Cultural contributions to adults' self-rated mental health problems and strengths: 7 culture clusters, 28 societies, 16 906 adults.

BACKGROUND: It is unknown how much variation in adult mental health problems is associated with differences between societal/cultural groups, over and above differences between individuals. METHODS: To test these relative contributions, a consortium of indigenous researchers collected Adult Self-Report (ASR) ratings from 16 906 18- to 59-year-olds in 28 societies that represented seven culture clusters identified in the Global Leadership and Organizational Behavioral Effectiveness study (e.g. Confucian, Anglo). The ASR is scored on 17 problem scales, plus a personal strengths scale. Hierarchical linear modeling estimated variance accounted for by individual differences (including measurement error), society, and culture cluster. Multi-level analyses of covariance tested age and gender effects. RESULTS: Across the 17 problem scales, the variance accounted for by individual differences ranged from 80.3% for DSM-oriented anxiety problems to 95.2% for DSM-oriented avoidant personality (mean = 90.7%); by society: 3.2% for DSM-oriented somatic problems to 8.0% for DSM-oriented anxiety problems (mean = 6.3%); and by culture cluster: 0.0% for DSM-oriented avoidant personality to 11.6% for DSM-oriented anxiety problems (mean = 3.0%). For strengths, individual differences accounted for 80.8% of variance, societal differences 10.5%, and cultural differences 8.7%. Age and gender had very small effects. CONCLUSIONS: Overall, adults' self-ratings of mental health problems and strengths were associated much more with individual differences than societal/cultural differences, although this varied across scales. These findings support cross-cultural use of standardized measures to assess mental health problems, but urge caution in assessment of personal strengths.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Discovery of 42 genome-wide significant loci associated with dyslexia.

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.

To Name or Not to Name: Eye Movements and Semantic Processing in RAN and Reading.

This study examined the well-established relationship between rapid naming and reading. Rapid automatized naming (RAN) has long been demonstrated as a strong predictor of reading abilities. Despite extensive research spanning over 4 decades, the underlying mechanisms of these causes remain a subject of inquiry. The current study investigated the role of eye movements and semantic processing in defining the RAN-reading relationship. The participants in this study were 42 English-speaking undergraduate students at a British university. The materials included a word reading task, two conventional RAN tasks (object and digit), and two RAN-like categorization tasks (object and digit). The results obtained suggested the interdependence between rapid naming and semantic processing. Hierarchical multiple regression analyses revealed that oculomotor control remains an integral part of variability in RAN and reading performance. Taken together, our results suggest that RAN and reading measures are correlated because both require rapid and accurate retrieval of phonological representations, semantic properties of visual stimuli, and stable co-ordination of eye movements.

A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures.

At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum P = 0.002 for non-word reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.

Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial.

BACKGROUND: Maternal folic acid (FA) supplementation before and in early pregnancy prevents neural tube defects (NTD), but it is uncertain whether continuing FA after the first trimester has benefits on offspring health. We aimed to evaluate the effect of FA supplementation throughout pregnancy on cognitive performance and brain function in the child. METHODS: Follow-up investigation of 11-year-old children, residing in Northern Ireland, whose mothers had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) in pregnancy and received 400 µg/day FA or placebo from the 14th gestational week. Cognitive performance (Full Scale Intelligence Quotient, Verbal Comprehension, Working Memory, Perceptual Reasoning, and Processing Speed) was assessed using the Wechsler Intelligence Scale for Children. Neuronal function was assessed using magnetoencephalographic (MEG) brain imaging. RESULTS: Of 119 mother-child pairs in the FASSTT trial, 68 children were assessed for neurocognitive performance at 11-year follow-up (Dec 2017 to Nov 2018). Children of mothers randomised to FA compared with placebo scored significantly higher in two Processing Speed tests, i.e. symbol search (mean difference 2.9 points, 95% CI 0.3 to 5.5, p = 0.03) and cancellation (11.3 points, 2.5 to 20.1, p = 0.04), whereas the positive effect on Verbal Comprehension was significant in girls only (6.5 points, 1.2 to 11.8, p = 0.03). MEG assessment of neuronal responses to a language task showed increased power at the Beta (13-30 Hz, p = 0.01) and High Gamma (49-70 Hz, p = 0.04) bands in children from FA-supplemented mothers, suggesting more efficient semantic processing of language. CONCLUSIONS: Continued FA supplementation in pregnancy beyond the early period currently recommended to prevent NTD can benefit neurocognitive development of the child. MEG provides a non-invasive tool in paediatric research to objectively assess functional brain activity in response to nutrition and other interventions. TRIAL REGISTRATION: ISRCTN ISRCTN19917787 . Registered on 15 May 2013.

Dynamic relationships between phonological memory and reading: A five year longitudinal study from age 4 to 9.

We reconcile competing theories of the role of phonological memory in reading development, by uncovering their dynamic relationship during the first 5 years of school. Phonological memory, reading and phoneme awareness were assessed in 780 phonics-educated children at age 4, 5, 6 and 9. Confirmatory factor analyses demonstrated that phonological memory loaded onto two factors: verbal short-term memory (verbal STM; phonological tasks that loaded primarily on serial order memory) and nonword repetition. Using longitudinal structural equation models, we found that verbal STM directly predicted early word-level reading from age 4 to 6, reflecting the importance of serial-order memory for letter-by-letter decoding. In contrast, reading had no reciprocal influence on the development of verbal STM. The relationship between nonword repetition and reading was bidirectional across the 5 years of study: nonword repetition and reading predicted each other both directly and indirectly (via phoneme awareness). Indirect effects from nonword repetition (and verbal STM) to reading support the view that phonological memory stimulates phonemically detailed representations through repeated encoding of complex verbal stimuli. Similarly, the indirect influence of reading on nonword repetition suggests that improved reading ability promotes the phoneme-level specificity of phonological representations. Finally, the direct influence from reading to nonword repetition suggests that better readers use orthographic cues to help them remember and repeat new words accurately. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=70LZfTR0BjE.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Auditory frequency discrimination in developmental dyslexia: A meta-analysis.

Auditory frequency discrimination has been used as an index of sensory processing in developmental language disorders such as dyslexia, where group differences have often been interpreted as evidence for a basic deficit in auditory processing that underpins and constrains individual variability in the development of phonological skills. Here, we conducted a meta-analysis to evaluate the cumulative evidence for group differences in frequency discrimination and to explore the impact of some potential moderator variables that could contribute to variability in effect-size estimations across studies. Our analyses revealed mean effect sizes for group differences on frequency discrimination tasks on the order of three-quarters of a standard deviation, but in the presence of substantial inter-study variability in their magnitude. Moderator variable analyses indicated that factors related both to participant variability on behavioural and cognitive variables associated with the dyslexia phenotype, and to variability in the task design, contributed to differences in the magnitude of effect size across studies. The apparently complex pattern of results was compounded by the lack of concurrent, standardised metrics of cognitive and reading component skills across the constituent studies. Differences on sensory processing tasks are often reported in studies of developmental disorders, but these need to be more carefully interpreted in the context of non-sensory factors, which may explain significant inter- and intra-group variance in the dependent measure of interest.

Long-term Effects of Cholestatic Liver Disease in Childhood on Neuropsychological Outcomes and Neurochemistry.

OBJECTIVES: Children with liver disease have increased risk of long-term cognitive deficits. We differentiated between the effects of chronic liver disease from that associated with transplantation by recruiting children with cholestatic liver disease (CLD) with and without transplantation. METHODS: Psychometric measures and magnetic resonance spectroscopy were obtained for 3 groups of children: stable liver disease without transplantation; CLD from birth with transplantation; and individuals healthy to 18 months of age, before transplantation for acute liver failure. RESULTS: Cognitive outcomes between children with different disease histories were significantly associated with the duration of liver disease but not the effects of transplantation, including that of immunosuppression. Lower intellectual ability was most frequently observed in the CLD group, whereas all of the acute liver failure group scored within the normal range. Myoinositol and glutamate/glutamine concentrations in cortex were significantly associated with disease duration across the cohort. Neurometabolite profiles in stable liver disease were consistent with subclinical encephalopathy. Impaired growth in early childhood was associated with later cognitive performance. CONCLUSION: Children with prolonged liver disease had the poorest cognitive outcomes despite successful transplantation, suggesting that prolonged cholestasis before transplantation adversely affects neurodevelopment, and reinforces the need for timely interventions.

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

Processing of structural neuroimaging data in young children: Bridging the gap between current practice and state-of-the-art methods.

The structure of the brain is subject to very rapid developmental changes during early childhood. Pediatric studies based on Magnetic Resonance Imaging (MRI) over this age range have recently become more frequent, with the advantage of providing in vivo and non-invasive high-resolution images of the developing brain, toward understanding typical and atypical trajectories. However, it has also been demonstrated that application of currently standard MRI processing methods that have been developed with datasets from adults may not be appropriate for use with pediatric datasets. In this review, we examine the approaches currently used in MRI studies involving young children, including an overview of the rationale for new MRI processing methods that have been designed specifically for pediatric investigations. These methods are mainly related to the use of age-specific or 4D brain atlases, improved methods for quantifying and optimizing image quality, and provision for registration of developmental data obtained with longitudinal designs. The overall goal is to raise awareness of the existence of these methods and the possibilities for implementing them in developmental neuroimaging studies.

Psychophysical measurements in children: challenges, pitfalls, and considerations.

Measuring sensory sensitivity is important in studying development and developmental disorders. However, with children, there is a need to balance reliable but lengthy sensory tasks with the child's ability to maintain motivation and vigilance. We used simulations to explore the problems associated with shortening adaptive psychophysical procedures, and suggest how these problems might be addressed. We quantify how adaptive procedures with too few reversals can over-estimate thresholds, introduce substantial measurement error, and make estimates of individual thresholds less reliable. The associated measurement error also obscures group differences. Adaptive procedures with children should therefore use as many reversals as possible, to reduce the effects of both Type 1 and Type 2 errors. Differences in response consistency, resulting from lapses in attention, further increase the over-estimation of threshold. Comparisons between data from individuals who may differ in lapse rate are therefore problematic, but measures to estimate and account for lapse rates in analyses may mitigate this problem.

Further evidence for a parent-of-origin effect at the NOP9 locus on language-related phenotypes.

BACKGROUND: Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5-10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required. METHODS: We used two independent family-based cohorts characterised with reading- and language-related traits: a longitudinal cohort (n = 106 informative families) including children with language and reading difficulties and a nuclear family cohort (n = 264 families) selected for dyslexia. RESULTS: We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study. CONCLUSIONS: A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits.

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.

Deconstructing phonological tasks: The contribution of stimulus and response type to the prediction of early decoding skills.

Phonological tasks are highly predictive of reading development but their complexity obscures the underlying mechanisms driving this association. There are three key components hypothesised to drive the relationship between phonological tasks and reading; (a) the linguistic nature of the stimuli, (b) the phonological complexity of the stimuli, and (c) the production of a verbal response. We isolated the contribution of the stimulus and response components separately through the creation of latent variables to represent specially designed tasks that were matched for procedure. These tasks were administered to 570 6 to 7-year-old children along with standardised tests of regular word and non-word reading. A structural equation model, where tasks were grouped according to stimulus, revealed that the linguistic nature and the phonological complexity of the stimulus predicted unique variance in decoding, over and above matched comparison tasks without these components. An alternative model, grouped according to response mode, showed that the production of a verbal response was a unique predictor of decoding beyond matched tasks without a verbal response. In summary, we found that multiple factors contributed to reading development, supporting multivariate models over those that prioritize single factors. More broadly, we demonstrate the value of combining matched task designs with latent variable modelling to deconstruct the components of complex tasks.

Syndromes of collateral-reported psychopathology for ages 18-59 in 18 Societies.

The purpose was to advance research and clinical methodology for assessing psychopathology by testing the international generalizability of an 8-syndrome model derived from collateral ratings of adult behavioral, emotional, social, and thought problems. Collateral informants rated 8,582 18-59-year-old residents of 18 societies on the Adult Behavior Checklist (ABCL). Confirmatory factor analyses tested the fit of the 8-syndrome model to ratings from each society. The primary model fit index (Root Mean Square Error of Approximation) showed good model fit for all societies, while secondary indices (Tucker Lewis Index, Comparative Fit Index) showed acceptable to good fit for 17 societies. Factor loadings were robust across societies and items. Of the 5,007 estimated parameters, 4 (0.08%) were outside the admissible parameter space, but 95% confidence intervals included the admissible space, indicating that the 4 deviant parameters could be due to sampling fluctuations. The findings are consistent with previous evidence for the generalizability of the 8-syndrome model in self-ratings from 29 societies, and support the 8-syndrome model for operationalizing phenotypes of adult psychopathology from multi-informant ratings in diverse societies.

Syndromes of Self-Reported Psychopathology for Ages 18-59 in 29 Societies.

This study tested the multi-society generalizability of an eight-syndrome assessment model derived from factor analyses of American adults' self-ratings of 120 behavioral, emotional, and social problems. The Adult Self-Report (ASR; Achenbach and Rescorla 2003) was completed by 17,152 18-59-year-olds in 29 societies. Confirmatory factor analyses tested the fit of self-ratings in each sample to the eight-syndrome model. The primary model fit index (Root Mean Square Error of Approximation) showed good model fit for all samples, while secondary indices showed acceptable to good fit. Only 5 (0.06%) of the 8,598 estimated parameters were outside the admissible parameter space. Confidence intervals indicated that sampling fluctuations could account for the deviant parameters. Results thus supported the tested model in societies differing widely in social, political, and economic systems, languages, ethnicities, religions, and geographical regions. Although other items, societies, and analytic methods might yield different results, the findings indicate that adults in very diverse societies were willing and able to rate themselves on the same standardized set of 120 problem items. Moreover, their self-ratings fit an eight-syndrome model previously derived from self-ratings by American adults. The support for the statistically derived syndrome model is consistent with previous findings for parent, teacher, and self-ratings of 1½-18-year-olds in many societies. The ASR and its parallel collateral-report instrument, the Adult Behavior Checklist (ABCL), may offer mental health professionals practical tools for the multi-informant assessment of clinical constructs of adult psychopathology that appear to be meaningful across diverse societies.

Adults with dyslexia demonstrate large effects of crowding and detrimental effects of distractors in a visual tilt discrimination task.

Previous research has shown that adults with dyslexia (AwD) are disproportionately impacted by close spacing of stimuli and increased numbers of distractors in a visual search task compared to controls [1]. Using an orientation discrimination task, the present study extended these findings to show that even in conditions where target search was not required: (i) AwD had detrimental effects of both crowding and increased numbers of distractors; (ii) AwD had more pronounced difficulty with distractor exclusion in the left visual field and (iii) measures of crowding and distractor exclusion correlated significantly with literacy measures. Furthermore, such difficulties were not accounted for by the presence of covarying symptoms of ADHD in the participant groups. These findings provide further evidence to suggest that the ability to exclude distracting stimuli likely contributes to the reported visual attention difficulties in AwD and to the aetiology of literacy difficulties. The pattern of results is consistent with weaker and asymmetric attention in AwD.