Whole-Brain Whole-Genome Framework for Imaging Genetics of Psychopathology and Cognition

The conception of the Research Domain Criteria (RDoC) apotheosized integration across differing biostatistical domains in studying psychiatric dysfunction. For example, an RDoC aim is the integration of MRI imaging and genetics, which represent differing foundations for the biological etiology of psychiatric and cognitive states. Though seemingly distal, recent work in both fields suggests that psychological phenomena are not represented by simple a proiri hypothesized candidates; instead we require large-data statistical approaches to find pathways for detection and treatment. That is to say, as genetics moves towards more whole-genome approaches, imaging moves towards more whole-brain approaches, and these whole-system approaches will likely be useful for research and clinical practice in the future. Imaging genetics, the field of study at the intersection of these biostatical perspectives, is unequipped to integrate these distal whole-system practices at the current time, with the most popular current approaches in imaging genetics resorting back to the antiquated candidate gene methods that failed to find replicable results. The purpose of this dissertation is to offer a framework for (some) integration in these fields at the whole-brain whole-genome (WBWG) level. While not exhaustive, the research, procedures, scripts, and methods here will help navigate this translational space. Study 1 demonstrates an approach to high-resolution mapping using the classical twin design to find patterns of association across the human cortex at high resolution for a dimensional measure of depression and a related psychiatric behavior. We then integrate these mapping results with results from the whole-genome and whole-brain literature more broadly in a big data framework. Study 2 demonstrates the effectiveness of whole-brain models as phenotypes for genetic studies of intelligence and discusses some practices for the application of whole-brain phenotypes in genetic studies. Finally, Study 3 conducts a whole-genome association study of cEF and uses the patterns across the genome to implicate particular biological/neurological pathways for analysis. The final chapter returns to discuss each study and how it fits into the general Whole-Brain Whole-Genome framework we lay out in chapter 1

Two weeks delayed bleeding in blunt liver injury: case report and review of the literature

Most cases of blunt hepatic trauma are treated nowadays non-operatively. This type of conservative treatment has resulted in increased complication rate. Delayed complications occur in cases that didn't require surgical intervention during the first 24 hours. The most common late complication is hemorrhage. We report a case of two weeks delayed hemorrhage after blunt hepatic trauma in an adult. We describe the diagnostic procedures, the surgical treatment and review the relevant literature

Whole-cortex mapping of common genetic influences on depression and a social deficits dimension

Social processes are associated with depression, particularly understanding and responding to others, deficits in which can manifest as callousness/unemotionality (CU). Thus, CU may reflect some of the genetic risk to depression. Further, this vulnerability likely reflects the neurological substrates of depression, presenting biomarkers to capture genetic vulnerability of depression severity. However, heritability varies within brain regions, so a high-resolution genetic perspective is needed. We developed a toolbox that maps genetic and environmental associations between brain and behavior at high resolution. We used this toolbox to estimate brain areas that are genetically associated with both depressive symptoms and CU in a sample of 258 same-sex twin pairs from the Colorado Longitudinal Twin Study (LTS). We then overlapped the two maps to generate coordinates that allow for tests of downstream effects of genes influencing our clusters. Genetic variance influencing cortical thickness in the right dorsal lateral prefrontal cortex (DLFPC) sulci and gyri, ventral posterior cingulate cortex (PCC), pre-somatic motor cortex (PreSMA), medial precuneus, left occipital-temporal junction (OTJ), parietal-temporal junction (PTJ), ventral somatosensory cortex (vSMA), and medial and lateral precuneus were genetically associated with both depression and CU. Split-half replication found support for both DLPFC clusters. Meta-analytic term search identified "theory of mind", "inhibit", and "pain" as likely functions. Gene and transcript mapping/enrichment analyses implicated calcium channels. CU reflects genetic vulnerability to depression that likely involves executive and social functioning in a distributed process across the cortex. This approach works to unify neuroimaging, neuroinformatics, and genetics to discover pathways to psychiatric vulnerability.</p

Genetic liability to cannabis use disorder and COVID-19 hospitalization

BACKGROUND: Vulnerability to COVID-19 hospitalization has been linked to behavioral risk factors, including combustible psychoactive substance use (e.g., tobacco smoking). Paralleling the COVID-19 pandemic crisis have been increasingly permissive laws for recreational cannabis use. Cannabis use disorder (CUD) is a psychiatric disorder that is heritable and genetically correlated with respiratory disease, independent of tobacco smoking. We examined the genetic relationship between CUD and COVID-19 hospitalization. METHODS: We estimated the genetic correlation between CUD (case: RESULTS: Genetic vulnerability to COVID-19 was correlated with genetic liability to CUD ( CONCLUSIONS: Problematic cannabis use and vulnerability to serious COVID-19 complications share genetic underpinnings that are unique from common correlates. While CUD may plausibly contribute to severe COVID-19 presentations, causal inference models yielded no evidence of putative causation. Curbing excessive cannabis use may mitigate the impact of COVID-19

Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids \u27not as prescribed\u27. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (

Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call meta-loci , showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci

Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call “meta-loci”, showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci

A large-scale genome-wide association study meta-analysis of cannabis use disorder

BACKGROUND: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. METHODS: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. FINDINGS: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10 INTERPRETATION: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. FUNDING: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences

Dietary advice for muscularity, leanness and weight control in Men's Health magazine: a content analysis

Background: The dietary content of advice in men’s lifestyle magazines has not been closely scrutinised. Methods: We carried out an analysis of such content in all 2009 issues (n = 11) of Men’s Health (MH) focusing on muscularity, leanness and weight control. Results: Promotion of a mesomorphic body image underpinned advice to affect muscle building and control weight. Diet advice was underpinned by a strong pseudo-scientific discourse, with citation of expert sources widely used to legitimise the information. Frequently multiple dietary components were advocated within one article e.g. fat, omega-3 fatty acids, thiamine, zinc and high-glycaemic index foods. Furthermore advice would cover numerous nutritional effects, e.g. strengthening bones, reducing stress and boosting testosterone, with little contextualisation. The emphasis on attainment of a mesomorphic body image permitted promotion of slimming diets. Advice to increase calorie and protein intake to augment muscle mass was frequent (183 and 262 references, respectively). Such an anabolic diet was advised in various ways, including consumption of traditional protein foods (217 references) and sports foods (107 references), thereby replicating muscle magazines’ support for nutritional supplements. Although advice to increase consumption of red meat was common (52 references), fish and non-flesh sources of protein (eggs, nuts & pulses, and soy products) together exceeded red meat in number of recommendations (206 references). Advice widely asserted micronutrients and phytochemicals from plant food (161 references) as being important in muscle building. This emphasis diverges from stereotypical gender-based food consumption patterns. Dietary advice for control of body weight largely replicated that of muscularity, with strong endorsement to consume fruits and vegetables (59 references), diets rich in nuts and pulses and fish (66 references), as well as specific micronutrients and phytochemicals (62 references). Notably there was emphasis on fat-burning, good fats and consumption of single foods, with relatively little mention of dietary restriction. Conclusions: Despite the widespread use of scientific information to endorse dietary advice, the content, format and scientific basis of dietary content of MH leaves much to be desired. The dietary advice as provided may not be conducive to public health

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder

Background Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. Methods We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. Results We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). Conclusions Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD