Generalized Analysis of Molecular Variance

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

Genetic analysis of hybridization and introgression between wild mongoose and brown lemurs.

BACKGROUND: Hybrid zones generally represent areas of secondary contact after speciation. The nature of the interaction between genes of individuals in a hybrid zone is of interest in the study of evolutionary processes. In this study, data from nuclear microsatellites and mitochondrial DNA sequences were used to genetically characterize hybridization between wild mongoose lemurs (Eulemur mongoz) and brown lemurs (E. fulvus) at Anjamena in west Madagascar. RESULTS: 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. CONCLUSION: 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.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Circadian polymorphisms associated with affective disorders

<p>Abstract</p> <p>Background</p> <p>Clinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>In <it>NR1D1</it>, rs2314339 was associated with bipolar disorder (P = 0.0005). Among the unrelated bipolar participants, 3 SNPs in <it>PER3 </it>and <it>CSNK1E </it>were associated with the BALM score. A <it>PPARGC1B </it>coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In <it>TEF</it>, 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.</p> <p>Conclusion</p> <p>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.</p

Sleep disturbance at pre-deployment is a significant predictor of post-deployment re-experiencing symptoms.

Background: Insomnia is common in service members and associated with many mental and physical health problems. Recently, longitudinal data have been used to assess the impact of disturbed sleep on mental health outcomes. These studies have consistently shown relationships between sleep disturbance and development of mental illness. Objective: The present study examined the longitudinal relationship between sleep disturbance and PTSD symptomatology in a cohort of Marines and Navy Corpsmen deployed to Iraq and Afghanistan (n = 2,404) assessed prior to deployment, as well as at -3 and 6 months post-deployment. Additionally, we aimed to investigate the extent to which these relationships are moderated by combat-stress severity, and to what extent these findings are replicated in a second, separate cohort of Marines and Navy corpsmen (n = 938) assessed with identical measures prior to deployment and within 3 months of return. Method: The present study employed latent variable path models to examine the relationships between pre-deployment sleep disturbance and post-deployment re-experiencing symptoms. Initial cross-lagged path models were conducted on discovery and replication samples to validate the hypothesized predictive relationships. Follow up moderation path models were then conducted to include the effect of combat-stress severity on these relationships. Results: Initial cross-lagged models supported a significant relationship between pre-deployment sleep disturbance and future re-experiencing PTSD symptoms at all time points. Initial moderation models showed a small moderator effect of combat-stress severity, though the main predictive relationship between pre-deployment sleep disturbance and PTSD symptoms remained significant. The moderator effect was not significant in the replication sample. Conclusions: The results of this study support pre-deployment sleep disturbance as a risk factor for development of post-deployment PTSD symptoms. Interventions aimed at normalizing sleep may be important in preventive measures for PTSD

CYBA Gene Polymorphisms and Adverse Outcomes in Acute Kidney Injury: A Prospective Cohort Study

Background: NADPH oxidase is an important enzyme involved in the generation of reactive oxygen species in acute kidney injury (AKI). Its key subunit, p22phox, is encoded by the highly polymorphic CYBA gene. Methods: We examined the associations of CYBA gene polymorphisms across the CYBA locus (rs8854, rs3794624, rs4673, rs4782390, and rs1049255) with dialysis requirement or in-hospital death in 256 hospitalized adults with AKI. Dominant and haplotype multivariable logistic regression analyses were performed, adjusted for sex, race, age, and severity of illness. Results: The baseline characteristics of the patients were not different among genotype groups with the exception of a lower prevalence of sepsis and shock in the CYBA rs8854 A-allele group; a higher prevalence of shock in the CYBA rs4782390 T-allele group, and a higher APACHE II score in the CYBA rs1049255 G-allele group. The CYBA rs8854 A-allele had an adjusted odds ratio (OR) of 0.41 (95% confidence interval, CI, 0.18–0.96) for the outcome of dialysis requirement or in-hospital death. The CYBA rs4673 T-allele and rs1049255 G-allele had unadjusted ORs of 1.69 (95% CI 1.03–2.79) and 1.66 (95% CI 1.01–2.73) for the composite outcome, respectively, which became non-significant after multivariable adjustment. The remaining 2 polymorphisms were not associated with the outcomes of interest. Finally, the presence of the CYBA A-A-G-G haplotype (generated from rs4782390, rs4673, rs3794624, and rs8854, all in Hardy-Weinberg equilibrium) was associated with an elevated OR of 1.81 (95% CI 1.07–3.08) for dialysis requirement or in-hospital death, which was attenuated after multivariable adjustment (OR 1.80; 95% CI 0.99–3.29). Conclusion: This study identifies several polymorphisms spanning the entire CYBA gene locus and a common haplotype as risk markers for dialysis requirement or in-hospital death in patients with AKI. Additional studies are needed to validate these findings

Reply to : On powerful GWAS in admixed populations

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Delayed sleep phase cases and controls

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Assessing Neuronal and Astrocyte Derived Exosomes From Individuals With Mild Traumatic Brain Injury for Markers of Neurodegeneration and Cytotoxic Activity.

Mild traumatic brain injury (mTBI) disproportionately affects military service members and is very difficult to diagnose. To-date, there is currently no blood-based, diagnostic biomarker for mTBI cases with persistent post concussive symptoms. To examine the potential of neuronally-derived (NDE) and astrocytic-derived (ADE) exosome cargo proteins as biomarkers of chronic mTBI in younger adults, we examined plasma exosomes from a prospective longitudinal study of combat-related risk and resilience, marine resiliency study II (MRSII). After return from a combat-deployment participants were interviewed to assess TBI exposure while on deployment. Plasma exosomes from military service members with mTBI (mean age, 21.7 years, n = 19, avg. days since injury 151), and age-matched, controls (deployed service members who did not endorse a deployment-related TBI or a pre-deployment history of TBI; mean age, 21.95 years, n = 20) were precipitated and enriched against a neuronal adhesion protein, L1-CAM, and an astrocyte marker, glutamine aspartate transporter (GLAST) using magnetic beads to immunocapture the proteins and subsequently selected by fluorescent activated cell sorting (FACS). Extracted protein cargo from NDE and ADE preparations were quantified for protein levels implicated in TBI neuropathology by standard ELISAs and on the ultra-sensitive single molecule assay (Simoa) platform. Plasma NDE and ADE levels of Aβ42 were significantly higher while plasma NDE and ADE levels of the postsynaptic protein, neurogranin (NRGN) were significantly lower in participants endorsing mTBI exposure compared to controls with no TBI history. Plasma NDE and ADE levels of Aβ40, total tau, and neurofilament light (NFL), P-T181-tau, P-S396-tau were either undetectable or not significantly different between the two groups. In an effort to understand the pathogenetic potential of NDE and ADE cargo proteins, neuron-like cultures were treated with NDE and ADE preparations from TBI and non-TBI groups. Lastly, we determined that plasma NDE but not ADE cargo proteins from mTBI samples were found to be toxic to neuron-like recipient cells in vitro. These data support the presence of markers of neurodegeneration in NDEs of mTBI and suggest that these NDEs can be used as tools to identify pathogenic mechanisms of TBI

A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function.

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 μM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease

High executive functioning is associated with reduced posttraumatic stress after trauma exposure among male U.S. military personnel

IntroductionEvidence suggests that executive function (EF) may play a key role in development of PTSD, possibly influenced by factors such as trauma type and timing. Since EF can be improved through intervention, it may be an important target for promoting resilience to trauma exposure. However, more research is needed to understand the relation between trauma exposure, EF, and PTSD. The goal of this study was to improve understanding of EF as a potential antecedent or protective factor for the development of PTSD among military personnel.MethodIn a cohort of U.S. Marines and Navy personnel (N = 1,373), the current study tested the association between exposure to traumatic events (pre-deployment and during deployment) and PTSD severity, and whether EF moderated these associations. Three types of pre-deployment trauma exposure were examined: cumulative exposure, which included total number of events participants endorsed as having happened to them, witnessed, or learned about; direct exposure, which included total number of events participants endorsed as having happened to them; and interpersonal exposure, which included total number of interpersonally traumatic events participants’ endorsed. EF was measured using the Penn Computerized Neurocognitive Battery.ResultsEF was associated with less PTSD symptom severity at pre-deployment, even when adjusting for trauma exposure, alcohol use, traumatic brain injury, and number of years in the military. EF also moderated the relation between cumulative trauma exposure and interpersonal trauma exposure and PTSD, with higher EF linked to a 20 and 33% reduction in expected point increase in PTSD symptoms with cumulative and interpersonal trauma exposure, respectively. Finally, higher pre-deployment EF was associated with reduced PTSD symptom severity at post-deployment, independent of deployment-related trauma exposure and adjusting for pre-deployment PTSD.ConclusionOur results suggest that EF plays a significant, if small role in the development of PTSD symptoms after trauma exposure among military personnel. These findings provide important considerations for future research and intervention and prevention, specifically, incorporating a focus on improving EF in PTSD treatment