A genome-wide screen for susceptibility loci in ankylosing spondylitis

Objective. To localize the regions containing genes that determine susceptibility to ankylosing spondylitis (AS). Methods. One hundred five white British families with 121 affected sibling pairs with AS were recruited, largely from the Royal National Hospital for Rheumatic Diseases AS database. A genome-wide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Council (UK) (MRC) set. The major histocompatibility complex (MHC) region was studied more intensively using 5 microsatellites lying within the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2-point analysis, and GeneHunter for multipoint analysis. Results. When only the MRC set was considered, 11 markers in 7 regions achieved a P value of ≤0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10-5) using marker D6S273, which lies in the HLA class III region. A further marker used in mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10-9). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422. Conclusion. The results of this study confirm the strong linkage of the MHC with AS, and provide suggestive evidence regarding the presence and location of non-MHC genes influencing susceptibility to the disease.

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Energy gap in the aetiology of body weight gain and obesity: A challenging concept with a complex evaluation and pitfalls

The concept of energy gap(s) is useful for understanding the consequence of a small daily, weekly, or monthly positive energy balance and the inconspicuous shift in weight gain ultimately leading to overweight and obesity. Energy gap is a dynamic concept: an initial positive energy gap incurred via an increase in energy intake (or a decrease in physical activity) is not constant, may fade out with time if the initial conditions are maintained, and depends on the 'efficiency' with which the readjustment of the energy imbalance gap occurs with time. The metabolic response to an energy imbalance gap and the magnitude of the energy gap(s) can be estimated by at least two methods, i.e. i) assessment by longitudinal overfeeding studies, imposing (by design) an initial positive energy imbalance gap; ii) retrospective assessment based on epidemiological surveys, whereby the accumulated endogenous energy storage per unit of time is calculated from the change in body weight and body composition. In order to illustrate the difficulty of accurately assessing an energy gap we have used, as an illustrative example, a recent epidemiological study which tracked changes in total energy intake (estimated by gross food availability) and body weight over 3 decades in the US, combined with total energy expenditure prediction from body weight using doubly labelled water data. At the population level, the study attempted to assess the cause of the energy gap purported to be entirely due to increased food intake. Based on an estimate of change in energy intake judged to be more reliable (i.e. in the same study population) and together with calculations of simple energetic indices, our analysis suggests that conclusions about the fundamental causes of obesity development in a population (excess intake vs. low physical activity or both) is clouded by a high level of uncertainty.

Direct photocatalytic conversion of aldehydes to esters using supported gold nanoparticles under visible light irradiation at room temperature

Visible light can drive esteri fi cation from aldehydes and alcohols using supported gold nanoparticles (Au/Al 2 O 3 ) as photo- catalysts at ambient temperatures. The gold nanoparticles (AuNPs) absorb visible light due to the localized surface plasmon resonance (LSPR) e ff ect, and the conduction electrons of the AuNPs gain the energy of the incident light. The energetic electrons, which concentrate at the NP surface, facilitate the activation of a range of aldehyde and alcohol substrates. The photocatalytic e ffi ciencies strongly depend on the Au loading, particle sizes of the AuNPs, irradiance, and wavelength of the light irradiation. Finally, a plausible reaction mechanism was proposed, and the Au/Al 2 O 3 catalysts can be reused several times without signi fi cantly losing activity. The knowledge acquired in this study may inspire further studies in new e ffi cient recyclable photocatalysts and a wide range of organic synthesis driven by sunlight.

A holistic, institution-wide approach to building sessional staff capacity

Sessional Academics enhance students’ learning experience by bringing a diverse range of perspectives and expertise into the classroom. As industry specialists, research students, and recent graduates who have excelled in their courses, they complement the discipline expertise of career academics. With increasing casualization of the academic workforce, Sessional Academics now deliver the majority of face-to-face undergraduate teaching in Australian Universities. To enable them to realize their full potential as effective contributors to student learning and course quality, universities need to offer effective training and access to advice and support and facilitate engagement in university life. However, in the face of complex and diverse contexts, overwhelming numbers, and the transitory nature of sessional cohorts, few universities have developed a comprehensive, systematic approach. During the past three years at QUT, we have set out to develop a multifaceted approach to Sessional Academic support and development. In this paper I will explain why and how we have done so, and describe the range of strategies and programs we have developed. They include a central academic development program, which is structured and scaffolded with learning objectives and outcomes, and aligned with a graduate certificate in Academic Practice; a Sessional Academic Success program, which deploys experienced, school-based sessional academic success advisors to provide local support, build a sense of community, and offer discipline focused academic development; an online, dialogic communication strategy; and opportunities to present and be acknowledged for good learning and teaching practices. Together, these strategies have impacted on sessional academics’ confidence, learning and teaching capacity, reflection and engagement.

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

Aims/hypothesis Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. Methods Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. Results The top ranked variant was rs3805931 with p = 2.66 × 10−7, but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10−5) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10−8). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. Conclusions/interpretation Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.

Genetic determinants of heel bone properties: Genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n 5 14 260), velocity of sound (VOS; n 5 15 514) and BMD (n 5 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n 5 11 452) and new genotyping in 15 cohorts (de novo n 5 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 3 108) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 3 1014). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 3 106 also had the expected direction of association with any fracture (P < 0.05), including threeSNPswithP < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, thisGWAstudy reveals the effect of several genescommon to central DXA-derivedBMDand heel ultrasound/DXAmeasures and points to anewgenetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Utility of temporal artery biopsy samples for genome-wide analysis of giant cell arteritis

Giant Cell Arteritis (GCA) is the most common vasculitis affecting the elderly. Archived formalin-fixed paraffin-embedded (FFPE) temporal artery biopsy (TAB) specimens potentially represent a valuable resource for large-scale genetic analysis of this disease. FFPE TAB samples were obtained from 12 patients with GCA. Extracted TAB DNA was assessed by real time PCR before restoration using the Illumina HD FFPE Restore Kit. Paired FFPE-blood samples were genotyped on the Illumina OmniExpress FFPE microarray. The FFPE samples that passed stringent quality control measures had a mean genotyping success of >97%. When compared with their matching peripheral blood DNA, the mean discordant heterozygote and homozygote single nucleotide polymorphisms calls were 0.0028 and 0.0003, respectively, which is within the accepted tolerance of reproducibility. This work demonstrates that it is possible to successfully obtain high-quality microarray-based genotypes FFPE TAB samples and that this data is similar to that obtained from peripheral blood.

Community uses of co-creative media digital storytelling and co-creative Media: The role of community arts and media in propagating and coordinating population-wide creative practice

How is creative expression and communication extended among whole populations? What is the social and cultural value of this activity? What roles do formal agencies, community-based organisations and content producer networks play? Specifically, how do participatory media and arts projects and networks contribute to building this capacity in the contemporary communications environment? The latest issue of CSJ article in a special issue on “Broadening Digital Storytelling Horizons” edited by Burcu Simsek.

Making an IMPACT: Campus-wide collaboration for course and learning space transformation

At Purdue University, the Libraries participate in a provost-initiated, campus-wide course redesign program called Instruction Matters: Purdue Academic Course Transformation (IMPACT). This initiative aims to bring active-learning to foundational courses traditionally taught through lectures. Purdue librarians recognized the IMPACT initiative as one way to enter the conversations blooming on our campus about the nature of learning, curriculum design, and how space design impacts potential learning. This article presents three perspectives: 1) the information literacy coordinator, 2) a libraries’ administrator with a gift for space planning, and; 3) an in-the-trenches liaison to course redesign projects. Each discusses the IMPACT initiative from his or her unique perspective and view of its impact on librarian roles. Collectively, the article explains why we think it is essential that this kind of campus effort is supported by libraries.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm

Background Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. Aim To identify genetic variants associated with forearm BMD and forearm fractures. Methods BMD at distal radius, measured by dualenergy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a metaanalysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. Results We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10-8) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01×10-9). The gene-based association test suggested an association between MEF2C and forearm BMD ( p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. Conclusions These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus

To discover quantitative trait loci for intraocular pressure, amajor risk factor for glaucoma and the only modifiable one,weperformed agenome-wide association studyonadiscoverycohort of2175individualsfromSydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10-8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30-0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.

Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-Analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Comparison of the performance of two commercial genome-wide association study genotyping platforms in Han Chinese samples

Most genome-wide association studies to date have been performed in populations of European descent, but there is increasing interest in expanding these studies to other populations. The performance of genotyping chips in Asian populations is not well established. Therefore, we sought to test the performance of widely used fixed-marker, genome-wide association studies chips in the Han Chinese population. Non-HapMap Chinese samples (n = 396) were genotyped using the Illumina OmniExpress and Affymetrix 6.0 platforms, whereas a subset also were genotyped using the Immunochip. Genotyped markers from the Affymetrix 6.0 and Illumina OmniExpress were used for full genome imputation based on the HapMap 2 JPT+CHB (Japanese from Tokyo, Japan and Chinese from Beijing, China) reference panel. The concordance between markers genotypes for the three platforms was very high whether directly genotyped or genotyped and imputed single nucleotide polymorphisms (SNPs; .99.8% for directly genotyped and .99.5% for genotyped and imputed SNPs, respectively) were compared. The OmniExpress chip data enabled more SNPs to be imputed, particularly SNPs with minor allele frequency .5%. The OmniExpress chip achieved better coverage of HapMap SNPs than the Affymetrix 6.0 chip (73.6% vs. 65.9%, respectively, for minor allele frequency .5%). The Affymetrix 6.0 and Illumina OmniExpress chip have similar genotyping accuracy and provide similar accuracy of imputed SNPs. The OmniExpress chip however provides better coverage of Asian HapMap SNPs, although its coverage of HapMap SNPs is moderate. © 2013 Jiang et al.