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.

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.

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.

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.

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.

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate.

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

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.

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.

The influence of X chromosome variants on trait neuroticism.

Autosomal variants have successfully been associated with trait neuroticism in genome-wide analysis of adequately powered samples. But such studies have so far excluded the X chromosome from analysis. Here, we report genetic association analyses of X chromosome and XY pseudoautosomal single nucleotide polymorphisms (SNPs) and trait neuroticism using UK Biobank samples (N = 405,274). Significant association was found with neuroticism on the X chromosome for 204 markers found within three independent loci (a further 783 were suggestive). Most of the lead neuroticism-related X chromosome variants were located in intergenic regions (n = 397). Involvement of HS6ST2, which has been previously associated with sociability behaviour in the dog, was supported by single SNP and gene-based tests. We found that the amino acid and nucleotide sequences are highly conserved between dogs and humans. From the suggestive X chromosome variants, there were 19 nearby genes which could be linked to gene ontology information. Molecular function was primarily related to binding and catalytic activity; notable biological processes were cellular and metabolic, and nucleic acid binding and transcription factor protein classes were most commonly involved. X-variant heritability of neuroticism was estimated at 0.22% (SE = 0.05) from a full dosage compensation model. A polygenic X-variant score created in an independent sample (maximum N ≈ 7,300) did not predict significant variance in neuroticism, psychological distress, or depressive disorder. We conclude that the X chromosome harbours significant variants influencing neuroticism, and might prove important for other quantitative traits and complex disorders.

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

A symptom level perspective on reactive and proactive aggressive behaviours and ADHD symptoms in childhood.

OBJECTIVE: Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most prevalent childhood disorders, affecting around 3.4% of children worldwide. A common and impairing correlate of ADHD is aggressive behaviour. ADHD symptoms and aggression are both heterogeneous and it has been speculated that certain symptoms of ADHD might be more important in aggressive behaviours of different types than others. This study uses a symptom-level analysis to investigate the concurrent and temporal links between ADHD symptoms and aggressive behaviours. METHODS: Using Gaussian Graphical Models and Graphical Vector Autoregression Models, longitudinal and cross-sectional networks of ADHD symptoms and aggressive behaviours, measured using parent-reported Social Behaviour Questionnaires, were estimated. Participants included 1,246 children taking part in the longitudinal Swiss z-proso cohort study at ages 7, 9 and 11. RESULTS: The longitudinal network highlighted that ADHD symptoms and aggressive behaviours share a multitude of reciprocal temporal relations, with inattentive ADHD symptoms preceding both reactive and proactive aggression. Cross-sectional networks suggested that hyperactive/impulsive symptoms were predominantly connected to reactive aggressive behaviours but also to a form of proactive aggression, namely dominating other children. CONCLUSION: Findings provide preliminary evidence which specific symptoms are the most promising targets for reducing aggressive behaviours in children with ADHD. They also highlight the potential importance of targeting feedback loops resulting from aggressive behaviours. Future research is needed to better understand the mechanisms through which ADHD and aggressive behaviours become linked.

Polygenic risks for joint developmental trajectories of internalizing and externalizing problems: findings from the ALSPAC cohort.

BACKGROUND: Joint developmental trajectories of internalizing and externalizing problems show considerable heterogeneity; however, this can be parsed into a small number of meaningful subgroups. Doing so offered insights into risk factors that lead to different patterns of internalizing/externalizing trajectories. However, despite both domains of problems showing strong heritability, no study has yet considered genetic risks as predictors of joint internalizing/externalizing problem trajectories. METHODS: Using parallel process latent class growth analysis, we estimated joint developmental trajectories of internalizing and externalizing difficulties assessed across ages 4 to 16 using the Strengths and Difficulties Questionnaire. Multinomial logistic regression was used to evaluate a range of demographic, perinatal, maternal mental health, and child and maternal polygenic predictors of group membership. Participants included 11,049 children taking part in the Avon Longitudinal Study of Parents and Children. Polygenic data were available for 7,127 children and 6,836 mothers. RESULTS: A 5-class model was judged optimal: Unaffected, Moderate Externalizing Symptoms, High Externalizing Symptoms, Moderate Internalizing and Externalizing Symptoms and High Internalizing and Externalizing Symptoms. Male sex, lower maternal age, maternal mental health problems, maternal smoking during pregnancy, higher child polygenic risk scores for ADHD and lower polygenic scores for IQ distinguished affected classes from the unaffected class. CONCLUSIONS: While affected classes could be relatively well separated from the unaffected class, phenotypic and polygenic predictors were limited in their ability to distinguish between different affected classes. Results thus add to existing evidence that internalizing and externalizing problems have mostly shared risk factors.

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.

Heterogeneity of Frailty Trajectories and Associated Factors in the Lothian Birth Cohort 1936.

INTRODUCTION: Recent research suggests that the experience of frailty progression may be heterogeneous, with latent subpopulations of older adults following distinct trajectories of frailty. We aimed to investigate this notion and determine whether certain factors are associated with the membership of these subpopulations. METHODS: Data from 5 data waves collected over 12 years in participants of the Lothian Birth Cohort 1936, aged 70 at baseline, were used to derive the frailty index (FI) (NW1 = 1,091, NW5 = 431). These were used in latent class mixed modelling to estimate subpopulations of frailty trajectories. RESULTS: A quadratic latent class mixed model found 3 distinct groupings, which followed a low (61%, n = 632), medium (36%, n = 368), or high (3%, n = 28) FI trajectory. Each grouping had different intercepts and slopes, with the high grouping following the steepest trajectory indicating a rapid increase in frailty. Findings showed that in general, those in the low grouping were younger, had higher education, higher age 11 cognitive ability, and were from a higher social class than those in the medium and high groupings. DISCUSSION/CONCLUSION: Our findings demonstrate heterogeneity in frailty trajectories over 12 years in individuals aged 70 years at baseline. Membership of higher frailty trajectory groupings was associated with lower social class, less education, and lower childhood cognitive ability, indicating the potential for future interventions to target individuals who are at the greatest risk of belonging to the high frailty trajectory. Future research is required to continue this line of inquiry by exploring other risk and protective factors, and importantly, to assess whether it is possible to realign an individual's membership to a less detrimental grouping of frailty trajectory.

Mechanisms of motoric cognitive risk-Hypotheses based on a systematic review and meta-analysis of longitudinal cohort studies of older adults.

We aimed to refine the hypothesis that motoric cognitive risk (MCR), a syndrome combining measured slow gait speed and self-reported cognitive complaints, is prognostic of incident dementia and other major causes of morbidity in older age. We propose mechanisms on the relationship between motor and cognitive function and describe a roadmap to validate these hypotheses. We systematically searched major electronic databases from inception to August 2021 for original longitudinal cohort studies of adults aged ≥60 years that compared an MCR group to a non-MCR group with any health outcome. Fifteen cohorts were combined by meta-analysis. Participants with MCR were at an increased risk of cognitive impairment (adjusted hazard ratio [aHR] 1.76, 95% CI 1.49-2.08; I2  = 24.9%), dementia (aHR 2.12, 1.85-2.42; 33.1%), falls (adjusted Relative Risk 1.38, 1.15-1.66; 62.1%), and mortality (aHR 1.49, 1.16-1.91; 79.2%). The prognostic value of MCR is considerable and mechanisms underlying the syndrome are proposed.

Prevalence of Mild Cognitive Impairment in the Lothian Birth Cohort 1936.

BACKGROUND: The Lothian Birth Cohort 1936 (LBC1936) is a highly phenotyped longitudinal study of cognitive and brain ageing. Given its substantial clinical importance, we derived an indicator of mild cognitive impairment (MCI) and amnestic and nonamnestic subtypes at 3 time points. METHODS: MCI status was derived at 3 waves of the LBC1936 at ages 76 (n=567), 79 (n=441), and 82 years (n=341). A general MCI category was derived as well as amnestic MCI (aMCI) and nonamnestic MCI (naMCI). A comparison was made between MCI derivations using normative data from the LBC1936 cohort versus the general UK population. RESULTS: MCI rates showed a proportional increase at each wave between 76 and 82 years from 15% to 18%. Rates of MCI subtypes also showed a proportional increase over time: aMCI 4% to 6%; naMCI 12% to 16%. Higher rates of MCI were found when using the LBC1936 normative data to derive MCI classification rather than UK-wide norms. CONCLUSIONS: We found that MCI and aMCI rates in the LBC1936 were consistent with previous research. However, naMCI rates were higher than expected. Future LBC1936 research should assess the predictive factors associated with MCI prevalence to validate previous findings and identify novel risk factors.

Common genetic variants influence human subcortical brain structures.

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.

Links between perinatal risk factors and maternal psychological distress: A network analysis.

INTRODUCTION: This paper explores a range of perinatal risk factors that may increase maternal vulnerability to postnatal psychological distress in a sample of 17 531 women participating in the Millennium Cohort Study, a diverse British, longitudinal birth cohort study. MATERIAL AND METHODS: Using a graphical network modeling framework, this study models the links between postnatal psychological distress and perinatal risk factors, while controlling for sociodemographic factors and history of depression and anxiety. Postnatal psychological distress was assessed at 9 months postpartum using the Rutter Malaise Inventory. RESULTS: Results of the graphical network models indicate that lower levels of happiness about the pregnancy (Edge weight [w] = 0.084, 95% CI = 0.069-0.100, b = 0.095), smoking during pregnancy (w = 0.026, 95% CI = -0.009-0.060, b = 0.029), infection during pregnancy (w = 0.071, 95% CI = 0.024-0.118, b = 0.090), hyperemesis gravidarum (w = 0.068, 95% CI = 0.013-0.123, b = 0.083), baby in special care (w = 0.048, 95% CI = -0.004-0.099, b = 0.062), not being white (w = 0.101, 95% CI = 0.062-0.140, b = 0.118), being from a more deprived area (w = -0.028, 95% CI = -0.051 to -0.005, b = -0.039), lower income (w = -0.025, 95% CI = -0.055-0.005, b = -0.036), and history of depression or anxiety (w = 0.574, 95% CI = 0.545-0.603, b = 0.764) were associated with increased psychological distress. CONCLUSIONS: Some perinatal risk factors may be directly associated with postnatal psychological distress, but many risk factors appear to be primarily associated with demographic factors. This emphasizes the importance of taking a holistic approach when evaluating an individual's risk of developing postnatal psychological distress.

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

BACKGROUND AND PURPOSE: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.