Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls ...and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.
Highlights • We studied the relation of cannabis involvement with suicidal thoughts and behaviors. • Cannabis involvement was related to suicidal ideation, albeit modestly. • Cannabis involvement was ...also related to unplanned suicide attempts, albeit modestly. • Strongest evidence for association, even after adjustment, was with cannabis problems. • Cannabis involvement was not related to suicide planning or planned attempts.
Summary
Background
Nickel allergy is common worldwide. It is associated with hand dermatitis, and sensitization is often induced by nickel‐releasing jewellery. The European Union (EU) introduced ...legislation to control nickel content and release from jewellery and other consumer items through the EU Nickel Directive 1994, which came into force in 2001 and is now part of the REACH regulation.
Objectives
To examine the effects of the EU nickel regulations on the prevalence of nickel allergy in four European countries.
Methods
Nickel patch‐test data from 180 390 patients were collected from national databases in Denmark, Germany, Italy and the U.K. from between 1985 and 2002 to 2010. Patients with suspected allergic contact dermatitis who had been patch tested with nickel sulfate 5% in petrolatum were included in the analysis. The main outcomes studied were the percentage of positive results to nickel patch tests, and changes in trends with time in an age‐ and sex‐stratified analysis.
Results
A statistically significant decrease in nickel allergy was observed in Danish, German and Italian women aged below 30 years. In female patients in the U.K. this was observed between 2004 and 2010. In young men, a statistically significant decrease in nickel allergy was observed in Germany and the U.K., whereas a nonsignificant increase was observed in Italy.
Conclusions
There has been a reduction in the prevalence of nickel allergy in young women, contemporaneous with the introduction of the nickel regulation. A reduction is also suggested in men in Germany and the U.K. A causative effect of the regulatory intervention is the most likely explanation.
What's already known about this topic?
Nickel allergy affects 10–15% of women in the general population and is associated with hand eczema.
Previous studies have shown a decrease in nickel allergy in young women in Denmark and Germany since regulations to control nickel release were implemented.
What does this study add?
Postregulation, a significant decrease in nickel allergy was seen in women with suspected dermatitis aged below 30 years in all four countries studied, and in men aged below 30 years in the U.K. and Germany, although an increase was seen in young Italian men.
This study of 180 390 patients shows that the EU nickel regulations are starting to reduce nickel allergy in young men and women, although allergy remains prevalent and more work needs to be done to improve compliance with the regulations.
We present the first evidence of Fe(II) complexation by natural organic ligands in estuarine waters. Across five diverse river/estuary systems we find evidence of terrestrially derived ligands with ...binding constants (log KFe(II)L) mainly in the range 6–8. These Fe(II) ligands were stable over short time periods (1–2days), generally equivalent to, or in excess of, ambient freshwater Fe(II) concentrations (which ranged from 12 to 3600nM) and had similar binding constants to ligands that were leached by water from vegetation and detritus (log KFe(II)L 7–8). A class of terrestrially derived ligands may therefore be important in stabilising Fe(II) concentrations in freshwater systems. However, in coastal seawater the impact of these ligands upon Fe(II) speciation is likely to be diminished due to a combination of dilution, loss of humic material during flocculation and increased ionic strength.
The temperate and sub-tropical river systems studied included the Beaulieu (England), Itchen (England), Cape Fear (North Carolina, USA), Winyah Bay (South Carolina, USA) and Loch Etive (Scotland). Freshwaters in each system possessed a broad range of dissolved organic carbon (DOC, 200–1300μM), labile dissolved Fe (LDFe, Fe<0.2μm available to ferrozine after reduction with ascorbic acid, 100nM–20μM) and pH (5.5–8.5). In the Itchen estuary, where anthropogenic discharge constitutes >10% of freshwater input, ligand binding constants were elevated (up to log KFe(II)L 11) and the expected decrease in LDFe with increasing salinity along the estuary was not observed (LDFe and DOC both peaked at a salinity of 7) due to effluent inputs.
•An excess of weak Fe(II) ligands exists in river water.•These weak Fe(II) ligands are less prevalent in higher salinity waters.•Effluent can be a significant source of both Fe(II) ligands and dissolved Fe to estuaries.
Decision tree analysis highlights patient subgroups and critical values in variables assessed. Importantly, the results are visually informative and often present clear clinical interpretation about ...risk factors faced by patients in these subgroups. The aim of this prospective study was to compare results of logistic regression with those of decision tree analysis of an observational, head-injury data set, including a wide range of secondary insults and 12-month outcomes.
One hundred twenty-four adult head-injured patients were studied during their stay in an intensive care unit by using a computerized data collection system. Verified values falling outside threshold limits were analyzed according to insult grade and duration with the aid of logistic regression. A decision tree was automatically produced from root node to target classes (Glasgow Outcome Scale GOS score). Among 69 patients, in whom eight insult categories could be assessed, outcome at 12 months was analyzed using logistic regression to determine the relative influence of patient age, admission Glasgow Coma Scale score, Injury Severity Score (ISS), pupillary response on admission, and insult duration. The most significant predictors of mortality in this patient set were duration of hypotensive, pyrexic, and hypoxemic insults. When good and poor outcomes were compared, hypotensive insults and pupillary response on admission were significant. Using decision tree analysis, the authors found that hypotension and low cerebral perfusion pressure (CPP) are the best predictors of death, with a 9.2% improvement in predictive accuracy (PA) over that obtained by simply predicting the largest outcome category as the outcome for each patient. Hypotension was a significant predictor of poor outcome (GOS Score 1-3). Low CPP, patient age, hypocarbia, and pupillary response were also good predictors of outcome (good/poor), with a 5.1% improvement in PA. In certain subgroups of patients pyrexia was a predictor of good outcome.
Decision tree analysis confirmed some of the results of logistic regression and challenged others. This investigation shows that there is knowledge to be gained from analyzing observational data with the aid of decision tree analysis.
Genetic influences contribute significantly to co-morbidity between conduct disorder and substance use disorders. Estimating the extent of overlap can assist in the development of phenotypes for ...genomic analyses.
Multivariate quantitative genetic analyses were conducted using data from 9577 individuals, including 3982 complete twin pairs and 1613 individuals whose co-twin was not interviewed (aged 24-37 years) from two Australian twin samples. Analyses examined the genetic correlation between alcohol dependence, nicotine dependence and cannabis abuse/dependence and the extent to which the correlations were attributable to genetic influences shared with conduct disorder.
Additive genetic (a(2) = 0.48-0.65) and non-shared environmental factors explained variance in substance use disorders. Familial effects on conduct disorder were due to additive genetic (a(2) = 0.39) and shared environmental (c(2) = 0.15) factors. All substance use disorders were influenced by shared genetic factors (rg = 0.38-0.56), with all genetic overlap between substances attributable to genetic influences shared with conduct disorder. Genes influencing individual substance use disorders were also significant, explaining 40-73% of the genetic variance per substance.
Among substance users in this sample, the well-documented clinical co-morbidity between conduct disorder and substance use disorders is primarily attributable to shared genetic liability. Interventions targeted at generally reducing deviant behaviors may address the risk posed by this shared genetic liability. However, there is also evidence for genetic and environmental influences specific to each substance. The identification of these substance-specific risk factors (as well as potential protective factors) is critical to the future development of targeted treatment protocols.
This paper examines genetic and environmental contributions to risk of cannabis dependence.
Symptoms of cannabis dependence and measures of social, family and individual risk factors were assessed in ...a sample of 6265 young adult male and female Australian twins born 1964-1971.
Symptoms of cannabis dependence were common: 11.0% of sample (15.1% of men and 7.8% of women) reported two or more symptoms of dependence. Correlates of cannabis dependence included educational attainment, exposure to parental conflict, sexual abuse, major depression, social anxiety and childhood conduct disorder. However, even after control for the effects of these factors, there was evidence of significant genetic effects on risk of cannabis dependence. Standard genetic modelling indicated that 44.7% (95% CI = 15-72.2) of the variance in liability to cannabis dependence could be accounted for by genetic factors, 20.1% (95% CI = 0-43.6) could be attributed to shared environment factors and 35.3% (95% CI = 26.4-45.7) could be attributed to non-shared environmental factors. However, while there was no evidence of significant gender differences in the magnitude of genetic and environmental influences, a model which assumed both genetic and shared environmental influences on risks of cannabis dependence among men and shared environmental but no genetic influences among women provided an equally good fit to the data.
There was consistent evidence that genetic risk factors are important determinants of risk of cannabis dependence among men. However, it remains uncertain whether there are genetic influences on liability to cannabis dependence among women.
Volcanogenic sediments are typically rich in Fe and Mn-bearing minerals that undergo substantial alteration during early marine diagenesis, however their impact on the global biogeochemical cycling ...of Fe and Mn has not been widely addressed. This study compares the near surface (0–20
cm below sea floor cmbsf) aqueous (<0.02
μm) and aqueous
+
colloidal here in after ‘dissolved’ (<0.2
μm) pore water Fe and Mn distributions, and ancillary O
2(aq),
NO
3
-
and solid-phase reactive Fe distributions, between two volcanogenic sediment settings: 1 a deep sea tephra-rich deposit neighbouring the volcanically active island of Montserrat and 2 mixed biosiliceous–volcanogenic sediments from abyssal depths near the volcanically inactive Crozet Islands archipelago. Shallow penetration of O
2(aq) into Montserrat sediments was observed (<1
cmbsf), and inferred to partially reflect oxidation of fine grained Fe(II) minerals, whereas penetration of O
2(aq) into abyssal Crozet sediments was >5
cmbsf and largely controlled by the oxidation of organic matter. Dissolved Fe and Mn distributions in Montserrat pore waters were lowest in the surface oxic-layer (0.3
μM Fe; 32
μM Mn), with maxima (20
μM Fe; 200
μM Mn) in the upper 1–15
cmbsf. Unlike Montserrat, Fe and Mn in Crozet pore waters were ubiquitously partitioned between 0.2
μm and 0.02
μm filtrations, indicating that the pore water distributions of Fe and Mn in the (traditionally termed) ‘dissolved’ size fraction are dominated by colloids, with respective mean abundances of 80% and 61%. Plausible mechanisms for the origin and composition of pore water colloids are discussed, and include prolonged exposure of Crozet surface sediments to early diagenesis compared to Montserrat, favouring nano-particulate goethite formation, and the elevated dissolved Si concentrations, which are shown to encourage fine-grained smectite formation. In addition, organic matter may stabilise authigenic Fe and Mn in the Crozet pore waters. We conclude that volcanogenic sediment diagenesis leads to a flux of colloidal material to the overlying bottom water, which may impact significantly on deep ocean biogeochemistry. Diffusive flux estimates from Montserrat suggest that diagenesis within tephra deposits of active island volcanism may also be an important source of dissolved Mn to the bottom waters, and therefore a source for the widespread hydrogenous MnO
x
deposits found in the Caribbean region.
Genetic influences on alcoholism risk are well-documented in men, but uncertain in women. We tested for gender differences in genetic influences on, and risk-factors for, DSM-III-R alcohol dependence ...(AD).
Diagnostic follow-up interviews were conducted in 1992-3 by telephone with twins from an Australian twin panel first surveyed in 1980-82 (N = 5889 respondents). Data were analysed using logistic regression models.
Significantly higher twin pair concordances were observed in MZ compared to DZ same-sex twin pairs in women and men, even when data were weighted to adjust for over-representation of well-educated respondents, and for selective attrition. AD risk was increased in younger birth cohorts, in Catholic males or women reporting no religious affiliation, in those reporting a history of conduct disorder or major depression and in those with high Neuroticism, Social Non-conformity, Toughmindedness, Novelty-Seeking or (in women only) Extraversion scores; and decreased in 'Other Protestants', weekly church attenders, and university-educated males. Controlling for these variables, however, did not remove the significant association with having an alcoholic MZ co-twin, implying that much of the genetic influence on AD risk remained unexplained. No significant gender difference in the genetic variance in AD was found (64% heritability, 95% confidence interval 32-73%).
Genetic risk-factors play as important a role in determining AD risk in women as in men. With the exception of certain sociocultural variables such as religious affiliation, the same personality, sociodemographic and axis I correlates of alcoholism risk are observed in women and men.
Associations between parental depression and offspring affective and disruptive disorders are well documented. Few genetically informed studies have explored the processes underlying ...intergenerational associations.
A semi-structured interview assessing DSM-III-R psychiatric disorders was administered to twins (n=1296) from the Australian Twin Register (ATR), their spouses (n=1046) and offspring (n=2555). We used the Children of Twins (CoT) design to delineate the extent to which intergenerational associations were consistent with a causal influence or due to genetic confounds.
In between-family analyses, parental depression was associated significantly with offspring depression hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.20-1.93 and conduct disorder (CD; HR 2.27, CI 1.31-3.93). Survival analysis indicated that the intergenerational transmission of depression is consistent with a causal (environmental) inference, with a significant intergenerational association in offspring of discordant monozygotic (MZ) twin pairs (HR 1.39, CI 1.00-1.94). Logistic regression analysis suggested that the parental depression-offspring CD association was due to shared genetic liability in the parents and offspring. No intergenerational association was found when comparing the offspring of discordant MZ twins odds ratio (OR) 1.41, CI 0.63-3.14, but offspring of discordant dizygotic (DZ) twins differed in their rates of CD (OR 2.53, CI 0.95-6.76). All findings remained after controlling for several measured covariates, including history of depression and CD in the twins' spouses.
The mechanisms underlying associations between parental depression and offspring psychopathology seem to differ depending on the outcome. The results are consistent with a causal environmental role of parental depression in offspring depression whereas common genetic factors account for the association of parental depression and offspring CD.
PDF
