has been argued to be a biological adaptation central to cumulative culture and survival, but also, in turn, to be a cultural adaptation dependent on norms. From the perspective of human agency, concern for the future has played a key role in raising agency for generations that follow by creating infrastructure and cultural inheritance. Here, in a population-representative sample of 756 twin-pairs, we present the first test of the genetic and environmental structure of generativity using the Loyola Generativity Scale (short). Genetic analysis of scale sum-scores revealed that shared environmental effects were comparable in magnitude or exceeded effects estimated for genetic differences (A = 0.30 CI95 [- 0.01, 0.61], C = 0.41 [0.25, 0.56], E = 0.86 [0.79, 0.93]). At the item level, a well-fitting genetically-informed model suggested 3 factors influencing generativity via a common-pathway structure. The first was tentatively characterized as reflecting a heritable general concern for the future. The second reflected being a valued source of advice and assistance. The third factor showed only unique environment effects and had as its strongest indicator having had a good influence on the lives of others. Replicability of this structure should be tested in the full version of the scale. Work is needed also to validate influences of generativity on vocations such as teaching and on philanthropic activity improving life for subsequent generations.

Genetic and Environmental Influences on Cognitive Abilities in Extreme Poverty.

To improve global human capital, an understanding of the interplay of endowment across the full range of socioeconomic status (SES) is needed. Relevant data, however, are absent in the nations with the most abject poverty (Tucker-Drob & Bates, 2016), where the lowest heritability and strong effects of SES are predicted. Here we report the first study of biopsychosocial gene-environment interaction in extreme poverty. In a sub-Saharan sample of early teenage twins (N = 3192), we observed substantial (~30-40%) genetic influence on cognitive abilities. Surprisingly, shared environmental influences were similar to those found in adolescents growing in Western affluent countries (25-28%). G × SES moderation was estimated at a` = .06 (p = .355). Family chaos did not moderate genetic effects but did moderate shared environment influence. Heritability of cognitive abilities in extreme poverty appears comparable to Western data. Reduced family chaos may be a modifiable factor promoting cognitive development.

umx: Twin and Path-Based Structural Equation Modeling in R.

Structural equation modeling (SEM) is an important research tool, both for path-based model specification (common in the social sciences) and also for matrix-based models (in heavy use in behavior genetics). We developed umx to give more immediate access, relatively concise syntax and helpful defaults for users in these two broad disciplines. umx supports development, modification and comparison of models, as well as both graphical and tabular outputs. The second major focus of umx, behavior genetic models, is supported via functions implementing standard multigroup twin models. These functions support raw and covariance data, including joint ordinal data, and give solutions for ACE models, including support for covariates, common- and independent-pathway models, and gene × environment interaction models. A tutorial site and question forum are also available.

The Nigerian Twin and Sibling Registry: An Update.

Here we provide an update of the 2013 report on the Nigerian Twin and Sibling Registry (NTSR). The major aim of the NTSR is to understand genetic and environmental influences and their interplay in psychological and mental health development in Nigerian children and adolescents. Africans have the highest twin birth rates among all human populations, and Nigeria is the most populous country in Africa. Due to its combination of large population and high twin birth rates, Nigeria has one of the largest twin populations in the world. In this article, we provide current updates on the NTSR samples recruited, recruitment procedures, zygosity assessment and findings emerging from the NTSR.