Identification of seven loci affecting mean telomere length and their association with disease

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 x 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.

A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications

BACKGROUND Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome-wide association study (GWAS) for phenotypes related to alcohol use and dependence. METHODS Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data. RESULTS No findings reached genome-wide significance (p = 8.4 x 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 x 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. CONCLUSIONS We conclude that: - 1) meta-analyses of consumption data may contribute usefully to gene discovery; - 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging, and; - 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies).

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25,000 single-nucleotide polymorphisms (SNPs) located within approximately 14,000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case-control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

Zygosity diagnosis in the absence of genotypic data: An approach using latent class analysis

For zygosity diagnosis in the absence of genotypic data, or in the recruitment phase of a twin study where only single twins from same-sex pairs are being screened, or to provide a test for sample duplication leading to the false identification of a dizygotic pair as monozygotic, the appropriate analysis of respondents' answers to questions about zygosity is critical. Using data from a young adult Australian twin cohort (N = 2094 complete pairs and 519 singleton twins from same-sex pairs with complete responses to all zygosity items), we show that application of latent class analysis (LCA), fitting a 2-class model, yields results that show good concordance with traditional methods of zygosity diagnosis, but with certain important advantages. These include the ability, in many cases, to assign zygosity with specified probability on the basis of responses of a single informant (advantageous when one zygosity type is being oversampled); and the ability to quantify the probability of misassignment of zygosity, allowing prioritization of cases for genotyping as well as identification of cases of probable laboratory error. Out of 242 twins (from 121 like-sex pairs) where genotypic data were available for zygosity confirmation, only a single case was identified of incorrect zygosity assignment by the latent class algorithm. Zygosity assignment for that single case was identified by the LCA as uncertain (probability of being a monozygotic twin only 76%), and the co-twin's responses clearly identified the pair as dizygotic (probability of being dizygotic 100%). In the absence of genotypic data, or as a safeguard against sample duplication, application of LCA for zygosity assignment or confirmation is strongly recommended.

Prevention of foot ulcers in the at-risk patient with diabetes: A systematic review

Background Prevention of foot ulcers in patients with diabetes is extremely important to help reduce the enormous burden of foot ulceration on both patient and health resources. A comprehensive analysis of reported interventions is not currently available, but is needed to better inform caregivers about effective prevention. The aim of this systematic review is to investigate the effectiveness of interventions to prevent first and recurrent foot ulcers in persons with diabetes who are at risk for ulceration. Methods The available medical scientific literature in PubMed, EMBASE, CINAHL and the Cochrane database was searched for original research studies on preventative interventions. Both controlled and non-controlled studies were selected. Data from controlled studies were assessed for methodological quality by two independent reviewers. Results From the identified records, a total of 30 controlled studies (of which 19 RCTs) and another 44 non-controlled studies were assessed and described. Few controlled studies, of generally low to moderate quality, were identified on the prevention of a first foot ulcer. For the prevention of recurrent plantar foot ulcers, multiple RCTs with low risk of bias show the benefit for the use of daily foot skin temperature measurements and consequent preventative actions, as well as for therapeutic footwear that demonstrates to relieve plantar pressure and that is worn by the patient. To prevent recurrence, some evidence exists for integrated foot care when it includes a combination of professional foot treatment, therapeutic footwear and patient education; for just a single session of patient education, no evidence exists. Surgical interventions can be effective in selected patients, but the evidence base is small. Conclusion The evidence base to support the use of specific self-management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong, but is small for the use of other, sometimes widely applied, interventions and is practically nonexistent for the prevention of a first foot ulcer and non-plantar foot ulcer.

IWGDF guidance on the prevention of foot ulcers in at-risk patients with diabetes

Recommendations - 1 To identify a person with diabetes at risk for foot ulceration, examine the feet annually to seek evidence for signs or symptoms of peripheral neuropathy and peripheral artery disease. (GRADE strength of recommendation: strong; Quality of evidence: low) - 2 In a person with diabetes who has peripheral neuropathy, screen for a history of foot ulceration or lower-extremity amputation, peripheral artery disease, foot deformity, pre-ulcerative signs on the foot, poor foot hygiene and ill-fitting or inadequate footwear. (Strong; Low) - 3 Treat any pre-ulcerative sign on the foot of a patient with diabetes. This includes removing callus, protecting blisters and draining when necessary, treating ingrown or thickened toe nails, treating haemorrhage when necessary and prescribing antifungal treatment for fungal infections. (Strong; Low) - 4 To protect their feet, instruct an at-risk patient with diabetes not to walk barefoot, in socks only, or in thin-soled standard slippers, whether at home or when outside. (Strong; Low) - 5 Instruct an at-risk patient with diabetes to daily inspect their feet and the inside of their shoes, daily wash their feet (with careful drying particularly between the toes), avoid using chemical agents or plasters to remove callus or corns, use emollients to lubricate dry skin and cut toe nails straight across. (Weak; Low) - 6 Instruct an at-risk patient with diabetes to wear properly fitting footwear to prevent a first foot ulcer, either plantar or non-plantar, or a recurrent non-plantar foot ulcer. When a foot deformity or a pre-ulcerative sign is present, consider prescribing therapeutic shoes, custom-made insoles or toe orthosis. (Strong; Low) - 7 To prevent a recurrent plantar foot ulcer in an at-risk patient with diabetes, prescribe therapeutic footwear that has a demonstrated plantar pressure-relieving effect during walking (i.e. 30% relief compared with plantar pressure in standard of care therapeutic footwear) and encourage the patient to wear this footwear. (Strong; Moderate) - 8 To prevent a first foot ulcer in an at-risk patient with diabetes, provide education aimed at improving foot care knowledge and behaviour, as well as encouraging the patient to adhere to this foot care advice. (Weak; Low) - 9 To prevent a recurrent foot ulcer in an at-risk patient with diabetes, provide integrated foot care, which includes professional foot treatment, adequate footwear and education. This should be repeated or re-evaluated once every 1 to 3 months as necessary. (Strong; Low) - 10 Instruct a high-risk patient with diabetes to monitor foot skin temperature at home to prevent a first or recurrent plantar foot ulcer. This aims at identifying the early signs of inflammation, followed by action taken by the patient and care provider to resolve the cause of inflammation. (Weak; Moderate) - 11 Consider digital flexor tenotomy to prevent a toe ulcer when conservative treatment fails in a high-risk patient with diabetes, hammertoes and either a pre-ulcerative sign or an ulcer on the distal toe. (Weak; Low) - 12 Consider Achilles tendon lengthening, joint arthroplasty, single or pan metatarsal head resection, or osteotomy to prevent a recurrent foot ulcer when conservative treatment fails in a high-risk patient with diabetes and a plantar forefoot ulcer. (Weak; Low) - 13 Do not use a nerve decompression procedure in an effort to prevent a foot ulcer in an at-risk patient with diabetes, in preference to accepted standards of good quality care. (Weak; Low)

Literacy, security, governmentality: Defining spaces, managing populations – How has education become part of whole of government security strategy?

In this paper I conduct a Foucauldian discourse analysis of a political speech given by Brendon Nelson in 2006 when the Australian Minister for Defence in the Howard Coalition Government. The speech connects conceptualisations of terror, globalization, education and literacy as part of a whole of government security strategy. The analysis examines this speech as an example of a liberal way of governing the conduct of diverse and unpredictable populations. My analysis suggests that the apparatus of government has been strategically used in order to biopolitically contain the rise of complex social forces and protect a set of homogenous cultural values. The purposes of education and uses of literacy are seen as instruments for the inscription of a coded set of values understood to be synonymous with civil society.

Energy and cities

Any plan for decoupling growth from fossil fuel use needs to prioritise locally appropriate, integrated and multi-faceted outcomes. Such transitions can be highly complex, given the physical and institutional characteristics of existing electricity infrastructure as well as various financial, technical and practical challenges. This Chapter applies a whole systems perspective to developing decoupling solutions, reflecting on the Dutch Sustainable Technology Development Program and Townsville City (Queensland, Australia). Key aspects considered include the need for demonstrating outcomes to multiple stakeholders, using pilot projects with integrated monitoring and evaluation, fostering collaborative approaches to energy management, cultivating cultures of ‘learning by doing’, and seeking synergies across multiple agendas.

The Situated Cases

In this chapter, we meet the eight children whose documented lives are the heart of this book. The children are spread across 6 continents, so we have some textual traveling to do. We find each child in a local school. There they venture into literacy along official paths negotiated with their teachers and, also, along unofficial paths tied to their desire for peer companionship and social belonging (Corsaro, 2011; Nelson, 2007). We are most interested in their literate productions—their composing, be it with stick and dirt, pencil, crayons, and paper, tablet computer, or chalk and slate. Each child is a unique story, and each story is told by an author with particular interests in the goings-on in school, that is, with a particular angle of vision. All the authors, though, take us into a child’s educational circumstance; they give us a sense of the school’s physical site and its official curricular guidelines. Most importantly, they collectively allow us a global view of children as symbol users and social participants in the official and the unofficial worlds of school. No matter where young children go to school, they are expected to learn to “write” (although writing, as the cases illustrate, does not always mean “composing”)...

The impact of Indigenous Community sports programs: The case of surfing

The objective of this research project was to consider the social impact of sport and physical activity on the lives of Indigenous Australians and their communities. There has been strong research interest in the links between sport and recreation programs and various health and social outcomes and a well-established body of literature exists on the use of sport to address social issues in mainstream society (A Thomson, Darcy and Pearce 2010). The consensus is that physical activity is an important contributor to health for all people (Nelson, Abbott and Macdonald 2010). While there is strong research interest, what remains unclear is the value and impact of sport and physical activity on Indigenous communities (Cairnduff 2001). Nelson (2009) drawing on the work of Jonas and Langton (1994) indicates that an ‘Aboriginal person is a descendant of an Indigenous inhabitant of Australia, identifi es as an Aboriginal, and is recognised as Aboriginal by members of the community in which he or she lives’ (p. 97). Even this defi nition has the potential to be politically charged. At a general level, the collective terms ‘Indigenous’ (capitalised) and ‘Aboriginal and Torres Strait Islander’ people (title capitalised) appear to be broadly acceptable terms. Indigenous groups cannot be considered to be homogenous as there is much diversity between and within groups (Nelson et al. 2010; Parker et al. 2006). It is therefore important this report is not viewed as taking an essentialist view of who Indigenous people are and how they develop. Rather, this paper attempts to describe and discuss the experiences of some individuals and their communities in site-specifi c surfi ng programs.

Editorial of "Student Success, volume 7, issue 1"

Welcome to Volume 7 of Student Success. This editorial has two parts: The first part maintains the “doing things differently” tradition, making readers aware by chronicling the publishing of the journal in an open access (OA) forum. Future editorials will briefly discuss other aspects and issues pertaining to the new scholarly publishing landscape that this journal adheres to, such as: Creative Commons Licencing; ORCID IDs; considerations of new peer review models and importantly; measuring research impact in OA publishing. The second part presents the usual editorial summary of the content of this issue.

Editorial: Biomarker and translational prostate cancer research

The existing clinical biomarkers for prostate cancer (PCa) are not ideal, since they cannot specifically differentiate between those patients who should be treated immediately and those who should avoid overtreatment. Current screening techniques lack specificity, and a decisive diagnosis of PCa is based on prostate biopsy. Although PCa screening is widely utilized nowadays, two-thirds of the biopsies performed are still unnecessary. Thus, the discovery of noninvasive PCa biomarkers remains an urgent unmet medical need. Once metastasized, there is still no curative therapy. A better understanding of sustained androgen receptor signalling in castration resistant prostate cancer (CRPC) has now led to the development of more effective therapies. We need a better understanding of the molecular and cellular aspects of prostate carcinogenesis and progression. Identification of cancer initiating cells and therapies against these populations is a promising way forward to fight this disease.