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Open Access Publications from the University of California

Scholarly Works (119 results)

  • Article
Department of Statistics Papers (2002)

Population based linkage disequilibrium genome screens represent one of the most recent approaches for the lo- calization of genes responsible for complex diseases. One open problem in this context is represented by the definition of an appropriate significance threshold that takes into account the multiple comparison problem. We explore the con- ceptual and practical implications of the multiple testing procedure known as False Discovery Rate (FDR). We argue that controlling the FDR better represents the interest of researcher in this area than more traditional approaches. We then explore the applicability of the Benjamini-Hochberg (BH) FDR controlling procedure in the specific context of association mapping from case-control data. We analyze the nature of dependency between the test statistics with an- alytic work and simulations and we conclude that the BH rule effectively controls FDR in our context of interest. The dependency between test statistics translates into a decrease of power, which highlights the necessity of developing resampling based rules to control FDR.

    Cover page: False Discovery Rate and Correction for Multiple Comparisons in Linkage Disequilibrium Genome Screens
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2009)
    Genetic approaches to dissecting complex traits in animal models increasingly use transcript levels as a molecular phenotype and as validation for predictions of gene function. A recent study in BMC Biology using these approaches shows the complexity of the genetic contribution to aggressive behavior in Drosophila.
      Cover page: The complex genetic basis of simple behavior
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2019)
      Internet-connected devices could transform our understanding of the causes of behavioural variation and its impact on health and disease, in particular for neuropsychiatric disorders.
        Cover page: Integrating behavioural health tracking in human genetics research
        • Article
        • Peer Reviewed
        Abstract Recent studies have identified a small number of genomic rearrangements that occur frequently in the general population. Bioinformatics tools are now available for systematic genome-wide surveys of higher-order structures predisposing to such common variations in genomic architecture. Segmental duplications (SDs) constitute up to 5 per cent of the genome and play an important role in generating additional rearrangements and in disease aetiology. We conducted a genome-wide database search for a form of SD, palindromic segmental duplications (PSDs), which consist of paired, inverted duplications, and which predispose to inversions, duplications and deletions. The survey was complemented by a search for SDs in tandem orientation (TSDs) that can mediate duplications and deletions but not inversions. We found more than 230 distinct loci with higher-order genomic structure that can mediate genomic variation, of these about 180 contained a PSD. A number of these sites were previously identified as harbouring common inversions or as being associated with specific genomic diseases characterised by duplication, deletions or inversions. Most of the regions, however, were previously unidentified; their characterisation should identify further common rearrangements and may indicate localisations for additional genomic disorders. The widespread distribution of complex chromosomal architecture suggests a potentially high degree of plasticity of the human genome and could uncover another level of genetic variation within human populations.
          Cover page: A genome-wide survey of segmental duplications that mediate common human genetic variation of chromosomal architecture
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2004)
          Recent studies have identified a small number of genomic rearrangements that occur frequently in the general population. Bioinformatics tools are now available for systematic genome-wide surveys of higher-order structures predisposing to such common variations in genomic architecture. Segmental duplications (SDs) constitute up to 5 per cent of the genome and play an important role in generating additional rearrangements and in disease aetiology. We conducted a genome-wide database search for a form of SD, palindromic segmental duplications (PSDs), which consist of paired, inverted duplications, and which predispose to inversions, duplications and deletions. The survey was complemented by a search for SDs in tandem orientation (TSDs) that can mediate duplications and deletions but not inversions. We found more than 230 distinct loci with higher-order genomic structure that can mediate genomic variation, of these about 180 contained a PSD. A number of these sites were previously identified as harbouring common inversions or as being associated with specific genomic diseases characterised by duplication, deletions or inversions. Most of the regions, however, were previously unidentified; their characterisation should identify further common rearrangements and may indicate localisations for additional genomic disorders. The widespread distribution of complex chromosomal architecture suggests a potentially high degree of plasticity of the human genome and could uncover another level of genetic variation within human populations.
            Cover page: A genome-wide survey of segmental duplications that mediate common human genetic variation of chromosomal architecture
            • Thesis
            • Peer Reviewed
            UCLA Electronic Theses and Dissertations (2018)

            Bipolar disorder (BD) is a highly heritable mood disorder with a complex genetic architecture. It is commonly treated prophylactically with the mood stabilizer lithium, although treatment responses vary widely across patients. Both how BD genetic variants confer risk and the molecular mechanisms underlying lithium’s therapeutic effects remain poorly understood. This dissertation begins with a review of recent findings from BD and lithium-response genetic studies and from BD and lithium treatment transcriptomic studies. This review will show that while presenting an opportunity to learn valuable information about underlying biology, gene expression studies investigating these phenotypes have had low sample sizes and inconsistent findings. Then, an original study attempting to fill this gap by exploring the whole blood transcriptome in a large BD case-control RNA sequencing sample is reported on. In this study, strong effects of lithium treatment and cell-type composition were revealed, pointing to potential therapeutic mechanisms of lithium, and underlining the importance of carefully correcting for these variables. To put these findings in the context of the current understanding of BD etiology and lithium treatment mechanisms, a comparison was made with findings previously reported highlighting a list of high-confidence lithium-associated genes. A gene-set analysis comparing genes with differential expression to genes implicated from major psychiatric genome-wide association studies revealed that the observed gene expression changes were unrelated to genetic risk. The findings herein contribute to the current understanding of the BD transcriptome in whole blood and provide evidence for the mechanistic actions of lithium treatment.

              Cover page: The molecular signatures of bipolar disorder and lithium treatment
              • Thesis
              • Peer Reviewed
              UCLA Electronic Theses and Dissertations (2023)

              Biobanks linked to Electronic Health Records (EHRs) herald a new era of opportunities for etiological research of Severe Mental Illness (SMI). However, because EHRs are not primarily designed for research, translating these opportunities into actionable insights demands innovative frameworks and accurate phenotyping tools. This dissertation harnesses the potential of EHRs from psychiatric hospitals for in-depth studies of SMI. I set the stage by contextualizing the relevance of EHRs in psychiatric genetic research. Then, I describe the organizational makeup and data types within the EHR of the Clinica San Juan de Dios in Manizales — a regional psychiatric hospital in Colombia. The subsequent chapters explore transdiagnostic phenotypes by combining clinical notes and diagnostic codes, leading to the delineation of disease trajectories in SMI. Then, I explore the extraction and validation of psychiatric diagnoses through both rule-based and machine learning strategies. And finally, I conclude with the design and validation of a Clinical Natural Language Processing (cNLP) tool for extracting highly detailed psychiatric phenotypes from unstructured text. Three strengths of EHRs are emphasized throughout this work: the integration of multi-dimensional data, enabling a comprehensive perspective of patient phenotypes; the innovative application of cNLP for symptom extraction from clinical narratives in Spanish; and the capacity of EHRs to provide longitudinal insights into patients' course of illness. Taken together, this dissertation not only highlights the potential of EHRs but also navigates the intricacies of employing them for psychiatric genetic research.

                Cover page: Methods for Extracting and Validating Psychiatric Phenotypes: Advancements Using Electronic Health Records in Colombia
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2017)
                The northern elephant seal, Mirounga angustirostris, was heavily hunted and declared extinct in the 19th century. However, a colony remained on remote Guadalupe Island, Mexico and the species has since repopulated most of its historical distribution. Here, we present a comprehensive evaluation of genetic variation in the species. First, we assess the effect of the demographic bottleneck on microsatellite variability and compare it with that found in other pinnipeds, demonstrating levels of variation similar to that in species that continue to be threatened with extinction. Next, we use sequence data from these markers to demonstrate that some of the limited polymorphism predates the bottleneck. However, most contemporary variation appears to have arisen recently and persisted due to exponential growth. We also describe how we use the range in allele size of microsatellites to estimate ancestral effective population size before the bottleneck, demonstrating a large reduction in effective size. We then employ a classical method for bacteria to estimate the microsatellite mutation rate in the species, deriving an estimate that is extremely similar to that estimated for a similar set of loci in humans, indicating consistency of microsatellite mutation rates in mammals. Finally, we find slight significant structure between some geographically separated colonies, although its biological significance is unclear. This work demonstrates that genetic analysis can be useful for evaluating the population biology of the northern elephant seal, in spite of the bottleneck that removed most genetic variation from the species.
                  Cover page: Molecular Population Genetics of the Northern Elephant Seal Mirounga angustirostris.
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2015)

                  Unlabelled

                  A small number of African green monkeys (AGMs) were introduced into the Caribbean from West Africa in the 1600s. To determine the impact of this population bottleneck on the AGM virome, we used metagenomics to compare the viral nucleic acids in the plasma of 43 wild AGMs from West Africa (Gambia) to those in 44 AGMs from the Caribbean (St. Kitts and Nevis). Three viruses were detected in the blood of Gambian primates: simian immunodeficiency virus (SIVagm; in 42% of animals), a novel simian pegivirus (SPgVagm; in 7% of animals), and numerous novel simian anelloviruses (in 100% of animals). Only anelloviruses were detected in the Caribbean AGMs with a prevalence and levels of viral genetic diversity similar to those in the Gambian animals. A host population bottleneck therefore resulted in the exclusion of adult-acquired SIV and pegivirus from the Caribbean AGMs. The successful importation of AGM anelloviruses into the Caribbean may be the result of their early transmission to infants, very high prevalence in African AGMs, and frequent coinfections with as many as 11 distinct variants.

                  Importance

                  The extent to which viruses can persist in small isolated populations depends on multiple host, viral, and environmental factors. The absence of prior infections may put an immunologically naive population at risk for disease outbreaks. Isolated populations originating from a small number of founder individuals are therefore considered at increased risk following contact with populations with a greater variety of viruses. Here, we compared the plasma virome of West African green monkeys to that in their descendants after importation of a small number of animals to the Caribbean. A lentivirus and a pegivirus were found in the West African population but not in the Caribbean population. Highly diverse anelloviruses were found in both populations. A small founder population, limited to infants and young juvenile monkeys, may have eliminated the sexually transmitted viruses from the Caribbean AGMs, while anelloviruses, acquired at an earlier age, persisted through the host population bottleneck.
                    Cover page: Local Virus Extinctions following a Host Population Bottleneck
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2015)
                    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 individuals 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.
                      Cover page: Memory systems in schizophrenia: Modularity is preserved but deficits are generalized.
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