Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Correction Volume: 10, Article Number: 2068 DOI: 10.1038/s41467-019-10160-w WOS:000466339700001General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P <5 x 10(-8)) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.Peer reviewe

Cortisol, cognition and the ageing prefrontal cortex

The structural and functional decline of the ageing human brain varies by brain region, cognitive function and individual. The underlying biological mechanisms are poorly understood. One potentially important mechanism is exposure to glucocorticoids (GCs; cortisol in humans); GC production is increasingly varied with age in humans, and chronic exposure to high levels is hypothesised to result in cognitive decline via cerebral remodelling. However, studies of GC exposure in humans are scarce and methodological differences confound cross-study comparison. Furthermore, there has been little focus on the effects of GCs on the frontal lobes and key white matter tracts in the ageing brain. This thesis therefore examines relationships among cortisol levels, structural brain measures and cognitive performance in 90 healthy, elderly community-dwelling males from the Lothian Birth Cohort 1936. Salivary cortisol samples characterised diurnal (morning and evening) and reactive profiles (before and after a cognitive test battery). Structural variables comprised Diffusion Tensor Imaging measures of major brain tracts and a novel manual parcellation method for the frontal lobes. The latter was based on a systematic review of current manual methods in the context of putative function and cytoarchitecture. Manual frontal lobe brain parcellation conferred greater spatial and volumetric accuracy when compared to both single- and multi-atlas parcellation at the lobar level. Cognitive ability was assessed via tests of general cognitive ability, and neuropsychological tests thought to show differential sensitivity to the integrity of frontal lobe sub-regions. The majority of, but not all frontal lobe test scores shared considerable overlap with general cognitive ability, and cognitive scores correlated most consistently with the volumes of the anterior cingulate. This is discussed in light of the diverse connective profile of the cingulate and a need to integrate information over more diffuse cognitive networks according to proposed de-differentiation or compensation in ageing. Individuals with higher morning, evening or pre-test cortisol levels showed consistently negative relationships with specific regional volumes and tract integrity. Participants whose cortisol levels increased between the start and end of cognitive testing showed selectively larger regional volumes and lower tract diffusivity (correlation magnitudes <.44). The significant relationships between cortisol levels and cognition indicated that flatter diurnal slopes or higher pre-test levels related to poorer test performance. In contrast, higher levels in the morning generally correlated with better scores (correlation magnitudes <.25). Interpretation of all findings was moderated by sensitivity to type I error, given the large number of comparisons conducted. Though there were limited candidates for mediation analysis, cortisol-function relationships were partially mediated by tract integrity (but not sub-regional frontal volumes) for memory and post-error slowing. This thesis offers a novel perspective on the complex interplay among glucocorticoids, cognition and the structure of the ageing brain. The findings suggest some role for cortisol exposure in determining age-related decline in complex cognition, mediated via brain structure

Enhanced switching and familial susceptibility for psychosis.

INTRODUCTION: Working Memory and Task-Switching are essential components of cognitive control, which underlies many symptoms evident across multiple neuropsychiatric disorders, including psychotic and mood disorders. Vulnerability to these disorders has a substantial genetic component, suggesting that clinically unaffected first-degree relatives may carry some vulnerability-related traits. Converging evidence from animal and human studies demonstrates that dopamine transmission, striatal and frontal brain regions, and attention and switching behaviors are essential components of a multilevel circuit involved in salience, and disruptions in that circuit may lead to features of psychosis. Yet, it is possible that unaffected relatives may also possess characteristics that protect against development of illness. We hypothesized that reduced switch cost in a cued task-switching task, may be a behavioral expression of this "resilience" phenotype that will be observable in unaffected relatives. METHODS: We tested a large community sample (n = 536) via the web, to assess different subcomponents of cognitive control, including task-switching and working memory, as well as risk-taking, among individuals who report having an affected relative with a psychotic or mood disorder. RESULTS: Healthy individuals with suspected genetic risk due to a self-reported familial history of a psychotic disorder demonstrated better task-switching performance compared to healthy people without a psychiatrically ill relative and those with a relative with a mood disorder. This result was specific to illness status and task domain, in that individuals with a personal history of depression or anxiety did not show improved task-switching performance, and this improvement was selective to task-switching and not seen in other putative cognitive control domains (working memory or risk taking). CONCLUSIONS: Although this study has limitations and independent replication is needed, these preliminary findings suggest a potential avenue for understanding susceptibility to these disorders by highlighting possible protective as well as vulnerability-related aspects of risk phenotypes

Memory systems in schizophrenia: Modularity is preserved but deficits are generalized

Objective: Schizophrenia patients exhibit impaired working and episodic memory, but this may represent generalized impairment across memory modalities or performance deficits restricted to particular memory systems in subgroups of patients. Furthermore, it is unclear whether deficits are unique from those associated with other disorders. Method: Healthy controls (n = 1101) and patients with schizophrenia (n = 58), bipolar disorder (n = 49) and attention-deficit-hyperactivity-disorder (n = 46) performed 18 tasks addressing primarily verbal and spatial episodic and working memory. Effect sizes for group contrasts were compared across tasks and the consistency of subjects' distributional positions across memory domains was measured. Results: Schizophrenia patients performed poorly relative to the other groups on every test. While low to moderate correlation was found between memory domains ( r= .320), supporting modularity of these systems, there was limited agreement between measures regarding each individual's task performance (ICC = .292) and in identifying those individuals falling into the lowest quintile (kappa = 0.259). A general ability factor accounted for nearly all of the group differences in performance and agreement across measures in classifying low performers. Conclusions: Pathophysiological processes involved in schizophrenia appear to act primarily on general abilities required in all tasks rather than on specific abilities within different memory domains and modalities. These effects represent a general shift in the overall distribution of general ability (i.e., each case functioning at a lower level than they would have if not for the illness), rather than presence of a generally low-performing subgroup of patients. There is little evidence that memory impairments in schizophrenia are shared with bipolar disorder and ADHD

A phenome-wide examination of neural and cognitive function.

This data descriptor outlines a shared neuroimaging dataset from the UCLA Consortium for Neuropsychiatric Phenomics, which focused on understanding the dimensional structure of memory and cognitive control (response inhibition) functions in both healthy individuals (130 subjects) and individuals with neuropsychiatric disorders including schizophrenia (50 subjects), bipolar disorder (49 subjects), and attention deficit/hyperactivity disorder (43 subjects). The dataset includes an extensive set of task-based fMRI assessments, resting fMRI, structural MRI, and high angular resolution diffusion MRI. The dataset is shared through the OpenfMRI project, and is formatted according to the Brain Imaging Data Structure (BIDS) standard