Distinct Patterns Of Association Research Articles

Apathy and intrinsic functional connectivity networks in amnestic mild cognitive impairment.

BackgroundAlthough several prior works reported that apathy is associated with conversion to Alzheimer’s disease in individuals with amnestic mild cognitive impairment (aMCI), effects of apathy on the functional connectivity (FC) of the brain remain unclear. In this study, we assessed the pattern of association between apathy and default mode network (DMN), salience network and central executive network (CEN) in aMCI subjects.MethodsFifty subjects with aMCI and 50 controls (CONs) participated in this study. They underwent clinical assessments and magnetic resonance imaging for the structural and resting-state scan. We explored the patterns of association between apathy inventory (IA) total score and the whole-brain voxel-wise FCs of the DMN, salience network and CEN in aMCI subjects.ResultsWe observed that the FCs of the DMN were less and those of CEN were more in the aMCI group than the CON group. Total IA score was negatively correlated with FCs of the anterior cingulate within the DMN, and positively correlated with FCs of the middle frontal, inferior frontal, and supramarginal gyrus within the CEN in the aMCI group.ConclusionOur findings suggest that distinctive patterns of association between apathy and FCs in the DMN and CEN in the aMCI group might reflect the putative role of functional network change in the development of apathy in aMCI.

Patterns of association of chronic medical conditions and major depression.

Age and sex-related patterns of association between medical conditions and major depressive episodes (MDE) are important for understanding disease burden, anticipating clinical needs and for formulating etiological hypotheses. General population estimates are especially valuable because they are not distorted by help-seeking behaviours. However, even large population surveys often deliver inadequate precision to adequately describe such patterns. In this study, data from a set of national surveys were pooled to increase precision, supporting more precise characterisation of these associations. The data were from a series of Canadian national surveys. These surveys used comparable sampling strategies and assessment methods for MDE. Chronic medical conditions were assessed using items asking about professionally diagnosed medical conditions. Individual-level meta-analysis methods were used to generate unadjusted, stratified and adjusted prevalence odds ratios for 11 chronic medical conditions. Random effects models were used in the meta-analysis. A procedure incorporating rescaled replicate bootstrap weights was used to produce 95% confidence intervals. Overall, conditions characterised by pain and inflammation tended to show stronger associations with MDE. The meta-analysis uncovered two previously undescribed patterns of association. Effect modification by age was observed in varying degrees for most conditions. This effect was most prominent for high blood pressure and cancer. Stronger associations were found in younger age categories. Migraine was an exception: the strength of association increased with age, especially in men. Second, especially for conditions predominantly affecting older age groups (arthritis, diabetes, back pain, cataracts, effects of stroke and heart disease) confounding by age was evident. For each condition, age adjustment resulted in strengthening of the associations. In addition to migraine, two conditions displayed distinctive patterns of association. Age adjusted odds ratios for thyroid disease reflected a weak association that was only significant in women. In epilepsy, a similar strength of association was found irrespective of age or sex. The prevalence of MDE is elevated in association with most chronic conditions, but especially those characterised by inflammation and pain. Effect modification by age may reflect greater challenges or difficulties encountered by young people attempting to cope with these conditions. This pattern, however, does not apply to migraine or epilepsy. Neurobiological changes associated with these conditions may offset coping-related effects, such that the association does not weaken with age. Prominent confounding by age for several conditions suggests that age adjustments are necessary in order to avoid underestimating the strength of these associations.

Cerebral vascular burden on hippocampal subfields in first-onset drug-naïve subjects with late-onset depression

BackgroundAlthough there is substantial evidence of associations between frontal-striatal circuits and cerebral vascular burden in late-onset depression (LOD), relationships between vascular burden and hippocampal subfields are not clear. The purpose of this study was to investigate relationships between cerebral vascular burden and hippocampal subfield volume in LOD patients. MethodsFifty subjects with LOD and 50 group-matched healthy control subjects underwent magnetic resonance imaging scanning. Hippocampal subfields volumes were measured and compared between the groups. In addition, association patterns between white matter hyperintensity (WMH) volumes, clinical measures and hippocampal subfield volumes were investigated in the LOD group. ResultsSubjects with LOD exhibited significant hippocampal volume reductions in the total hippocampus, cornu ammonis (CA) 1 and 3 and dentate gyrus (DG) areas compared with healthy subjects. Total WMH volume was negatively correlated with left total hippocampal volume and CA1 in the LOD group. In addition, depression severity was negatively associated with left and right CA3 volumes in the LOD group. LimitationOur findings of distinctive relationships between WMH and hippocampal subfields demonstrate a simple correlation, but do not prove causation ConclusionThis study is the first to elaborate distinctive association patterns between hippocampal subfield volumes and cerebral vascular burden in LOD. These structural changes in the hippocampal CA1, CA3 and DG areas might be at the core of the underlying neurobiological mechanisms of hippocampal dysfunction in LOD. However, longitudinal studies will be needed to identify the mechanisms of these structural changes.

The life-cycle of Gorgocephalus yaaji Bray & Cribb, 2005 (Digenea: Gorgocephalidae) with a review of the first intermediate hosts for the superfamily Lepocreadioidea Odhner, 1905.

Using novel molecular and morphological data we elucidated the life-cycle of Gorgocephalus yaaji Bray & Cribb, 2005 from off Lizard Island, on the northern Great Barrier Reef, Australia. ITS2 rDNA sequences generated for larval trematodes from the infected snail species Echinolittorina austrotrochoides Reid (Littorinidae) were identical to those from adult G.yaaji from the fish Kyphosus cinerascens (Forsskål) (Kyphosidae). Cercariae develop in rediae in E. austrotrochoides, emerge from the snail, encyst on algae as metacercariae, and are inferred to then be consumed by the herbivorous definitive fish host, K.cinerascens. In addition, we generated the first ITS2 rDNA sequences for a gorgocephalid previously reported from the littorind gastropod Austrolittorina unifasciata Gray. Although infections previously reported from A.unifasciata were the first larval gorgocephalids characterised, this study is the first to connect an intramolluscan infection to a sexual adult. In light of the new life-cycle information, a review of mollusc associations for the digenean superfamily Lepocreadioidea was performed, highlighting gaps in the knowledge and revealing patterns of host-parasite association. We find that distinct patterns of first intermediate host association are discernible for three lepocreadioid lineages: the Aephnidiogenidae Yamaguti, 1934, Gorgocephalidae Manter, 1966, and the Lepocreadiidae Odhner, 1905. However, the evolutionary origin for these patterns of host association remains unclear.

Exploration of caregiver behavior on fear of emotion, spirituality, and self-compassion

Self-compassion has positive implications for psychological health; however, less is known regarding the role and impact of early experiences, attitudes toward emotion, and spirituality in the development of self-compassion. Structural path analysis was used to explore the impact of emotionally validating or invalidating caregiver behavior on fear of emotion, spirituality and self-compassion. Initial analyses indicated that fear of emotion served as an important mediator between caregiver validation/invalidation and self-compassion. Although the initial model demonstrated excellent fit, exploratory analyses revealed distinct patterns of associations when accounting for participant and caregiver gender, with fear of emotion playing a stronger mediating role for females. Results suggest that caregiver interactions differentially influence self-compassion based on gender. Potential explanations and implications are discussed.

Distinct Patterns of Association of Variants at 11q23.3 Chromosomal Region with Coronary Artery Disease and Dyslipidemia in the Population of Andhra Pradesh, India.

In our attempt to comprehensively understand the nature of association of variants at 11q23.3 apolipoprotein gene cluster region, we genotyped a prioritized set of 96 informative SNPs using Fluidigm customized SNP genotyping platform in a sample of 508 coronary artery disease (CAD) cases and 516 controls. We found 12 SNPs as significantly associated with CAD at P <0.05, albeit only four (rs2849165, rs17440396, rs6589566 and rs633389) of these remained significant after Benjamin Hochberg correction. Of the four, while rs6589566 confers risk to CAD, the other three SNPs reduce risk for the disease. Interaction of variants that belong to regulatory genes BUD13 and ZPR1 with APOA5-APOA4 intergenic variants is also observed to significantly increase the risk towards CAD. Further, ROC analysis of the risk scores of the 12 significant SNPs suggests that our study has substantial power to confer these genetic variants as predictors of risk for CAD, as illustrated by AUC (0.763; 95% CI: 0.729–0.798, p = <0.0001). On the other hand, the protective SNPs of CAD are associated with elevated Low Density Lipoprotein Cholesterol and Total Cholesterol levels, hence with dyslipidemia, in our sample of controls, which may suggest distinct effects of the variants at 11q23.3 chromosomal region towards CAD and dyslipidemia. It may be necessary to replicate these findings in the independent and ethnically heterogeneous Indian samples in order to establish this as an Indian pattern. However, only functional analysis of the significant variants identified in our study can provide more precise understanding of the mechanisms involved in the contrasting nature of their effects in manifesting dyslipidemia and CAD.

Posttraumatic stress symptoms, co-morbid psychiatric symptoms and distorted cognitions among flood victims of different ages

Background: In literature, the effect of age on posttraumatic stress disorder (PTSD) is inconclusive; the effect on flood-related PTSD is particularly unclear. Little is known on distorted cognitions among flood victims, although cognition distortions and PTSD have been linked among victims of other traumas.Aims: To investigate: (1) whether flood-related PTSD, psychiatric co-morbidity and cognitive distortions would differ according to age and (2) distinctive patterns of association between the preceding variables for different age groups.Methods: One hundred and fifty-four flood victims of different ages completed standardized questionnaires measuring PTSD, psychiatric co-morbidity and cognitive distortions.Results: Adolescents and young adults reported significantly fewer PTSD, psychiatric co-morbidity and distorted cognition symptoms than people who were older. Preoccupation with danger and hopelessness were associated with both outcomes for adolescents, people in their thirties and middle-aged/older people. For young adults, helplessness was associated with PTSD; hopelessness and preoccupation with danger with psychiatric co-morbidity.Conclusions: Adolescents and young adults buffered against flood-related psychological distress better than older people. Distorted cognitions related to distress outcomes differently depending on age.

Analysis of Glial Distribution in Drosophila Adult Brains.

Neurons and glia are the two major cell types in the nervous system and work closely with each other to program neuronal interplay. Traditionally, neurons are thought to be the major cells that actively regulate processes like synapse formation, plasticity, and behavioral output. Glia, on the other hand, serve a more supporting role. To date, accumulating evidence has suggested that glia are active participants in virtually every aspect of neuronal function. Despite this, fundamental features of how glia interact with neurons, and their spatial relationships, remain elusive. Here, we describe the glial cell population in Drosophila adult brains. Glial cells extend and tightly associate their processes with major structures such as the mushroom body (MB), ellipsoid body (EB), and antennal lobe (AL) in the brain. Glial cells are distributed in a more concentrated manner in the MB. Furthermore, subsets of glia exhibit distinctive association patterns around different neuronal structures. Whereas processes extended by astrocyte-like glia and ensheathing glia wrap around the MB and infiltrate into the EB and AL, cortex glia stay where cell bodies of neurons are and remain outside of the synaptic regions structured by EB or AL.

CLASSIFICATION OF ANXIETY DISORDERS COMORBID WITH MAJOR DEPRESSION: COMMON OR DISTINCT INFLUENCES ON RISK?

Anxiety and depression display frequent comorbidity. Individuals with comorbid disorders also often have more extreme symptomatology than those with single disorders. This correlation between comorbidity and severity poses an interesting question: Are comorbid forms of anxiety and depression essentially just more severe versions of the pure disorders? In a large major depression (MD) case-control sample of individuals from the China, Oxford and VCU Experimental Research on Genetic Epidemiology project, we examined the patterns of lifetime anxiety comorbidity (including generalized anxiety disorder--GAD, panic disorder, and five phobia subtypes) among MD cases (N = 5,864) in this population. Binary and multinomial logistic regression was used to estimate associations between risk factors and outcomes including MD as well as latent class membership, which were compared using continuation ratios. We found a five-class solution to fit best, and each resulting class had a distinct pattern of association with the tested risk factors. The use of continuation ratios suggests that a class characterized by high endorsement of GAD is comparable to a more severely affected "pure MD" group. The other three classes (characterized by agoraphobia, various specific phobias, and by high endorsement of all comorbid anxiety disorders, respectively) appear to differ meaningfully from MD alone. Risk for MD resulting from environmental and psychosocial factors may also predispose individuals to GAD, and less consistently, other anxiety disorders. Presentations of MD with certain phobias display distinguishably different patterns of risk, however, and are therefore likely qualitatively distinct.

Neural plasticity in fathers of human infants

Fathering plays an important role in infants’ socioemotional and cognitive development. Previous studies have identified brain regions that are important for parenting behavior in human mothers. However, the neural basis of parenting in human fathers is largely unexplored. In the current longitudinal study, we investigated structural changes in fathers’ brains during the first 4 months postpartum using voxel-based morphometry analysis. Biological fathers (n = 16) with full-term, healthy infants were scanned at 2–4 weeks postpartum (time 1) and at 12–16 weeks postpartum (time 2). Fathers exhibited increase in gray matter (GM) volume in several neural regions involved in parental motivation, including the hypothalamus, amygdala, striatum, and lateral prefrontal cortex. On the other hand, fathers exhibited decreases in GM volume in the orbitofrontal cortex, posterior cingulate cortex, and insula. The findings provide evidence for neural plasticity in fathers’ brains. We also discuss the distinct patterns of associations among neural changes, postpartum mood symptoms, and parenting behaviors among fathers.

Similar and contrasting dimensions of social cognition in schizophrenia and healthy subjects

Schizophrenia patients experience substantial impairments in social cognition (SC) and these deficits are associated with their poor functional outcome. Though SC is consistently shown to emerge as a cognitive dimension distinct from neurocognition, the dimensionality of SC is poorly understood. Moreover, comparing the components of SC between schizophrenia patients and healthy comparison subjects would provide specific insights on the construct validity of SC. We conducted principal component analyses of eight SC test scores (representing four domains of SC, namely, theory of mind, emotion processing, social perception and attributional bias) independently in 170 remitted schizophrenia patients and 111 matched healthy comparison subjects. We also conducted regression analyses to evaluate the relative contribution of individual SC components to other symptom dimensions, which are important clinical determinants of functional outcome (i.e., neurocognition, negative symptoms, motivational deficits and insight) in schizophrenia. A three-factor solution representing socio-emotional processing, social–inferential ability and external attribution components emerged in the patient group that accounted for 64.43% of the variance. In contrast, a two-factor solution representing socio-emotional processing and social–inferential ability was derived in the healthy comparison group that explained 56.5% of the variance. In the patient group, the social–inferential component predicted negative symptoms and motivational deficits. Our results suggest the presence of a multidimensional SC construct. The dimensionality of SC observed across the two groups, though not identical, displayed important parallels. Individual components also demonstrated distinct patterns of association with other symptom dimensions, thus supporting their external validity.

Investigating exposure to violence and mental health in a diverse urban community sample: data from the South East London Community Health (SELCoH) survey.

BackgroundGeneral population surveys have seldom examined violence as a multidimensional concept and in relation to an array of mental disorders.MethodsData from the South East London Community Health Study was used to examine the prevalence, overlap and distribution of proximal witnessed, victimised and perpetrated violence and their association with current mental disorders. We further investigated the cumulative effect of lifetime exposure to violence on current mental disorders. Unadjusted and adjusted (for confounders and violence) models were examined.ResultsIn the last twelve months, 7.4% reported witnessing violence, 6.3% victimisation and 3.2% perpetration of violence. There was a significant overlap across violence types, with some shared correlates across the groups such as being younger and male. Witnessing violence in the past year was associated with current common mental disorders (CMD) and post-traumatic stress disorder (PTSD) symptoms. Proximal perpetration was associated with current CMD, PTSD symptoms and past 12 months drug use; whereas proximal victimisation was associated with lifetime and past 12 months drug use. Lifetime exposure to two or more types of violence was associated with increased risk for all mental health outcomes, suggesting a cumulative effect.ConclusionExposure to violence needs to be examined in a multi-faceted manner: i) as discrete distal and proximal events, which may have distinct patterns of association with mental health and ii) as a concept with different but overlapping dimensions, thus also accounting for possible cumulative effects.

Abstract 22: Influence of Smoking and Sex on Genetic Associations of Body Fat Distribution: The Giant (Genetic Investigation of ANthropometric Traits) Consortium

Visceral fat and smoking are important risk factors for CVD and other long-term poor health outcomes. Central adiposity is frequently assessed in population studies using waist-to-hip ratio adjusted for BMI (WHRadjBMI). Genome-wide association studies (GWAS) have discovered loci that influence WHRadjBMI, sometimes with sex-specific effects. However, we do not know whether and how smoking behavior influences the association between genetic variants and WHRadjBMI. Our study investigates the influence of smoking and genetic variants on WHRadjBMI, with particular consideration for differential effects by sex. Forty-one GIANT GWAS (108,397 participants) were used to investigate the influence of smoking on SNP WHRadjBMI associations using sex-stratified models considering SNP main effects adjusted for smoking status, and SNP main effects stratified by smoking status. Results from each study were meta-analyzed using an inverse-variance weighted fixed-effects model for men and women separately as well as combined. A total of 19 SNPs reached genome-wide significance (p&lt;5x10-8) having adjusted the SNP effect for smoking across strata (women, men, and combined), including 11 previously reported WHRadjBMI loci. For known WHRadjBMI loci, the influence of smoking varied by sex. In women, four known WHRadjBMI SNPs (TBX15, DNM3, RSPO3, and ADAMTS9) had a greater effect in smokers vs. nonsmokers (TBX15: β(SE) = 0.0506 (0.014), p = 3.84x10-4) vs. β(SE) = 0.0382 (0.0072), p = 1.14x10-7). Three of these (TBX15, DNM3, RSPO3) have been previously associated with tobacco use disorder (TUD). In men, three known WHRadjBMI loci (ADAMTS9, DNM3, ZNRF3) had a greater effect among smokers vs nonsmokers (ZNRF3: β(SE) = 0.0365 (0.0148), p = 1.37x10-2) vs β(SE) = 0.0192 (0.0088), p = 12.87x10-2). Eight of our 19 top SNPs have not been previously associated with WHRadjBMI (within 500 kb). Of these eight loci, distinct patterns of association by smoking and sex were again noted. In addition, one locus (ABCA1) has been previously associated with TUD. In addition to identifying novel loci associated with body fat distribution, these findings underscore the importance of considering the effect of smoking when investigating the genetics of obesity related phenotypes and emphasize the need to consider sex separately when studying the effects of smoking on body fat distribution.

TMEM106B Influences Volume of Left-Sided Temporal Lobe and Interhemispheric Structures in the General Population

Frontotemporal lobar degeneration is a neurodegenerative disease characterized by brain atrophy of the frontal and anterior temporal lobes. The associated frontotemporal dementia syndromes are clinically heterogeneous, and the pattern of affected cortical regions varies among subtypes. The TMEM106B rs1990622 polymorphism is associated with frontotemporal lobar degeneration, but little is known about how it affects the brain. We investigated the rs1990622 polymorphism in relation to regional brain volumes to identify potential structures through which TMEM106B confers risk for frontotemporal lobar degeneration. In 4413 nondemented and stroke-free participants from the population-based Rotterdam Study, 150 cortical brain structures and 6 commissural regions were segmented from magnetic resonance imaging. A distinct pattern of association was found between rs1990622 and gray matter volume of left-sided temporal brain regions important for language processing, including the superior temporal gyrus (β=-88.8 μL per risk allele, p=7.64×10(-5)), which contains Wernicke's area. The risk allele was also associated with a smaller anterior commissure cross-sectional area (β=-.167 mm2 per risk allele, p=4.90×10(-5)) and posterior part of the corpus callosum (β=-15.3 μL per risk allele, p=1.23×10(-5)), both of which contain temporal lobe commissural tracts. The asymmetric, predominantly left-sided involvement suggests an effect of TMEM106B on functions lateralized to the dominant hemisphere, such as language. These results show that, in nondemented persons, TMEM106B influences the volume of temporal brain regions that are important for language processing.

Social Reward Questionnaire (SRQ): development and validation.

Human beings seek out social interactions as a source of reward. To date, there have been limited attempts to identify different forms of social reward, and little is known about how the value of social rewards might vary between individuals. This study aimed to address both these issues by developing the Social Reward Questionnaire (SRQ), a measure of individual differences in the value of different social rewards. Exploratory factor analysis (EFA) was run on an initial set of 75 items (N = 305). Based on this analysis, confirmatory factor analysis (CFA) was then conducted on a second sample (N = 505) with a refined 23-item scale. This analysis was used to test a six-factor structure, which resulted in good model fit (CFI = 0.96, RSMEA = 0.07). The factors represent six subscales of social reward defined as follows: Admiration; Negative Social Potency; Passivity; Prosocial Interactions; Sexual Reward; and Sociability. All subscales demonstrated good test-retest reliability and internal consistency. Each subscale also showed a distinct pattern of associations with external correlates measuring personality traits, attitudes, and goals, thus demonstrating construct validity. Taken together, the findings suggest that the SRQ is a reliable, valid measure that can be used to assess individual differences in the value experienced from different social rewards.

Identification of a novel Parkinson’s disease locus via stratified genome-wide association study

BackgroundParkinson’s disease (PD) is complex and heterogeneous. The numerous susceptibility loci that have been identified reaffirm the complexity of PD but do not fully explain it; e.g., it is not known if any given PD susceptibility gene is associated with all PD or a disease subtype. We also suspect that important disease genes may have escaped detection because of this heterogeneity. We used presence/absence of family history to subdivide the cases and performed genome-wide association studies (GWAS) in Sporadic-PD and Familial-PD separately. The aim was to uncover new genes and gain insight into the genetic architecture of PD.ResultsEmploying GWAS on the NeuroGenetics Research Consortium (NGRC) dataset stratified by family history (1565 Sporadic-PD, 435 Familial-PD, 1986 controls), we identified a novel locus on chromosome 1p21 in Sporadic-PD (PNGRC = 4×10-8) and replicated the finding (PReplication = 6×10-3; PPooled = 4×10-10) in 1528 Sporadic-PD and 796 controls from the National Institutes of Neurologic Disease and Stroke (NINDS) Repository. This is the fifth PD locus to be mapped to the short arm of chromosome 1. It is flanked by S1PR1 and OLFM3 genes, and is 200 kb from a multiple sclerosis susceptibility gene. The second aim of the study was to extend the stratified GWAS to the well-established PD genes. SNCA_ rs356220 was associated with both Sporadic-PD (OR = 1.37, P = 1×10-9) and Familial-PD (OR = 1.40, P = 2×10-5). HLA_rs3129882 was more strongly associated with Sporadic-PD (OR = 1.38, P = 5×10-10) than Familial-PD (OR = 1.12, P = 0.15). In the MAPT region, virtually every single nucleotide polymorphism (SNP) had a stronger effect-size and lower P-value in Familial-PD (peak P = 8×10-7) than in Sporadic-PD (peak P = 2×10-5).ConclusionsWe discovered and replicated a new locus for Sporadic-PD which had escaped detection in un-stratified GWAS. This demonstrates that by stratifying on a key variable the power gained due to diminished heterogeneity can sometimes outweigh the power lost to reduced sample size. We also detected distinct patterns of disease associations for previously established PD susceptibility genes, which gives an insight to the genetic architecture of the disease and could aid in the selection of appropriate study population for future studies.

Domain-Specific Effects of Prenatal Exposure to PCBs, Mercury, and Lead on Infant Cognition: Results from the Environmental Contaminants and Child Development Study in Nunavik

Background: Polychlorinated biphenyls (PCBs), methylmercury (MeHg), and lead (Pb) are environmental contaminants known for their adverse effects on cognitive development.Objectives: In this study we examined the effects of prenatal exposure to PCBs, MeHg, and Pb on cognitive development in a sample of Inuit infants from Arctic Québec.Methods: Mothers were recruited at local prenatal clinics. PCBs, mercury (Hg), Pb, and two seafood nutrients—docosahexaenoic acid (DHA) and selenium (Se)—were measured in umbilical cord blood. Infants (n = 94) were assessed at 6.5 and 11 months of age on the Fagan Test of Infant Intelligence (FTII), A-not-B test, and Bayley Scales of Infant Development–2nd Edition (BSID-II).Results: Multiple regression analyses revealed that higher prenatal PCB exposure was associated with decreased FTII novelty preference, indicating impaired visual recognition memory. Prenatal Hg was associated with poorer performance on A-not-B, which depends on working memory and is believed to be a precursor of executive function. Prenatal Pb was related to longer FTII fixation durations, indicating slower speed of information processing.Conclusions: PCBs, MeHg, and Pb each showed specific and distinct patterns of adverse associations with the outcomes measured during infancy. By contrast, none of these exposures was associated with performance on the BSID-II, a global developmental measure. The more focused, narrow band measures of cognitive function that appeared to be sensitive to these exposures also provide early indications of long-term impairment in specific domains that would otherwise not likely be evident until school age.Citation: Boucher O, Muckle G, Jacobson JL, Carter RC, Kaplan-Estrin M, Ayotte P, Dewailly É, Jacobson SW. 2014. Domain-specific effects of prenatal exposure to PCBs, mercury, and lead on infant cognition: results from the Environmental Contaminants and Child Development Study in Nunavik. Environ Health Perspect 122:310–316; http://dx.doi.org/10.1289/ehp.1206323

Network-based analysis reveals distinct association patterns in a semantic MEDLINE-based drug-disease-gene network.

BackgroundA huge amount of associations among different biological entities (e.g., disease, drug, and gene) are scattered in millions of biomedical articles. Systematic analysis of such heterogeneous data can infer novel associations among different biological entities in the context of personalized medicine and translational research. Recently, network-based computational approaches have gained popularity in investigating such heterogeneous data, proposing novel therapeutic targets and deciphering disease mechanisms. However, little effort has been devoted to investigating associations among drugs, diseases, and genes in an integrative manner.ResultsWe propose a novel network-based computational framework to identify statistically over-expressed subnetwork patterns, called network motifs, in an integrated disease-drug-gene network extracted from Semantic MEDLINE. The framework consists of two steps. The first step is to construct an association network by extracting pair-wise associations between diseases, drugs and genes in Semantic MEDLINE using a domain pattern driven strategy. A Resource Description Framework (RDF)-linked data approach is used to re-organize the data to increase the flexibility of data integration, the interoperability within domain ontologies, and the efficiency of data storage. Unique associations among drugs, diseases, and genes are extracted for downstream network-based analysis. The second step is to apply a network-based approach to mine the local network structure of this heterogeneous network. Significant network motifs are then identified as the backbone of the network. A simplified network based on those significant motifs is then constructed to facilitate discovery. We implemented our computational framework and identified five network motifs, each of which corresponds to specific biological meanings. Three case studies demonstrate that novel associations are derived from the network topology analysis of reconstructed networks of significant network motifs, further validated by expert knowledge and functional enrichment analyses.ConclusionsWe have developed a novel network-based computational approach to investigate the heterogeneous drug-gene-disease network extracted from Semantic MEDLINE. We demonstrate the power of this approach by prioritizing candidate disease genes, inferring potential disease relationships, and proposing novel drug targets, within the context of the entire knowledge. The results indicate that such approach will facilitate the formulization of novel research hypotheses, which is critical for translational medicine research and personalized medicine.

Mitochondrial Ribosomal RNA (rRNA) Methyltransferase Family Members Are Positioned to Modify Nascent rRNA in Foci near the Mitochondrial DNA Nucleoid

We have identified RNMTL1, MRM1, and MRM2 (FtsJ2) as members of the RNA methyltransferase family that may be responsible for the three known 2'-O-ribose modifications of the 16 S rRNA core of the large mitochondrial ribosome subunit. These proteins are confined to foci located in the vicinity of mtDNA nucleoids. They show distinct patterns of association with mtDNA nucleoids and/or mitochondrial ribosomes in cell fractionation studies. We focused on the role of the least studied protein in this set, RNMTL1, to show that this protein interacts with the large ribosomal subunit as well as with a series of non-ribosomal proteins that may be involved in coupling of the rate of rRNA transcription and ribosome assembly in mitochondria. siRNA-directed silencing of RNMTL1 resulted in a significant inhibition of translation on mitochondrial ribosomes. Our results are consistent with a role for RNMTL1 in methylation of G(1370) of human 16 S rRNA.

Gender-specific gene-environment interaction in alcohol dependence: the impact of daily life events and GABRA2.

Gender-moderated gene-environment interactions are rarely explored, raising concerns about inaccurate specification of etiological models and inferential errors. The current study examined the influence of gender, negative and positive daily life events, and GABRA2 genotype (SNP rs279871) on alcohol dependence, testing two- and three-way interactions between these variables using multi-level regression models fit to data from 2,281 White participants in the Collaborative Study on the Genetics of Alcoholism. Significant direct effects of variables of interest were identified, as well as gender-specific moderation of genetic risk on this SNP by social experiences. Higher levels of positive life events were protective for men with the high-risk genotype, but not among men with the low-risk genotype or women, regardless of genotype. Our findings support the disinhibition theory of alcohol dependence, suggesting that gender differences in social norms, constraints and opportunities, and behavioral undercontrol may explain men and women's distinct patterns of association.