Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation

Background: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic “smoking methylation pattern”, and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. Methods: Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. Results: Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top “smoking methylation pattern” genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. Conclusion: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight

Transcription factors relevant to auxin signalling coordinate broad-spectrum metabolic shifts including sulphur metabolism

A systems approach has previously been used to follow the response behaviour of Arabidopsis thaliana plants upon sulphur limitation. A response network was reconstructed from a time series of transcript and metabolite profiles, integrating complex metabolic and transcript data in order to investigate a potential causal relationship. The resulting scale-free network allowed potential transcriptional regulators of sulphur metabolism to be identified. Here, three sulphur-starvation responsive transcription factors, IAA13, IAA28, and ARF-2 (ARF1-Binding Protein), all of which are related to auxin signalling, were selected for further investigation. IAA28 overexpressing and knock-down lines showed no major morphological changes, whereas IAA13- and ARF1-BP-overexpressing plants grew more slowly than the wild type. Steady-state metabolite levels and expression of pathway-relevant genes were monitored under normal and sulphate-depleted conditions. For all lines, changes in transcript and metabolite levels were observed, yet none of these changes could exclusively be linked to sulphur stress. Instead, up- or down-regulation of the transcription factors caused metabolic changes which in turn affected sulphur metabolism. Auxin-relevant transcription factors are thus part of a complex response pattern to nutrient starvation that serve as coordinators of the metabolic shifts driving sulphur homeostasis rather then as direct effectors of the sulphate assimilation pathway. This study provides the first evidence ever presented that correlates auxin-related transcriptional regulators with primary plant metabolism

A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence

Contents of cysteine (upper row), γ-glutamylcysteine (GEC; middle row), and glutathione (GSH; lower row) are shown for plants overexpressing , , and , respectively, or down-regulated with respect to

Plants were grown for 10 weeks on soil before thiol extraction. knock-downs are represented by cross-hatched columns, overexpressing lines by white columns, and wild-type (WT) and empty-vector control lines (EV) by black columns. Values are the mean ±SD of three independent experiments. Asterisks indicate that the difference between the wild-type plants and the manipulated transgenic plants was significant using -tests ( ≤0.05).<p><b>Copyright information:</b></p><p>Taken from "Transcription factors relevant to auxin signalling coordinate broad-spectrum metabolic shifts including sulphur metabolism"</p><p></p><p>Journal of Experimental Botany 2008;59(10):2831-2846.</p><p>Published online Jan 2008</p><p>PMCID:PMC2486478.</p><p></p

Heat map generated from amino acid measurements reflecting log base 2-transformed and normalized amino acid levels and its similarity among themselves and the genotypes

The top colour bar indicates the relative log base 2-fold changes ranging between reduced relative (red) and increased relative (blue) contents of amino acids with respect to the wild-type.<p><b>Copyright information:</b></p><p>Taken from "Transcription factors relevant to auxin signalling coordinate broad-spectrum metabolic shifts including sulphur metabolism"</p><p></p><p>Journal of Experimental Botany 2008;59(10):2831-2846.</p><p>Published online Jan 2008</p><p>PMCID:PMC2486478.</p><p></p

Heat-map visualization and cluster tree representations of amino acid contents and genotypes

Data were obtained from experiments where plants were starved of sulphate for 10 d. The heat-map was generated by using log base 2-transformed fold changes. The given data represent the ratio of the determined amino acids for control and starved plants. Each amino acid is represented by a single column and each genotype by a single row. Red indicates decreased relative metabolite content whereas blue indicates increased relative contents of amino acids compared with the wild-type. Separated heat-map visualization of amino acid contents in control and mutant plants are presented in in available at online and the respective diagrams in Fig. S2.<p><b>Copyright information:</b></p><p>Taken from "Transcription factors relevant to auxin signalling coordinate broad-spectrum metabolic shifts including sulphur metabolism"</p><p></p><p>Journal of Experimental Botany 2008;59(10):2831-2846.</p><p>Published online Jan 2008</p><p>PMCID:PMC2486478.</p><p></p