Identification and Functional Analysis of Genes Involved in Gliomagenesis

The median survival of glioma patient is still very poor and new therapeutic targets have to be discovered. The aim of this thesis is to identify genetic alterations in glioma and functionally characterize the most promising candidates. We describe several novel methods used to identify these mutations

Food Security Crop Price Transmission and Formation in Nigeria

The three studies in this dissertation explore the current conditions and operations of markets for seven key food security crops (cassava, cowpeas, maize, millet, rice, sorghum, and yams) in Nigeria. Chapter 2 is an empirical analysis of the current agricultural statistics system in Nigeria. A number of sources gather and report agricultural statistics for the country. Since there has not been an agricultural census implemented there for multiple decades, however, there is no objective source for data verification. Therefore, this study uses two additional types of “on the ground information” to assess if agricultural production estimates reflect growing conditions: prices and remote sensing data in the form of the normalized difference vegetation index (NDVI). The results show that existing production estimates are poorly correlated with both prices and the NDVI. Prices and the NDVI data are highly correlated, however. These findings imply that existing production estimates do not reflect growing conditions, and, therefore, are of poor quality. Chapter 3 is a comprehensive analysis of crop price transmission from global and neighbor country prices to Nigerian commercial hub and urban markets, and from commercial hubs to other urban and rural markets within the country. The results show that tradability matters for price transmission, but that tradability varies across crops and scopes of markets. Nigerian urban rice prices are highly correlated with prices on global markets and those in neighboring countries. Coarse grain prices appear disconnected from global markets, however, but move closely with those in neighboring countries. Large margins were estimated for prices of rice imported from global markets (in all regions), and for coarse grains to Southern Nigerian markets only. The existence of large margins implies that there are transactions costs and/or quality premiums that vary systematically with the world price, and/or mark-ups by traders with market power in these markets. While domestic market prices are almost always cointegrated, perfect price transmission is generally found only between commercial hubs and other urban markets. Moreover, long lags were found for price transmission across all scopes of markets, but especially between urban and rural prices in some regions. These results imply that local conditions (e.g., weather) are relatively more important than external market prices for explaining price variation in rural markets, especially in the short-run. Chapter 4 incorporates NDVI data into price formation models to estimate whether observable growing conditions explain price variation in Nigerian food security crop markets. Four issues related to use of NDVI data that exist within the literature are investigated: whether NDVI is a valid proxy for expected production, how NDVI is a proxy for seasonality, the relationship between market size and the area scope used to average NDVI values across space, and if anomalous harvest expectations can change long-run price variation and price relationships between markets. The results show that information on growing conditions is more informative for isolated than interconnected markets. Even for those local prices, however, other non-weather and non-external market price factors are relatively more important for explanation of price variation. An implication of these results is that Nigeria cannot plausibly rely solely on direct imports from global markets to meet short-run demand during future weather shock periods. Thus, storage is required to ensure stability of food security, either for imports or domestically produced surpluses acquired in non-crisis periods. Given the isolation of rural markets, local and on-farm stocks are at least as important as large facilities in commercial hubs. Improvement of village level and on-farm storage systems and elimination of other market distortions that inhibit trade between urban and rural markets would make public storage less needed. The findings on poor quality of agricultural statistics indicate a clear priority to improve agricultural data, to facilitate better planning of any food security strategies. A combination of surveys with remote sensed and crowd sourced data may improve feasibility in the funding constrained environment

A Fragmented Parallel Stream: The Bass Lines of Eddie Gomez in the Bill Evans Trio

Eddie Gomez was the bassist in the Bill Evans Trio for eleven years. His contribution to the group’s sound was considerable, but while there has been some recognition of his virtuoso solos in the trio there has been little academic interest in his bass lines. This essay examines bass lines from the album Since We Met, recorded in 1974 by Evans, Gomez and drummer Marty Morell. Analysis of the bass accompaniments to the piano solos on “Since We Met” and “Time Remembered” reveals that they form a fragmented two-feel. A traditional two-feel employs two notes to emphasise the first and third beats in bar of 4/4 time. In Gomez’s bass lines these two notes are frequently replaced with short rhythmic motifs. These motifs occur in a variety of forms and at different metric displacements that alternately propel and retard the forward motion of the music. Additionally, Gomez uses a wide range of register and varied articulations to create a richly diverse bass line. The resulting effect has often been interpreted as interactive or conversational with the soloist. However there is very little interaction between the bass line and Evans’ solo. The bass line is a parallel stream to the solo that energises and colours the music

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of big data (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA\u27s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Social and non-social autism symptom and trait domains are genetically dissociable

The core diagnostic criteria for autism comprise two symptom domains – social and communication difficulties, and unusually repetitive and restricted behaviour, interests and activities. There is some evidence to suggest that these two domains are dissociable, yet, this hypothesis has not been tested using molecular genetics. We test this using a GWAS of a non-social autistic trait, systemizing (N = 51,564), defined as the drive to analyse and build systems. We demonstrate that systemizing is heritable and genetically correlated with autism. In contrast, we do not identify significant genetic correlations between social autistic traits and systemizing. Supporting this, polygenic scores for systemizing are significantly positively associated with restricted and repetitive behaviour but not with social difficulties in autistic individuals. These findings strongly suggest that the two core domains of autism are genetically dissociable, and point at how to fractionate the genetics of autism

Decreased Left Caudate Volume Is Associated with Increased Severity of Autistic-Like Symptoms in a Cohort of ADHD Patients and Their Unaffected Siblings

Autism spectrum disorder (ASD) symptoms frequently occur in individuals with attention-deficit/ hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural brain correlates, knowledge of the structural brain profile of individuals with ADHD with raised ASD symptoms is limited. The presence of ASD-like symptoms was measured by the Children's Social Behavior Questionnaire (CSBQ) in a sample of typically developing controls (n = 154), participants with ADHD (n = 239), and their unaffected siblings (n = 144) between the ages of 8 and 29. Structural magnetic resonance imaging (MRI) correlates of ASD ratings were analysed by studying the relationship between ASD ratings and grey matter volumes using mixed effects models which controlled for ADHD symptom count and total brain volume. ASD ratings were significantly elevated in participants with ADHD relative to controls and unaffected siblings. For the entire group (participants with ADHD, unaffected siblings and TD controls), mixed effect models revealed that the left caudate nucleus volume was negatively correlated with ASD ratings (t = 2.83; P = 0.005). The current findings are consistent with the role of the caudate nucleus in executive function, including the selection of goals based on the evaluation of action outcomes and the use of social reward to update reward representations. There is a specific volumetric profile associated with subclinical ASD-like symptoms in participants with ADHD, unaffected siblings and controls with the caudate nucleus and globus pallidus being of critical importance in predicting the level of ASD-like symptoms in all three groups.</p

Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings

Contains fulltext : 168270.pdf (publisher's version ) (Closed access)BACKGROUND: Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample. METHODS: We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered. RESULTS: Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8-30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results. LIMITATIONS: Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional. CONCLUSION: Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research

The evolutionary history of common genetic variants influencing human cortical surface area

Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000–3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure

Social and non-social autism symptoms and trait domains are genetically dissociable

Abstract: The core diagnostic criteria for autism comprise two symptom domains – social and communication difficulties, and unusually repetitive and restricted behaviour, interests and activities. There is some evidence to suggest that these two domains are dissociable, though this hypothesis has not yet been tested using molecular genetics. We test this using a genome-wide association study (N = 51,564) of a non-social trait related to autism, systemising, defined as the drive to analyse and build systems. We demonstrate that systemising is heritable and genetically correlated with autism. In contrast, we do not identify significant genetic correlations between social autistic traits and systemising. Supporting this, polygenic scores for systemising are significantly and positively associated with restricted and repetitive behaviour but not with social difficulties in autistic individuals. These findings strongly suggest that the two core domains of autism are genetically dissociable, and point at how to fractionate the genetics of autism

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer’s disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain “insulinopathies” were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (rg = −0.315, p = 3.9 × 10−8), OCD and obesity (rg = −0.379, p = 3.4 × 10−5), and OCD and T2DM (rg = −0.172, p = 3 × 10−4). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p &lt; 6.17 × 10−4). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p &lt; 2.06 × 10−4). Overall, our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on “insulinopathies” of the brain