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.

Childhood Reading Ability and Pain in Childhood Through to Midlife.

Dyslexia and pain have recently been shown to correlate on a genetic level, but there has been little exploration of this association on the phenotypic level despite reports of increased pain in Attention Deficit Hyperactivity Disorder, which commonly co-occurs with dyslexia. In this study we test for an association between reading ability, which is the primary feature of dyslexia, and pain both in childhood and adulthood. Logistic regression modeling was used to test associations between reading ability in childhood and pain from childhood to midlife in a large UK birth cohort; the 1958 National Child Development Study. Associations were found between poor childhood reading ability and increased headache and abdominal pain in childhood, and between poor childhood reading ability and headache, eye pain, back pain, and rheumatism in adulthood. Mediation analyses indicated that socioeconomic status (defined by employment) fully mediated the association between poor reading ability in childhood and back pain at age 42. By contrast, the association between reading ability and eye pain acted independently of socioeconomic status. Different mechanisms were thus indicated for the association of reading with different pain types, including manual labor and a potential shared biological pathway. PERSPECTIVE: This study found a relationship between poor reading ability in childhood and pain in childhood and adulthood. Those with reading difficulties should be monitored for pain symptoms. Future research may uncover shared biological mechanisms, increasing our understanding of pain and potential treatments.

Associations Between a General Factor and Group Factor from the Spanish-Language Eysenck Personality Questionnaire-Revised Short Form's Neuroticism Scale and the Revised NEO Personality Inventory Domains and Facets.

Prior studies used exploratory bifactor analyses to examine the structure of the Neuroticism scale from the Short-scale Eysenck Personality Questionnaire-Revised (EPQ-RS). These studies revealed a general factor and two group factors-Anxious-Tense and Worried-Vulnerable. These factors were related to poorer mental health, but their associations with physical health differed, as did their genetic and neurobiological underpinnings. A later study found that their associations with the Big Five Inventory-2 Short Form's factors and facets differed. We reanalyzed data on 1,006 Spanish students who completed Spanish-language versions of the EPQ-RS and the Revised NEO Personality Inventory (NEO PI-R). Using confirmatory factor analysis, we showed that a model comprising the general factor and a group factor-Anxious-Tense-fit well. In later correlations, a joint factor analysis, and simultaneous multiple regressions, we showed that the EPQ-RS's general factor and the group factor had different patterns of associations with the NEO PI-R domains and facets. These associations were consistent with the definition of the EPQ-RS Neuroticism scale's general factor and that of the group factor. Further investigation into the EPQ-RS Neuroticism scale's structure can improve our understanding of neuroticism's relationship with health and other outcomes.

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning.

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

The shared genetic architecture and evolution of human language and musical rhythm.

Rhythm and language-related traits are phenotypically correlated, but their genetic overlap is largely unknown. Here, we leveraged two large-scale genome-wide association studies performed to shed light on the shared genetics of rhythm (N=606,825) and dyslexia (N=1,138,870). Our results reveal an intricate shared genetic and neurobiological architecture, and lay groundwork for resolving longstanding debates about the potential co-evolution of human language and musical traits.

A Longitudinal Study of Physical Activity and Personality in the Wellbeing of Older Adults.

Objective: This study examines the interactions of physical activity and personality traits in the subjective wellbeing (SWB) of older adults. Methods: 520 Scottish participants (262 male; 258 female) completed self-reported surveys measuring their level of physical activity, personality, and SWB in 2011-2013 (mean age = 76.23 ± .68) and in 2014-2016 (mean age = 79.31 ± .62). Results: While all of the Big Five personality traits predicted SWB across the 3-year period in the expected direction, neither physical activity nor its joint effect with any of the personality traits was a significant predictor of subsequent SWB. Discussion: Further research on older adults with higher variation in age, exercise level, and cultural background is needed to disentangle how physical activity and personality influence SWB.

Cognitive aging and experience of playing a musical instrument.

Musical instrument training has been found to be associated with higher cognitive performance in older age. However, it is not clear whether this association reflects a reduced rate of cognitive decline in older age (differential preservation), and/or the persistence of cognitive advantages associated with childhood musical training (preserved differentiation). It is also unclear whether this association is consistent across different cognitive domains. Our sample included 420 participants from the Lothian Birth Cohort 1936. Between ages 70 and 82, participants had completed the same 13 cognitive tests (every 3 years), measuring the cognitive domains of verbal ability, verbal memory, processing speed, and visuospatial ability. At age 82, participants reported their lifetime musical experiences; 40% had played a musical instrument, mostly in childhood and adolescence. In minimally adjusted models, participants with greater experience playing a musical instrument tended to perform better across each cognitive domain at age 70 and this association persisted at subsequent waves up to age 82. After controlling for additional covariates (childhood cognitive ability, years of education, socioeconomic status, and health variables), only associations with processing speed (ß = 0.131, p = .044) and visuospatial ability (ß = 0.154, p = .008) remained statistically significant. Participants with different amounts of experience playing a musical instrument showed similar rates of decline across each cognitive domain between ages 70 and 82. These results suggest a preserved differentiation effect: Cognitive advantages (in processing speed and visuospatial ability) associated with experience playing a musical instrument (mostly earlier in life) are preserved during older age. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Identification of loci involved in childhood visual acuity and associations with cognitive skills and educational attainment.

Visual acuity significantly contributes to quality of life. Deficits in childhood are associated with reading difficulties, which can have detrimental effects on education outcomes. In adults, it has been observed that vision defects such as myopia are associated with higher educational attainment (EA). Understanding genetic factors contributing to visual acuity could help to dissect its links with cognitive skills, neurodevelopmental conditions, and education. We examined associations between distance visual acuity, cognitive measures including school grades, and neurodevelopmental conditions in a longitudinal cohort of British children (ALSPAC, n = 6807, M age = 11.8). We performed a genome-wide association study (GWAS, n = 5571) on visual acuity and tested for genetic associations with relevant phenotypes using polygenic scores (PGS) and genetic correlation analyses. Visual acuity was associated with better cognitive performance and school grades, and reduced in individuals with reading difficulties compared to controls. GWAS revealed genetic associations at the NPLOC4 locus and highlighted other genes involved in sensory function. In line with positive genetic correlations between visual acuity and cognitive measures, EA PGS were positively associated with visual acuity, while there was a less robust negative association with myopia PGS. In conclusion, increased visual acuity is associated with a range of positive outcomes, including better school grades. Our results suggest an association between a higher EA PGS and slightly increased visual acuity in childhood. This could indicate gene-environment correlation, in which environmental exposures linked to higher EA might have detrimental effects on vision offsetting the initial positive effect.

Bioenvironmental Predictors of Childhood Reading and Speech Difficulties.

PURPOSE: Reading and speech difficulties are common in childhood, yet it is not fully understood how much of their etiology is shared. This partly derives from methodological issues related to overlooking the potential co-occurrence between the two sets of difficulties. This study investigated the effects of five bioenvironmental predictors in a sample assessed for such co-occurrence. METHOD: A combination of exploratory and confirmatory analyses was performed on longitudinal data from the National Child Development Study. Exploratory latent class analysis was performed on children's reading, speech, and language outcomes at ages 7 and 11 years. Membership in the obtained classes was modeled using a regression with sex and four early-life predictors: gestation period, socioeconomic status, maternal education, and the home reading environment. RESULTS: The model yielded four latent classes that broadly reflected (1) average reading and speech, (2) excellent reading, (3) reading difficulties, and (4) speech difficulties. Early-life factors significantly predicted class membership. Male sex and preterm birth emerged as risk factors for both reading and speech difficulties. Protective effects against reading difficulties were identified for maternal education, and lower (but not higher) levels of socioeconomic status and the home reading environment. CONCLUSIONS: Co-occurrence of reading and speech difficulties in the sample was low, and differential patterns of effect of the social environment were supported. Reading outcomes were under stronger malleable influence than speech outcomes.

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning.

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components : gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 41 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.15 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

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.

Socioeconomic status as a risk factor for motoric cognitive risk syndrome in a community-dwelling population: A longitudinal observational study.

BACKGROUND: Motoric cognitive risk (MCR) is a syndrome characterised by measured slow gait speed and self-reported cognitive complaints. MCR is a high-risk state for adverse health outcomes in older adults, particularly cognitive impairment and dementia. Previous studies have identified risk factors for MCR, but the effect of socioeconomic status has, to date, been insufficiently examined. This study explored the association between MCR and socioeconomic status, as determined by occupational social class and years of education. METHODS: Some 692 community-based adults of the Lothian Birth Cohort 1936 (LBC1936), aged 70 years at baseline, were followed up after 6 years and classified into non-MCR and MCR groups. We applied logistic regression analyses adjusting for demographic, lifestyle, and health covariates to investigate the association between MCR and years of education and occupational social class, categorised into manual versus non-manual occupations. RESULTS: MCR prevalence at age 76 years was 5.6% (95% CI 4.0-7.6). After multivariate adjustment, participants of lower socioeconomic status (manual occupation) had a greater than three-fold increased likelihood of MCR (adjusted odds ratio 3.55, 95% CI 1.46-8.74; p = 0.005) compared with those of higher socioeconomic status (non-manual occupation). CONCLUSIONS: Working in a manual job earlier in life triples the risk of MCR later in life, regardless of education. Unravelling this association will likely reveal important pathophysiological mechanisms underlying MCR and may unearth modifiable risk factors which could be targeted to reduce the incidence of MCR and, ultimately, dementia. Policy and healthcare practice addressing dementia risks such as MCR in their social context and early in the lifecourse could be effective strategies for reducing health inequalities in older age.

Social expectations as a possible mechanism for adult personality change: Limited empirical evidence for the social investment principle.

OBJECTIVE: Personality traits change in both mean levels and variance across the life span but the mechanisms underlying these developmental trends remain unclear. Social Investment Principle (SIP) suggests that social expectations drive personality changes in adulthood. Accordingly, we tested whether differences between personality traits in social expectations for them can explain their different change trajectories in young adulthood. METHODS: A pool of 257 personality items was used to measure personality traits' means and variances (N = 1096), and levels expected by friends, partners and bosses/supervisors (N = 121). RESULTS: Raters were consistent in their expectations for how young adults should think, feel and behave. Traits under stronger expectations had higher mean levels and lower variances than traits under lower expectations; trait means and variances increased with age, but inconsistently with the SIP, these increases were unrelated to the traits' expected levels. CONCLUSION: Our results are only partially consistent with the SIP.

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

Motoric cognitive risk syndrome trajectories and incident dementia over 10 years.

Background: Motoric Cognitive Risk (MCR) syndrome is a high-risk state for adverse health outcomes in older adults characterised by measured slow gait speed and self-reported cognitive complaints. The recent addition to the Lothian Birth Cohort 1936 of robust dementia outcomes enabled us to assess the prognostic value of MCR for dementia and explore the various trajectories of participants diagnosed with MCR. Methods: We classified 680 community-dwelling participants free from dementia into non-MCR or MCR groups at mean [SD] age 76.3 [0.8] years. We used Cox and competing risk regression methods, adjusted for potential confounders, to evaluate the risk of developing all-cause incident dementia over 10 years of follow-up. Secondarily, we followed the trajectories for individuals with and without MCR at baseline and categorised them into subgroups based on whether MCR was still present at the next research wave, three years later. Results: The presence of MCR increased the risk of incident dementia (adjusted HR 2.34, 95%CI 1.14-4.78, p = 0.020), as did fewer years of education and higher depression symptoms. However, MCR has a heterogenous progression trajectory. The MCR progression subgroups each have different prognostic values for incident dementia. Conclusion: MCR showed similar prognostic ability for dementia in a Scottish cohort as for other populations. MCR could identify a target group for early interventions of modifiable risk factors to prevent incident dementia. This study illustrates the heterogeneous nature of MCR progression. Exploring the underlying reasons will be important work in future work.

Prevalence and predictors of Motoric Cognitive Risk syndrome in a community-dwelling older Scottish population: A longitudinal observational study.

OBJECTIVES: Motoric Cognitive Risk (MCR) is a gait-based predementia syndrome that is easy to measure and prognostic of dementia and falls. We aimed to examine the prevalence and risk factors for MCR, and assess its overlap with Mild Cognitive Impairment, Prefrailty, and Frailty, in a cohort of older Scottish adults without dementia. METHODS: In this longitudinal prospective study, we classified 690 participants (mean [SD] age 76.3 [0.8] years; wave 3) of the Lothian Birth Cohort 1936 (LBC1936) into non-MCR or MCR groups. We examined their baseline (age 69.5 [0.8] years; wave 1) risk factors for MCR at waves 3, 4, and 5 (6, 9, and 12 years later respectively). RESULTS: MCR prevalence rate ranged from 5.3% to 5.7% across the three waves. The presence of MCR was associated with older baseline age (6 and 9 years later), lower occupational socioeconomic status (6 years later), and worse scores in a range of tests of executive function (6, 9 and 12 years later). Approximately 46% of the MCR group also had Mild Cognitive Impairment, and almost everyone in the MCR group had either Prefrailty or Frailty. CONCLUSIONS: The prevalence of MCR in this Scottish cohort is lower than the pooled global average, possibly reflecting the general good health of the LBC cohort. However, it is higher than the prevalence in two neighbouring countries' cohorts, which may reflect the younger average ages of those cohorts. Future LBC1936 research should assess the risk factors associated with MCR to validate previous findings and analyse novel predictive factors, particularly socioeconomic status.

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.

Within-person Relations between Domains of Socio-emotional Development during Childhood and Adolescence.

Adolescence is a critical period in the development of mental health with nearly 1 in 5 adolescents suffering from mental health problems and more than 40 percent of these experiencing at least one co-occurring mental health disorder. This study investigates whether there are differences in the relations between key dimensions of child and adolescent mental health in adolescence compared to childhood. Mental health and related socio-emotional traits were measured longitudinally at ages 4, 7, 8, 9, 11, 13, and 16 in the Avon Longitudinal Study of Parents and Children (N = 11279) using the Strengths and Difficulties Questionnaires. Graphical Vector Autoregression models were used to analyse the temporal within-person relations between conduct problems, emotional problems, hyperactivity/inattention, peer problems and prosociality across childhood (ages 4 to 9) and adolescence (11 to 16). Results suggest that adolescence is characterised by an increase in the number and strength of temporal relations between socio-emotional difficulties. In particular, in adolescence there were bidirectional connections between peer problems and emotional problems, between conduct problems and hyperactivity/inattention and between prosociality and conduct problems as well as hyperactivity/inattention. In childhood, conduct problems and prosociality were reciprocally related. Results also suggested peer problems as a potential mediating factor between conduct and emotional problems in childhood. Overall, this study suggests that different domains of socio-emotional development influence each other over development. Adolescence is characterised by an increase in temporal connections, which may be one factor underlying the increased vulnerability to the onset of mental health problems during that period.