Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

High Levels of Sediment Contamination Have Little Influence on Estuarine Beach Fish Communities

While contaminants are predicted to have measurable impacts on fish assemblages, studies have rarely assessed this potential in the context of natural variability in physico-chemical conditions within and between estuaries. We investigated links between the distribution of sediment contamination (metals and PAHs), physico-chemical variables (pH, salinity, temperature, turbidity) and beach fish assemblages in estuarine environments. Fish communities were sampled using a beach seine within the inner and outer zones of six estuaries that were either heavily modified or relatively unmodified by urbanization and industrial activity. All sampling was replicated over two years with two periods sampled each year. Shannon diversity, biomass and abundance were all significantly higher in the inner zone of estuaries while fish were larger on average in the outer zone. Strong differences in community composition were also detected between the inner and outer zones. Few differences were detected between fish assemblages in heavily modified versus relatively unmodified estuaries despite high concentrations of sediment contaminants in the inner zones of modified estuaries that exceeded recognized sediment quality guidelines. Trends in species distributions, community composition, abundance, Shannon diversity, and average fish weight were strongly correlated to physico-chemical variables and showed a weaker relationship to sediment metal contamination. Sediment PAH concentrations were not significantly related to the fish assemblage. These findings suggest that variation in some physico-chemical factors (salinity, temperature, pH) or variables that co-vary with these factors (e.g., wave activity or grain size) have a much greater influence on this fish assemblage than anthropogenic stressors such as contamination

CADM1 is a strong neuroblastoma candidate gene that maps within a 3.72 Mb critical region of loss on 11q23

<p>Abstract</p> <p>Background</p> <p>Recurrent loss of part of the long arm of chromosome 11 is a well established hallmark of a subtype of aggressive neuroblastomas. Despite intensive mapping efforts to localize the culprit 11q tumour suppressor gene, this search has been unsuccessful thus far as no sufficiently small critical region could be delineated for selection of candidate genes.</p> <p>Methods</p> <p>To refine the critical region of 11q loss, the chromosome 11 status of 100 primary neuroblastoma tumours and 29 cell lines was analyzed using a BAC array containing a chromosome 11 tiling path. For the genes mapping within our refined region of loss, meta-analysis on published neuroblastoma mRNA gene expression datasets was performed for candidate gene selection. The DNA methylation status of the resulting candidate gene was determined using re-expression experiments by treatment of neuroblastoma cells with the demethylating agent 5-aza-2'-deoxycytidine and bisulphite sequencing.</p> <p>Results</p> <p>Two small critical regions of loss within 11q23 at chromosomal band 11q23.1-q23.2 (1.79 Mb) and 11q23.2-q23.3 (3.72 Mb) were identified. In a first step towards further selection of candidate neuroblastoma tumour suppressor genes, we performed a meta-analysis on published expression profiles of 692 neuroblastoma tumours. Integration of the resulting candidate gene list with expression data of neuroblastoma progenitor cells pinpointed <it>CADM1 </it>as a compelling candidate gene. Meta-analysis indicated that <it>CADM1 </it>expression has prognostic significance and differential expression for the gene was noted in unfavourable neuroblastoma versus normal neuroblasts. Methylation analysis provided no evidence for a two-hit mechanism in 11q deleted cell lines.</p> <p>Conclusion</p> <p>Our study puts <it>CADM1 </it>forward as a strong candidate neuroblastoma suppressor gene. Further functional studies are warranted to elucidate the role of <it>CADM1 </it>in neuroblastoma development and to investigate the possibility of <it>CADM1 </it>haploinsufficiency in neuroblastoma.</p

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

The genetic and environmental aetiology of spatial, mathematics and general anxiety

Individuals differ in their level of general anxiety as well as in their level of anxiety towards specific activities, such as mathematics and spatial tasks. Both specific anxieties correlate moderately with general anxiety, but the aetiology of their association remains unexplored. Moreover, the factor structure of spatial anxiety is to date unknown. The present study investigated the factor structure of spatial anxiety, its aetiology, and the origins of its association with general and mathematics anxiety in a sample of 1,464 19-21-year-old twin pairs from the UK representative Twins Early Development Study. Participants reported their general, mathematics and spatial anxiety as part of an online battery of tests. We found that spatial anxiety is a multifactorial construct, including two components: navigation anxiety and rotation/visualization anxiety. All anxiety measures were moderately heritable (30% to 41%), and non-shared environmental factors explained the remaining variance. Multivariate genetic analysis showed that, although some genetic and environmental factors contributed to all anxiety measures, a substantial portion of genetic and non-shared environmental influences were specific to each anxiety construct. This suggests that anxiety is a multifactorial construct phenotypically and aetiologically, highlighting the importance of studying anxiety within specific contexts

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference