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Search Results: 1 - 10 of 404495 matches for " Caroline M. Nievergelt "
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Generalized Analysis of Molecular Variance
Caroline M Nievergelt,Ondrej Libiger,Nicholas J Schork
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030051
Abstract: Many studies in the fields of genetic epidemiology and applied population genetics are predicated on, or require, an assessment of the genetic background diversity of the individuals chosen for study. A number of strategies have been developed for assessing genetic background diversity. These strategies typically focus on genotype data collected on the individuals in the study, based on a panel of DNA markers. However, many of these strategies are either rooted in cluster analysis techniques, and hence suffer from problems inherent to the assignment of the biological and statistical meaning to resulting clusters, or have formulations that do not permit easy and intuitive extensions. We describe a very general approach to the problem of assessing genetic background diversity that extends the analysis of molecular variance (AMOVA) strategy introduced by Excoffier and colleagues some time ago. As in the original AMOVA strategy, the proposed approach, termed generalized AMOVA (GAMOVA), requires a genetic similarity matrix constructed from the allelic profiles of individuals under study and/or allele frequency summaries of the populations from which the individuals have been sampled. The proposed strategy can be used to either estimate the fraction of genetic variation explained by grouping factors such as country of origin, race, or ethnicity, or to quantify the strength of the relationship of the observed genetic background variation to quantitative measures collected on the subjects, such as blood pressure levels or anthropometric measures. Since the formulation of our test statistic is rooted in multivariate linear models, sets of variables can be related to genetic background in multiple regression-like contexts. GAMOVA can also be used to complement graphical representations of genetic diversity such as tree diagrams (dendrograms) or heatmaps. We examine features, advantages, and power of the proposed procedure and showcase its flexibility by using it to analyze a wide variety of published data sets, including data from the Human Genome Diversity Project, classical anthropometry data collected by Howells, and the International HapMap Project.
A Survey of Genomic Studies Supports Association of Circadian Clock Genes with Bipolar Disorder Spectrum Illnesses and Lithium Response
Michael J. McCarthy, Caroline M. Nievergelt, John R. Kelsoe, David K. Welsh
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032091
Abstract: Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian “clock genes” associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential “core” clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.
Genetic analysis of hybridization and introgression between wild mongoose and brown lemurs
Jennifer Pastorini, Alphonse Zaramody, Deborah J Curtis, Caroline M Nievergelt, Nicholas I Mundy
BMC Evolutionary Biology , 2009, DOI: 10.1186/1471-2148-9-32
Abstract: Two segments of mtDNA have been sequenced and 12 microsatellite loci screened in 162 brown lemurs and mongoose lemurs. Among the mongoose lemur population at Anjamena, we identified two F1 hybrids (one also having the mtDNA haplotype of E. fulvus) and six other individuals with putative introgressed alleles in their genotype. Principal component analysis groups both hybrids as intermediate between E. mongoz and E. fulvus and admixture analyses revealed an admixed genotype for both animals. Paternity testing proved one F1 hybrid to be fertile. Of the eight brown lemurs genotyped, all have either putative introgressed microsatellite alleles and/or the mtDNA haplotype of E. mongoz.Introgression is bidirectional for the two species, with an indication that it is more frequent in brown lemurs than in mongoose lemurs. We conclude that this hybridization occurs because mongoose lemurs have expanded their range relatively recently. Introgressive hybridization may play an important role in the unique lemur radiation, as has already been shown in other rapidly evolving animals.Hybridization among animals has traditionally been viewed as an unusual event. However, recent genetic studies have shown that it occurs more commonly than originally believed [1,2]. Hybridization may occur due to human impact, such as between domestic or captive species, wild and domestic species [3,4] or between introduced and native species [5,6]. Natural hybridization has been found across the animal kingdom, including insects [7], fish [8], amphibians [9], birds [10,11], carnivores [12], and monkeys [13-15]. Among the Malagasy lemurs, a few cases of hybridization between subspecies have been reported in the wild [16-19].Harrison [20] defined hybridization as "the interbreeding of individuals from two populations, or groups of populations, which are distinguishable on the basis of one or more heritable characters." Hybridization occurs when there are incomplete reproductive barriers between two taxa
Circadian polymorphisms associated with affective disorders
Daniel F Kripke, Caroline M Nievergelt, EJ Joo, Tatyana Shekhtman, John R Kelsoe
Journal of Circadian Rhythms , 2009, DOI: 10.1186/1740-3391-7-2
Abstract: Four groups of subjects were recruited from several sources: 1) bipolar proband-parent trios or sib-pair-parent nuclear families, 2) unrelated bipolar participants who had completed the BALM morningness-eveningness questionnaire, 3) sib pairs from the GenRed Project having at least one sib with early-onset recurrent unipolar depression, and 4) a sleep clinic patient group who frequently suffered from depression. Working mainly with the SNPlex assay system, from 2 to 198 polymorphisms in genes related to circadian function were genotyped in the participant groups. Associations with affective disorders were examined with TDT statistics for within-family comparisons. Quantitative trait associations were examined within the unrelated samples.In NR1D1, rs2314339 was associated with bipolar disorder (P = 0.0005). Among the unrelated bipolar participants, 3 SNPs in PER3 and CSNK1E were associated with the BALM score. A PPARGC1B coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In TEF, rs738499 was associated with unipolar depression; in a replication study, rs738499 was also associated with the QIDS-SR depression scale in the sleep clinic patient sample.Along with anti-manic effects of lithium and the antidepressant effects of bright light, these findings suggest that perturbations of the circadian gene network at several levels may influence mood disorders, perhaps ultimately through regulation of MAOA and its modulation of dopamine transmission. Twenty-three associations of circadian polymorphisms with affective symptoms met nominal significance criteria (P < 0.05), whereas 15 would be expected by chance, indicating that many represented false discoveries (Type II errors). Some evidence of replication has been gathered, but more studies are needed to ascertain if circadian gene polymorphisms contribute to susceptibility to affective disorders.The idea that circadian rh
Delayed sleep phase cases and controls
Daniel F Kripke, Katharine M Rex, Sonia Ancoli-Israel, Caroline M Nievergelt, Walt Klimecki, John R Kelsoe
Journal of Circadian Rhythms , 2008, DOI: 10.1186/1740-3391-6-6
Abstract: We recruited a case series of 205 participants, along with 221 controls (DSPD-C) with normal sleep, roughly matched for age, gender, and ancestry. A representative sample of San Diego adults recruited some years before was already available to confirm the control group. Both DSPD and DSPD-C provided blood or saliva samples for DNA and completed extensive questionnaires about sleep habits, sleep history, family history, sleep quality, morningness-eveningness traits, depression, mania, and seasonality of symptoms. The DSPD group wore wrist actigraphs for a median of 13.2 days. The representative sample collected previously had undergone actigraphic recordings, from which 48 hours of data were generally available.The DSPD and DSPD-C samples showed almost no overlap on morningness-eveningness scores. DSPD cases went to bed and arose about 3 hours later than the DSPD-C and the representative sample. DSPD cases reported more difficulties with sleep, poorer sleep quality, and more depression, but there was no significant difference in a history of mania. DSPD cases reported more family history of late bedtimes, but female DSPD reported that their fathers' bedtimes were later than the fathers of male DSPD.These results indicate a DSPD phenotype is familial and associated with unipolar depression.Some people are characteristically "larks" who retire and awaken early or "owls" who stay up late and awaken late. Larks also tend to be "morning" types who are energetic early in the morning, whereas owls are "evening" types whose energy may increase late in the evening. These traits have been described with morningness-eveningness scales (MES) such as the Horne-?stberg Scale (HO) [1]. Though mild variations in habitual bedtime are often easily accommodated, extreme forms of morningness or eveningness may produce social distress and disability.When distressing, the severe forms of morningness and eveningness are termed Advanced Sleep Phase Disorder (ASPD, the larks) and Delayed Sle
Polymorphisms in melatonin synthesis pathways: possible influences on depression
Daniel F Kripke, Caroline M Nievergelt, Greg J Tranah, Sarah S Murray, Michael J McCarthy, Katharine M Rex, Neeta Parimi, John R Kelsoe
Journal of Circadian Rhythms , 2011, DOI: 10.1186/1740-3391-9-8
Abstract: To replicate and further explore these ideas, rs4446909 was genotyped in four research groups, as part of a panel of 610 SNPs surveyed by an Illumina Golden Gate assay. In 768 cases with delayed sleep phase disorder or matched controls, rs4446909 was indeed associated with the depressive symptoms on a self-report scale (P = 0.01, R2 = 0.007). However, there was no significant association of rs4446909 with self-reported depression in a sleep clinic patient group or with two groups of elderly men and women from multicenter studies, nor was the response to lithium treatment associated with rs4446909 in bipolar patients. No associations of two AANAT SNPs with depression were found.The evidence did not support a strong influence of rs4446909 upon mood, but the partial replication may be consistent with a modest effect. It is possible that larger or younger subject groups with improved phenotype ascertainment might demonstrate more persuasive replication.The psychiatric literature contains a number of inconsistent studies of melatonin in affective disorders, reporting that there is a "low melatonin syndrome" or high morning melatonin associated with depression, or that the timing of melatonin secretion may be either advanced or delayed [1-7]. The circadian phase of melatonin secretion has been hypothesized to be a causal element in affective disorders. New evidence suggests that late melatonin elevations may suppress pars tuberalis TEF, a photoperiodic switch which might control human depression [8]. Such a mechanism would be consistent with apparent comorbidity of delayed sleep phase disorder and depression [9]. The problems contributing to inconsistent theories about melatonin's role in depression include the difficulties of obtaining complete overnight melatonin secretion profiles from onset to offset, especially in very disturbed patients, assay difficulties, differences between the home and hospital environments, effects of medications, and the heterogeneity of patie
Tracing Sub-Structure in the European American Population with PCA-Informative Markers
Peristera Paschou equal contributor ,Petros Drineas equal contributor,Jamey Lewis,Caroline M. Nievergelt,Deborah A. Nickerson,Joshua D. Smith,Paul M. Ridker,Daniel I. Chasman,Ronald M. Krauss,Elad Ziv
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000114
Abstract: Genetic structure in the European American population reflects waves of migration and recent gene flow among different populations. This complex structure can introduce bias in genetic association studies. Using Principal Components Analysis (PCA), we analyze the structure of two independent European American datasets (1,521 individuals–307,315 autosomal SNPs). Individual variation lies across a continuum with some individuals showing high degrees of admixture with non-European populations, as demonstrated through joint analysis with HapMap data. The CEPH Europeans only represent a small fraction of the variation encountered in the larger European American datasets we studied. We interpret the first eigenvector of this data as correlated with ancestry, and we apply an algorithm that we have previously described to select PCA-informative markers (PCAIMs) that can reproduce this structure. Importantly, we develop a novel method that can remove redundancy from the selected SNP panels and show that we can effectively remove correlated markers, thus increasing genotyping savings. Only 150–200 PCAIMs suffice to accurately predict fine structure in European American datasets, as identified by PCA. Simulating association studies, we couple our method with a PCA-based stratification correction tool and demonstrate that a small number of PCAIMs can efficiently remove false correlations with almost no loss in power. The structure informative SNPs that we propose are an important resource for genetic association studies of European Americans. Furthermore, our redundancy removal algorithm can be applied on sets of ancestry informative markers selected with any method in order to select the most uncorrelated SNPs, and significantly decreases genotyping costs.
Heritable Influence of DBH on Adrenergic and Renal Function: Twin and Disease Studies
Dalal N. Pasha, Jason T. Davis, Fangwen Rao, Yuqing Chen, Gen Wen, Maple M. Fung, Manjula Mahata, Kuixing Zhang, Danuta Trzebinska, Maja Mustapic, C. Makena Hightower, Michael S. Lipkowitz, Ming Ji, Michael G. Ziegler, Caroline M. Nievergelt, Daniel T. O'Connor
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082956
Abstract: Background Elevated sympathetic activity is associated with kidney dysfunction. Here we used twin pairs to probe heritability of GFR and its genetic covariance with other traits. Methods We evaluated renal and adrenergic phenotypes in twins. GFR was estimated by CKD-EPI algorithm. Heritability and genetic covariance of eGFR and associated risk traits were estimated by variance-components. Meta-analysis probed reproducibility of DBH genetic effects. Effect of DBH genetic variation on renal disease was tested in the NIDDK-AASK cohort. Results Norepinephrine secretion rose across eGFR tertiles while eGFR fell (p<0.0001). eGFR was heritable, at h2 = 67.3±4.7% (p = 3.0E-18), as were secretion of norepinephrine (h2 = 66.5±5.0%, p = 3.2E-16) and dopamine (h2 = 56.5±5.6%, p = 1.8E-13), and eGFR displayed genetic co-determination (covariance) with norepinephrine (ρG = ?0.557±0.088, p = 1.11E-08) as well as dopamine (ρG = ?0.223±0.101, p = 2.3E-02). Since dopamine β-hydroxylase (DBH) catalyzes conversion of dopamine to norepinephrine, we studied functional variation at DBH; DBH promoter haplotypes predicted transcriptional activity (p<0.001), plasma DBH (p<0.0001) and norepinephrine (p = 0.0297) secretion; transcriptional activity was inversely (p<0.0001) associated with basal eGFR. Meta-analysis validated DBH haplotype effects on eGFR across 3 samples. In NIDDK-AASK, we established a role for DBH promoter variation in long-term renal decline rate (GFR slope, p = 0.003). Conclusions The heritable GFR trait shares genetic determination with catecholamines, suggesting new pathophysiologic, diagnostic and therapeutic approaches towards disorders of GFR as well as CKD. Adrenergic activity may play a role in progressive renal decline, and genetic variation at DBH may assist in profiling subjects for rational preventive treatment.
Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes
Erin N. Smith,Daniel L. Koller,Corrie Panganiban,Szabolcs Szelinger,Peng Zhang,Judith A. Badner,Thomas B. Barrett,Wade H. Berrettini,Cinnamon S. Bloss,William Byerley,William Coryell,Howard J. Edenberg,Tatiana Foroud,Elliot S. Gershon,Tiffany A. Greenwood,Yiran Guo,Maria Hipolito,Brendan J. Keating,William B. Lawson,Chunyu Liu,Pamela B. Mahon,Melvin G. McInnis,Francis J. McMahon,Rebecca McKinney,Sarah S. Murray,Caroline M. Nievergelt,John I. Nurnberger Jr.,Evaristus A. Nwulia,James B. Potash,John Rice,Thomas G. Schulze,William A. Scheftner,Paul D. Shilling,Peter P. Zandi,Sebastian Z?llner,David W. Craig ,Nicholas J. Schork ,John R. Kelsoe
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002134
Abstract: Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10?7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.
Alpha-synuclein truncation and disease  [PDF]
Caroline M. Ritchie, Philip J. Thomas
Health (Health) , 2012, DOI: 10.4236/health.2012.431175
Abstract: Alpha-synuclein is the major component of Lewy bodies, insoluble protein aggregates, found in patients with Parkinson’s disease, diffuse Lewy body disease, and the Lewy body variant of Alzheimer’s disease. Alpha-synuclein has been found within Lewy bodies to contain many different modifications, including nitration, phosphorylation, ubiquitination, and truncation. C-terminally truncated forms of alpha-synuclein aggregate faster than the full-length protein in vitro, and are thus believed to play a role in Lewy body formation and disease progression. Pathological studies of post mortem brain tissue and the generation of transgenic mouse models further support a role of C-terminally truncated forms of alpha-synuclein in disease. Several enzymes, some of which function extracellularly, have been implicated in the production of these C-terminally truncated forms of alpha-synuclein. However, the enzymes responsible for alphasynuclein truncation in vivo have not yet been firmly established.
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