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1.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
2.  Availability of arsenic in human milk in women and its correlation with arsenic in urine of breastfed children living in arsenic contaminated areas in Bangladesh 
Environmental Health  2014;13(1):101.
Background
Early life exposure to inorganic arsenic may be related to adverse health effects in later life. However, there are few data on postnatal arsenic exposure via human milk. In this study, we aimed to determine arsenic levels in human milk and the correlation between arsenic in human milk and arsenic in mothers and infants urine.
Methods
Between March 2011 and March 2012, this prospective study identified a total of 120 new mother-baby pairs from Kashiani (subdistrict), Bangladesh. Of these, 30 mothers were randomly selected for human milk samples at 1, 6 and 9 months post-natally; the same mother baby pairs were selected for urine sampling at 1 and 6 months. Twelve urine samples from these 30 mother baby pairs were randomly selected for arsenic speciation.
Results
Arsenic concentration in human milk was low and non-normally distributed. The median arsenic concentration in human milk at all three time points remained at 0.5 μg/L. In the mixed model estimates, arsenic concentration in human milk was non-significantly reduced by -0.035 μg/L (95% CI: -0.09 to 0.02) between 1 and 6 months and between 6 and 9 months. With the progression of time, arsenic concentration in infant’s urine increased non-significantly by 0.13 μg/L (95% CI: -1.27 to 1.53). Arsenic in human milk at 1 and 6 months was not correlated with arsenic in the infant’s urine at the same time points (r = -0.13 at 1 month and r = -0.09 at 6 month). Arsenite (AsIII), arsenate (AsV), monomethyl arsonic acid (MMA), dimethyl arsinic acid (DMA) and arsenobetaine (AsB) were the constituents of total urinary arsenic; DMA was the predominant arsenic metabolite in infant urine.
Conclusions
We observed a low arsenic concentration in human milk. The concentration was lower than the World Health Organization’s maximum permissible limit (WHO Permissible Limit 15 μg/kg-bw/week). Our findings support the safety of breastfeeding even in arsenic contaminated areas.
doi:10.1186/1476-069X-13-101
PMCID: PMC4265415  PMID: 25471535
Arsenic; Human milk; Bangladesh
3.  Prediction of Age-related Macular Degeneration in the General Population 
Ophthalmology  2013;120(12):2644-2655.
Purpose
Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD based on data from population-based studies.
Design
Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC).
Participants
People (n = 10106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline.
Methods
Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan–Meier product-limit analysis.
Main Outcome Measures
Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits.
Results
Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval [CI], 0.01–0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2–31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores.
Conclusions
Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies.
doi:10.1016/j.ophtha.2013.07.053
PMCID: PMC3986722  PMID: 24120328
4.  Biochemical Validation of the Older Australian’s Food Frequency Questionnaire Using Carotenoids and Vitamin E 
Nutrients  2014;6(11):4906-4917.
Background: Validation of a food frequency questionnaire (FFQ) is important, as inaccurate and imprecise information may affect the association between dietary exposure and health outcomes. Objective: This study assessed the validity of the Older Australian’s FFQ against plasma carotenoids and Vitamin E. Methods: A random subsample (n = 150) of 2420 participants in the Hunter Community Study, aged 55–85 years, were included. Correlations between crude and energy-adjusted FFQ estimates of carotenoids, Vitamin E, and fruit and vegetables with corresponding biomarkers were determined. Percentages of participants correctly classified in the same quartile, and in the same ± 1 quartile, by the two methods were calculated. Results: Significant correlations (P < 0.05) were observed for α-carotene (r = 0.26–0.28), β-carotene (r = 0.21–0.25), and β-cryptoxanthin (r = 0.21–0.23). Intakes of fruits and vegetables also showed similar correlations with these plasma carotenoids. Lycopene was only significantly correlated with fruit and vegetable intakes (r = 0.19–0.23). Weak correlations were observed for lutein + zeaxanthin (r = 0.12–0.16). For Vitamin E, significant correlation was observed for energy-adjusted FFQ estimate and biomarker (r = 0.20). More than 68% of individuals were correctly classified within the same or adjacent quartile, except for lutein + zeaxanthin. Conclusion: With the exception of lutein + zeaxanthin, the Older Australian’s FFQ provides reasonable rankings for individuals according to their carotenoids, Vitamin E, fruit and vegetable intakes.
doi:10.3390/nu6114906
PMCID: PMC4245571  PMID: 25383938
validation; food frequency questionnaire; biomarkers; carotenoids; vitamin E
5.  Confirmation of Childhood Acute Lymphoblastic Leukemia Variants, ARID5B and IKZF1, and Interaction with Parental Environmental Exposures 
PLoS ONE  2014;9(10):e110255.
Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child’s sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38–1.93, P = 2.13×10−9), and IKZF1 rs1110701 (OR 1.69, CI 1.42–2.02, p = 7.26×10−9). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.
doi:10.1371/journal.pone.0110255
PMCID: PMC4195717  PMID: 25310577
6.  Genome wide analysis of blood pressure variability and ischemic stroke 
Background and Purpose
Visit-to-visit variability in BP is associated with ischemic stroke. We sought to determine whether such variability has a genetic aetiology and whether genetic variants associated with BP variability are also associated with ischemic stroke.
Methods
A GWAS for loci influencing BP variability was undertaken in 3,802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study where long-term visit-to-visit and within visit BP measures were available. Since BP variability is strongly associated with ischemic stroke, we genotyped the sentinel SNP in an independent ischemic stroke population comprising of 8,624 cases and 12,722 controls and in 3,900 additional (Scandinavian) participants from the ASCOT study in order to replicate our findings.
Results
The ASCOT discovery GWAS identified a cluster of 17 correlated SNPs within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (p=1.4×10−8). Conditional analysis on rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in ischemic stroke patients found no association for overall stroke (OR 1.02; 95% CI 0.97-1.07; p=0.52) or its sub-types: CE (OR 1.07; 95% CI 0.97-1.16; p=0.17), LVD (OR 0.98; 95% 0.89-1.07; p=0.60) and SVD (OR 1.07; 95% CI 0.97-1.17; p=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (p=0.18).
Conclusions
We identified a cluster of SNPs at the NLGN1 locus showing significant association with BP variability. Follow up analyses did not support an association with risk of ischemic stroke and its subtypes.
doi:10.1161/STROKEAHA.113.002186
PMCID: PMC3904673  PMID: 23929743
Blood pressure variability; stroke; GWAS; gene; polymorphism
7.  Self-reported contacts for mental health problems by rural residents: predicted service needs, facilitators and barriers 
BMC Psychiatry  2014;14(1):249.
Background
Rural and remote Australians face a range of barriers to mental health care, potentially limiting the extent to which current services and support networks may provide assistance. This paper examines self-reported mental health problems and contacts during the last 12 months, and explores cross-sectional associations between potential facilitators/barriers and professional and non-professional help-seeking, while taking into account expected associations with socio-demographic and health-related factors.
Methods
During the 3-year follow-up of the Australian Rural Mental Health Study (ARMHS) a self-report survey was completed by adult rural residents (N = 1,231; 61% female; 77% married; 22% remote location; mean age = 59 years), which examined socio-demographic characteristics, current health status factors, predicted service needs, self-reported professional and non-professional contacts for mental health problems in the last 12 months, other aspects of help-seeking, and perceived barriers.
Results
Professional contacts for mental health problems were reported by 18% of the sample (including 14% reporting General Practitioner contacts), while non-professional contacts were reported by 16% (including 14% reporting discussions with family/friends). Perceived barriers to health care fell under the domains of structural (e.g., costs, distance), attitudinal (e.g., stigma concerns, confidentiality), and time commitments. Participants with 12-month mental health problems who reported their needs as met had the highest levels of service use. Hierarchical logistic regressions revealed a dose-response relationship between the level of predicted need and the likelihood of reporting professional and non-professional contacts, together with associations with socio-demographic characteristics (e.g., gender, relationships, and financial circumstances), suicidal ideation, and attitudinal factors, but not geographical remoteness.
Conclusions
Rates of self-reported mental health problems were consistent with baseline findings, including higher rural contact rates with General Practitioners. Structural barriers displayed mixed associations with help-seeking, while attitudinal barriers were consistently associated with lower service contacts. Developing appropriate interventions that address perceptions of mental illness and attitudes towards help-seeking is likely to be vital in optimising treatment access and mental health outcomes in rural areas.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-014-0249-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-014-0249-0
PMCID: PMC4172961  PMID: 25193400
Rural; Mental health; Service utilisation; Treatment barriers; Attitudes
8.  A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach 
PLoS Genetics  2014;10(7):e1004469.
Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10−7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05–1.32); meta-analysis p = 2.6×10−8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10−15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
Author Summary
Ischaemic stroke places an enormous burden on global healthcare. However, the disease processes that lead to stroke are not fully understood. Genome-wide association studies have recently established that common genetic variants can increase risk of ischaemic stroke and its subtypes. In this study, we aimed to identify novel genetic associations with ischaemic stroke and its subtypes by addressing the fact that younger onset cases may have a stronger genetic component, and using this information in our analyses. We identify a novel genetic variant on chromosome 11 (rs660599), which is associated with increased risk of large artery stroke. We also show that mRNA expression of the nearest gene (MMP12) is higher in arteries with the disease process underlying large artery stroke (atherosclerosis). Finally, we evaluate our novel analysis approach, and show that our method is likely to identify further associations with ischaemic stroke.
doi:10.1371/journal.pgen.1004469
PMCID: PMC4117446  PMID: 25078452
9.  Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error 
Human Molecular Genetics  2013;22(13):2754-2764.
Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (‘Cooperative Health Research in the Region of Augsburg’); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10−9) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
doi:10.1093/hmg/ddt116
PMCID: PMC3674806  PMID: 23474815
10.  Thyroid Antibodies, Autoimmunity and Cognitive Decline: Is There a Population-Based Link? 
Background
Autoimmunity is considered an uncommon but under-recognised cause of cognitive decline.
Methods
Serum samples from 3,253 randomly selected subjects enrolled in the Hunter Community Study, aged 55-85 years, were assayed for thyrotropin stimulatory hormone, anti-thyroid peroxidase antibodies (TPO-Ab), anti-nuclear antibodies (ANA) and extractable nuclear antigens (ENA). Cognitive function was assessed using the Audio Recorded Cognitive Screen (ARCS) tool.
Results
TPO-Ab were found in 8.4% and ANA in 27.9% of the study population, of whom 3% had positive ENA findings. No relationship was found between the ARCS score and either TPO-Ab (coefficient = 0.133; 95% CI −0.20, 0.82, p = 0.616), ANA at a low (coefficient = 1.01; 95% CI −2.58, 0.55, p = 0.203) or a high titre (coefficient = −0.65; 95% CI −2.59, 1.28, p = 0.508), or ENA antibodies (coefficient = 5.12; 95% CI −0.53, 10.77; p = 0.076).
Conclusions
Autoantibody findings are common in an aging population and are not associated with cognitive decline.
doi:10.1159/000362716
PMCID: PMC4067731  PMID: 24987403
Dementia; Hashimoto disease; Encephalitis; Autoantibodies; Anti-nuclear antibodies; Nuclear antigens; Autoimmune thyroiditis; Mild cognitive impairment
11.  Exploring lifetime occupational exposure and SLE flare: a patient-focussed pilot study 
Lupus Science & Medicine  2014;1(1):e000023.
Introduction
Environmental effectors, such as ultraviolet radiation exposure, infection and stress, have been established as having a role in exacerbating lupus symptoms. However, unpredictable patterns of flare events still remain a mystery. Occupational effectors have also been suggested as having a contributing role; however, they are not widely researched. In this paper we report a pilot study designed to generate focus areas for future research regarding occupational exposures and systemic lupus erythematosus (SLE).
Methods
The study explored potential links between exposures and the occurrence of patient-reported flare events in 80 Australian women with SLE (American College of Rheumatology (ACR) criteria classified). Specifically, the study assessed the hypothesis that occupational exposure is associated with significant changes in the likelihood of lupus flares. Lifetime employment history was analysed with the Finnish Job Exposure Matrix (FINJEM), 40 different semiquantified exposure class estimates for a wide number of occupations based on probability of exposure (p≥5%=exposed) were analysed with the construction of negative binomial regression models to test relationships between occupational agents and flare days. A backward stepwise elimination was used to generate a parsimonious model.
Results
Significant associations were noted for exposure classes of manual handling burden, (p=0.02, incidence rate ratio (IRR) 1.01), Iron (p=0.00, IRR 1.37), wood dust (p=0.00, IRR 3.34) and asbestos (p=0.03, IRR 2.48).
Conclusion
Exposure assessment results indicated that occupations, such as nursing, with a high manual handling burden, posed increased risk to patients with SLE, however, the greatest risk was associated with wood dust and iron exposure with teachers and specialist labourers.
doi:10.1136/lupus-2014-000023
PMCID: PMC4213832  PMID: 25379190
12.  Quantitative 99mTc DTPA renal transplant scintigraphic parameters: assessment of interobserver agreement and correlation with graft pathologies 
Various 99mTc DTPA scintigraphic quantitative parameters for renal graft function assessment have been recommended, but none is universally accepted. In this study, 439 dynamic renal transplant scintigraphies (DRTS) were retrospectively analysed. In the first set of studies, four observers analysed the 47 random DRTS and interobserver agreement of eleven derived parameters was assessed. In the other set of studies, 181 instances of DRTS, performed on 127 recipients with renal biopsies within five days of each other were selected for correlation with pathology. Hilson’s Perfusion index (HI), ΔP, P:Pl, P:U & T10 were selected for this analysis. The pathologies were categorized into renal vascular compromise (RVC; n = 20), acute tubular necrosis (ATN; n = 40), vascular rejection (VR; n = 34), interstitial rejection (IR; n = 33), normal (NOR; n = 36) and unclassified pathologies (n = 18). A majority of the parameters showed good Intraclass correlation (ICC). HI differentiated well between grafts with RVC and the remainder of the study cohort, (p < 0.0001; AUC = 0.84); at a cut-off > 278, it had 84% sensitivity and 78% specificity (Likelihood ratio = 3.8). At < 278, it had 98% ‘negative’ predictive value for RVC. HI also showed reasonable association with VR (p = 0.02; AUC = 0.62) and IR (p = 0.009; AUC = 0.65). However, significant overlap of HI values between various subgroups was noted. Other parameters had good ICC but were not effective in differentiating graft pathologies. Of the measured parameters, only HI proved to be useful for the pathological assessment, particularly in the identification of vascular compromise. This parameter, however, has lower specificity in differentiating the other pathologies.
PMCID: PMC3999401  PMID: 24795835
Acute tubular necrosis; Hilson’s index; interobserver agreement; quantitative renal transplant DTPA scintigraphy; rejection; renal artery stenosis; renal graft
13.  Thrombolysis ImPlementation in Stroke (TIPS): evaluating the effectiveness of a strategy to increase the adoption of best evidence practice – protocol for a cluster randomised controlled trial in acute stroke care 
Background
Stroke is a leading cause of death and disability internationally. One of the three effective interventions in the acute phase of stroke care is thrombolytic therapy with tissue plasminogen activator (tPA), if given within 4.5 hours of onset to appropriate cases of ischaemic stroke.
Objectives
To test the effectiveness of a multi-component multidisciplinary collaborative approach compared to usual care as a strategy for increasing thrombolysis rates for all stroke patients at intervention hospitals, while maintaining accepted benchmarks for low rates of intracranial haemorrhage and high rates of functional outcomes for both groups at three months.
Methods and design
A cluster randomised controlled trial of 20 hospitals across 3 Australian states with 2 groups: multi- component multidisciplinary collaborative intervention as the experimental group and usual care as the control group. The intervention is based on behavioural theory and analysis of the steps, roles and barriers relating to rapid assessment for thrombolysis eligibility; it involves a comprehensive range of strategies addressing individual-level and system-level change at each site. The primary outcome is the difference in tPA rates between the two groups post-intervention. The secondary outcome is the proportion of tPA treated patients in both groups with good functional outcomes (modified Rankin Score (mRS <2) and the proportion with intracranial haemorrhage (mRS ≥2), compared to international benchmarks.
Discussion
TIPS will trial a comprehensive, multi-component and multidisciplinary collaborative approach to improving thrombolysis rates at multiple sites. The trial has the potential to identify methods for optimal care which can be implemented for stroke patients during the acute phase. Study findings will include barriers and solutions to effective thrombolysis implementation and trial outcomes will be published whether significant or not.
Trial registration
Australian New Zealand Clinical Trials Registry: ACTRN12613000939796
doi:10.1186/1748-5908-9-38
PMCID: PMC4016636  PMID: 24666591
Collaborative intervention; Thrombolysis; Acute stroke; Evidence-based practice; Quality improvement; Cluster randomised controlled trial; Multidisciplinary approach
14.  The Architecture of Risk for Type 2 Diabetes: Understanding Asia in the Context of Global Findings 
The prevalence of Type 2 diabetes is rising rapidly in both developed and developing countries. Asia is developing as the epicentre of the escalating pandemic, reflecting rapid transitions in demography, migration, diet, and lifestyle patterns. The effective management of Type 2 diabetes in Asia may be complicated by differences in prevalence, risk factor profiles, genetic risk allele frequencies, and gene-environment interactions between different Asian countries, and between Asian and other continental populations. To reduce the worldwide burden of T2D, it will be important to understand the architecture of T2D susceptibility both within and between populations. This review will provide an overview of known genetic and nongenetic risk factors for T2D, placing the results from Asian studies in the context of broader global research. Given recent evidence from large-scale genetic studies of T2D, we place special emphasis on emerging knowledge about the genetic architecture of T2D and the potential contribution of genetic effects to population differences in risk.
doi:10.1155/2014/593982
PMCID: PMC3976842  PMID: 24744783
15.  Importance of different types of prior knowledge in selecting genome-wide findings for follow-up 
Genetic epidemiology  2013;37(2):10.1002/gepi.21705.
Biological plausibility and other prior information could help select genome-wide association (GWA) findings for further follow-up, but there is no consensus on which types of knowledge should be considered or how to weight them. We used experts’ opinions and empirical evidence to estimate the relative importance of 15 types of information at the single nucleotide polymorphism (SNP) and gene levels. Opinions were elicited from ten experts using a two-round Delphi survey. Empirical evidence was obtained by comparing the frequency of each type of characteristic in SNPs established as being associated with seven disease traits through GWA meta-analysis and independent replication, with the corresponding frequency in a randomly selected set of SNPs. SNP and gene characteristics were retrieved using a specially developed bioinformatics tool. Both the expert and the empirical evidence rated previous association in a meta-analysis or more than one study as conferring the highest relative probability of true association, while previous association in a single study ranked much lower. High relative probabilities were also observed for location in a functional protein domain, while location in a region evolutionarily conserved in vertebrates was ranked high by the data but not by the experts. Our empirical evidence did not support the importance attributed by the experts to whether the gene encodes a protein in a pathway or shows interactions relevant to the trait. Our findings provide insight into the selection and weighting of different types of knowledge in SNP or gene prioritization, and point to areas requiring further research.
doi:10.1002/gepi.21705
PMCID: PMC3725558  PMID: 23307621
Gene prioritization; Genome-wide association studies; Bioinformatics databases
16.  SNP prioritization using a Bayesian probability of association 
Genetic epidemiology  2012;37(2):10.1002/gepi.21704.
Prioritization is the process whereby a set of possible candidate genes or SNPs is ranked so that the most promising can be taken forward into further studies. In a genome-wide association study, prioritization is usually based on the p-values alone, but researchers sometimes take account of external annotation information about the SNPs such as whether the SNP lies close to a good candidate gene. Using external information in this way is inherently subjective and is often not formalized, making the analysis difficult to reproduce. Building on previous work that has identified fourteen important types of external information, we present an approximate Bayesian analysis that produces an estimate of the probability of association. The calculation combines four sources of information: the genome-wide data, SNP information derived from bioinformatics databases, empirical SNP weights, and the researchers’ subjective prior opinions. The calculation is fast enough that it can be applied to millions of SNPS and although it does rely on subjective judgments, those judgments are made explicit so that the final SNP selection can be reproduced. We show that the resulting probability of association is intuitively more appealing than the p-value because it is easier to interpret and it makes allowance for the power of the study. We illustrate the use of the probability of association for SNP prioritization by applying it to a meta-analysis of kidney function genome-wide association studies and demonstrate that SNP selection performs better using the probability of association compared with p-values alone.
doi:10.1002/gepi.21704
PMCID: PMC3725584  PMID: 23280596
replication; prior knowledge; genome-wide studies
17.  Is Serum Zinc Associated with Pancreatic Beta Cell Function and Insulin Sensitivity in Pre-Diabetic and Normal Individuals? Findings from the Hunter Community Study 
PLoS ONE  2014;9(1):e83944.
Aim
To determine if there is a difference in serum zinc concentration between normoglycaemic, pre-diabetic and type-2 diabetic groups and if this is associated with pancreatic beta cell function and insulin sensitivity in the former 2 groups.
Method
Cross sectional study of a random sample of older community-dwelling men and women in Newcastle, New South Wales, Australia. Beta cell function, insulin sensitivity and insulin resistance were calculated for normoglycaemic and prediabetes participants using the Homeostasis Model Assessment (HOMA-2) calculator.
Result
A total of 452 participants were recruited for this study. Approximately 33% (N = 149) had diabetes, 33% (N = 151) had prediabetes and 34% (N = 152) were normoglycaemic. Homeostasis Model Assessment (HOMA) parameters were found to be significantly different between normoglycaemic and prediabetes groups (p<0.001). In adjusted linear regression, higher serum zinc concentration was associated with increased insulin sensitivity (p = 0.01) in the prediabetic group. There was also a significant association between smoking and worse insulin sensitivity.
Conclusion
Higher serum zinc concentration is associated with increased insulin sensitivity. Longitudinal studies are required to determine if low serum zinc concentration plays a role in progression from pre-diabetes to diabetes.
doi:10.1371/journal.pone.0083944
PMCID: PMC3885544  PMID: 24416185
18.  Clinical and Biochemical Correlates of Serum L-Ergothioneine Concentrations in Community-Dwelling Middle-Aged and Older Adults 
PLoS ONE  2014;9(1):e84918.
Background
Despite the increasing interest towards the biological role of L-ergothioneine, little is known about the serum concentrations of this unusual aminothiol in older adults. We addressed this issue in a representative sample of community-dwelling middle-aged and older adults.
Methods
Body mass index, estimated glomerular filtration rate, serum concentrations of L-ergothioneine, taurine, homocysteine, cysteine, glutathione, cysteinylglycine, and glutamylcysteine were evaluated in 439 subjects (age 55–85 years) randomly selected from the Hunter Community Study.
Results
Median L-ergothioneine concentration in the entire cohort was 1.01 IQR 0.78–1.33 µmol/L. Concentrations were not affected by gender (P = 0.41) or by presence of chronic medical conditions (P = 0.15). By considering only healthy subjects, we defined a reference interval for L-ergothioneine serum concentrations from 0.36 (90% CI 0.31–0.44) to 3.08 (90% CI 2.45–3.76) µmol/L. Using stepwise multiple linear regression analysis L-ergothioneine was negatively correlated with age (rpartial = −0.15; P = 0.0018) and with glutamylcysteine concentrations (rpartial = −0.13; P = 0.0063).
Conclusions
A thorough analysis of serum L-ergothioneine concentrations was performed in a large group of community-dwelling middle-aged and older adults. Reference intervals were established. Age and glutamylcysteine were independently negatively associated with L-ergothioneine serum concentration.
doi:10.1371/journal.pone.0084918
PMCID: PMC3879362  PMID: 24392160
19.  Ischaemic stroke is associated with the ABO locus: the Euroclot study 
Annals of neurology  2013;73(1):16-31.
Objectives
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischaemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Methods
Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n=2,100 Stage 1) were examined in ischemic stroke (n=4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases 55,000 controls) was used for replication (Stage 3).
Results
Stage 1 identified 524 SNPs from 23 LD blocks having significant association (p<5 ×10-8) with one or more coagulation/fibrin phenotypes. Most striking associations included SNP rs5985 with factor XIII activity (p=2.6×10-186), rs10665 with FVII (p = 2.4×10-47) and rs505922 in the ABO gene with both von Willebrand Factor (vWF p=4.7×10-57) and factor VIII (p=1.2×10-36). In Stage 2, the 23 independent SNPs were examined in stroke cases/non-cases using MORGAM and WTCCC2 collections. SNP rs505922 was nominally associated with ischaemic stroke, odds ratio = 0.94 (95% confidence intervals, 0.88-0.99), p=0.023. Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta=0.066 (0.02) p = 0.001, a finding specific to large vessel and cardioembolic stroke (p = 0.001 and p = <0.001 respectively) but not seen with small vessel stroke (p=0.811).
Interpretation
ABO gene variants are associated with large vessel and cardioembolic stroke but not small vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
doi:10.1002/ana.23838
PMCID: PMC3582024  PMID: 23381943
GWAS; thrombosis; stroke; coagulation factor; stroke subtype
20.  Short Sleep Duration Is Associated with Risk of Future Diabetes but Not Cardiovascular Disease: a Prospective Study and Meta-Analysis 
PLoS ONE  2013;8(11):e82305.
Epidemiologic studies have observed association between short sleep duration and both cardiovascular disease (CVD) and type 2 diabetes, although these results may reflect confounding by pre-existing illness. This study aimed to determine whether short sleep duration predicts future CVD or type 2 diabetes after accounting for baseline health. Baseline data for 241,949 adults were collected through the 45 and Up Study, an Australian prospective cohort study, with health outcomes identified via electronic database linkage. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals. Compared to 7h sleep, <6h sleep was associated with incident CVD in participants reporting ill-health at baseline (HR=1·38 [95% CI: 1·12-1·70]), but not after excluding those with baseline illness and adjusting for baseline health status (1·03 [0·88-1·21]). In contrast, the risk of incident type 2 diabetes was significantly increased in those with <6h versus 7h sleep, even after excluding those with baseline illness and adjusting for baseline health (HR=1·29 [1·08-1·53], P=0.004). This suggests the association is valid and does not simply reflect confounding or reverse causation. Meta-analysis of ten prospective studies including 447,124 participants also confirmed an association between short sleep and incident diabetes (1·33 [1·20-1·48]). Obtaining less than 6 hours of sleep each night (compared to 7 hours) may increase type 2 diabetes risk by approximately 30%.
doi:10.1371/journal.pone.0082305
PMCID: PMC3840027  PMID: 24282622
21.  Genome-wide association study of endometrial cancer in E2C2 
Human Genetics  2013;133(2):211-224.
Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-013-1369-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-013-1369-1
PMCID: PMC3898362  PMID: 24096698
22.  Integrating and extending cohort studies: lessons from the eXtending Treatments, Education and Networks in Depression (xTEND) study 
Background
Epidemiologic studies often struggle to adequately represent populations and outcomes of interest. Differences in methodology, data analysis and research questions often mean that reviews and synthesis of the existing literature have significant limitations. The current paper details our experiences in combining individual participant data from two existing cohort studies to address questions about the influence of social factors on health outcomes within a representative sample of urban to remote areas of Australia. The eXtending Treatments, Education and Networks in Depression study involved pooling individual participant data from the Australian Rural Mental Health Study (T0 N = 2639) and the Hunter Community Study (T0 N = 3253) as well as conducting a common three-year follow-up phase (T1 N = 3513). Pooling these data extended the capacity of these studies by: enabling research questions of common interest to be addressed; facilitating the harmonization of baseline measures; permitting investigation of a range of psychosocial, physical and contextual factors over time; and contributing to the development and implementation of targeted interventions for persons experiencing depression and alcohol issues.
Discussion
The current paper describes the rationale, challenges encountered, and solutions devised by a project aiming to maximise the benefits derived from existing cohort studies. We also highlight opportunities for such individual participant data analyses to assess common assumptions in research synthesis, such as measurement invariance, and opportunities for extending ongoing cohorts by conducting a common follow-up phase.
Summary
Pooling individual participant data can be a worthwhile venture, particularly where adequate representation is beyond the scope of existing research, where the effects of interest are small though important, where events are of relatively low frequency or rarely observed, and where issues are of immediate regional or national interest. Benefits such as these can enhance the utility of existing projects and strengthen requests for further research funding.
doi:10.1186/1471-2288-13-122
PMCID: PMC3856520  PMID: 24093910
Cohort studies; Remoteness; Mental health; Individual participant data analysis; Research methods
23.  Is dietary zinc protective for type 2 diabetes? Results from the Australian longitudinal study on women’s health 
Background
Animal studies have shown that zinc intake has protective effects against type 2 diabetes, but few studies have been conducted to examine this relationship in humans. The aim of this study is to investigate if dietary zinc is associated with risk of type 2 diabetes in a longitudinal study of mid-age Australian women.
Methods
Data were collected from a cohort of women aged 45-50 years at baseline, participating in the Australian Longitudinal Study on Women’s Health. A validated food frequency questionnaire was used to assess dietary intake and other nutrients. Predictors of 6-year incidence of type 2 diabetes were examined using multivariable logistic regression.
Results
From 8921 participants, 333 incident cases of type 2 diabetes were identified over 6 years of follow-up. After adjustment for dietary and non-dietary factors, the highest quintile dietary zinc intake had almost half the odds of developing type 2 diabetes (OR = 0.50, 95% C.I. 0.32–0.77) compared with the lowest quintile. Similar findings were observed for the zinc/iron ratio; the highest quintile had half the odds of developing type 2 diabetes (OR = 0.50, 95% C.I 0.30-0.83) after multivariable adjustment of covariates.
Conclusions
Higher total dietary zinc intake and high zinc/iron ratio are associated with lower risk of type 2 diabetes in women. This finding is a positive step towards further research to determine if zinc supplementation may reduce the risk of developing type 2 diabetes.
doi:10.1186/1472-6823-13-40
PMCID: PMC4015935  PMID: 24093747
Diabetes; Australia; Women & Zinc
24.  Development of an Electronic Alcohol Screening and Brief Intervention Program for Hospital Outpatients With Unhealthy Alcohol Use 
JMIR Research Protocols  2013;2(2):e36.
Background
Alcohol screening and brief intervention is recommended for widespread implementation in health care systems, but it is not used routinely in most countries for a variety of reasons. Electronic screening and brief intervention (e-SBI), in which patients complete a Web-based questionnaire and are provided with personalized feedback on their drinking, is a promising alternative to practitioner delivered intervention, but its efficacy in the hospital outpatient setting has not been established.
Objective
The objective of our study was to establish the feasibility of conducting a full-scale randomized controlled trial to determine whether e-SBI reduces alcohol consumption in hospital outpatients with hazardous or harmful drinking.
Methods
The study was conducted in the outpatient department of a large public hospital in Newcastle (population 540,000), Australia. Adults with appointments at a broad range of medical and surgical outpatient clinics were invited to complete an e-SBI program on a laptop, and to report their impressions via a short questionnaire. Follow-up assessments were conducted 2-8 weeks later by email and post.
Results
We approached 172 outpatients and 108/172 (62.8%) agreed to participate. Of the 106 patients capable of self-administering the e-SBI, 7/106 (6.6%) did not complete it (3 due to technical problems and 4 because they were called for their appointment), 15/106 (14.2%) indicated that they had not consumed any alcohol in the past 12 months, 43/106 (40.6%) screened negative for unhealthy alcohol use (scored less than 5 on the Alcohol Use Disorders Identification Test Consumption [AUDIT-C] questions), 33/106 (31.1%) screened positive for hazardous or harmful drinking (AUDIT-C score 5-9), and 8/106 (7.5%) screened positive for possible alcohol dependence (AUDIT-C score 10-12). Among the subgroup with hazardous or harmful drinking, 27/33 (82%) found the feedback on their drinking very, quite, or somewhat useful, 33/33 (100%) thought the intervention would appeal to most or some of the people who attend the service, and 22/30 (73%) completed the follow-up. We also found that some well established procedures used in trials of e-SBI in the primary care setting did not translate to the hospital outpatient setting (1) we experienced delays because the e-SBI program had to be developed and maintained by the health service’s information technology staff for security reasons, (2) recruiting patients as they left the reception desk was impractical because patients tended to arrive at the beginning of the clinics with few arrivals thereafter, and (3) use of a laptop in a fixed location resulted in some patients rushing through the e-SBI so they could return to their seat in the area they had been advised to wait in.
Conclusions
e-SBI is acceptable to outpatients and with some adaptation to organizational and physical conditions, it is feasible to recruit and screen patients and to deliver the intervention without disrupting normal service provision. This suggests that e-SBI could be provided routinely in this important setting if shown to be efficacious.
doi:10.2196/resprot.2697
PMCID: PMC3786128  PMID: 24055787
alcohol; drinking; screening; brief intervention; hospital; outpatients; Internet
25.  GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment 
Rietveld, Cornelius A. | Medland, Sarah E. | Derringer, Jaime | Yang, Jian | Esko, Tõnu | Martin, Nicolas W. | Westra, Harm-Jan | Shakhbazov, Konstantin | Abdellaoui, Abdel | Agrawal, Arpana | Albrecht, Eva | Alizadeh, Behrooz Z. | Amin, Najaf | Barnard, John | Baumeister, Sebastian E. | Benke, Kelly S. | Bielak, Lawrence F. | Boatman, Jeffrey A. | Boyle, Patricia A. | Davies, Gail | de Leeuw, Christiaan | Eklund, Niina | Evans, Daniel S. | Ferhmann, Rudolf | Fischer, Krista | Gieger, Christian | Gjessing, Håkon K. | Hägg, Sara | Harris, Jennifer R. | Hayward, Caroline | Holzapfel, Christina | Ibrahim-Verbaas, Carla A. | Ingelsson, Erik | Jacobsson, Bo | Joshi, Peter K. | Jugessur, Astanand | Kaakinen, Marika | Kanoni, Stavroula | Karjalainen, Juha | Kolcic, Ivana | Kristiansson, Kati | Kutalik, Zoltán | Lahti, Jari | Lee, Sang H. | Lin, Peng | Lind, Penelope A. | Liu, Yongmei | Lohman, Kurt | Loitfelder, Marisa | McMahon, George | Vidal, Pedro Marques | Meirelles, Osorio | Milani, Lili | Myhre, Ronny | Nuotio, Marja-Liisa | Oldmeadow, Christopher J. | Petrovic, Katja E. | Peyrot, Wouter J. | Polašek, Ozren | Quaye, Lydia | Reinmaa, Eva | Rice, John P. | Rizzi, Thais S. | Schmidt, Helena | Schmidt, Reinhold | Smith, Albert V. | Smith, Jennifer A. | Tanaka, Toshiko | Terracciano, Antonio | van der Loos, Matthijs J.H.M. | Vitart, Veronique | Völzke, Henry | Wellmann, Jürgen | Yu, Lei | Zhao, Wei | Allik, Jüri | Attia, John R. | Bandinelli, Stefania | Bastardot, François | Beauchamp, Jonathan | Bennett, David A. | Berger, Klaus | Bierut, Laura J. | Boomsma, Dorret I. | Bültmann, Ute | Campbell, Harry | Chabris, Christopher F. | Cherkas, Lynn | Chung, Mina K. | Cucca, Francesco | de Andrade, Mariza | De Jager, Philip L. | De Neve, Jan-Emmanuel | Deary, Ian J. | Dedoussis, George V. | Deloukas, Panos | Dimitriou, Maria | Eiriksdottir, Gudny | Elderson, Martin F. | Eriksson, Johan G. | Evans, David M. | Faul, Jessica D. | Ferrucci, Luigi | Garcia, Melissa E. | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Per | Harris, Juliette M. | Harris, Tamara B. | Hastie, Nicholas D. | Heath, Andrew C. | Hernandez, Dena G. | Hoffmann, Wolfgang | Hofman, Adriaan | Holle, Rolf | Holliday, Elizabeth G. | Hottenga, Jouke-Jan | Iacono, William G. | Illig, Thomas | Järvelin, Marjo-Riitta | Kähönen, Mika | Kaprio, Jaakko | Kirkpatrick, Robert M. | Kowgier, Matthew | Latvala, Antti | Launer, Lenore J. | Lawlor, Debbie A. | Lehtimäki, Terho | Li, Jingmei | Lichtenstein, Paul | Lichtner, Peter | Liewald, David C. | Madden, Pamela A. | Magnusson, Patrik K. E. | Mäkinen, Tomi E. | Masala, Marco | McGue, Matt | Metspalu, Andres | Mielck, Andreas | Miller, Michael B. | Montgomery, Grant W. | Mukherjee, Sutapa | Nyholt, Dale R. | Oostra, Ben A. | Palmer, Lyle J. | Palotie, Aarno | Penninx, Brenda | Perola, Markus | Peyser, Patricia A. | Preisig, Martin | Räikkönen, Katri | Raitakari, Olli T. | Realo, Anu | Ring, Susan M. | Ripatti, Samuli | Rivadeneira, Fernando | Rudan, Igor | Rustichini, Aldo | Salomaa, Veikko | Sarin, Antti-Pekka | Schlessinger, David | Scott, Rodney J. | Snieder, Harold | Pourcain, Beate St | Starr, John M. | Sul, Jae Hoon | Surakka, Ida | Svento, Rauli | Teumer, Alexander | Tiemeier, Henning | Rooij, Frank JAan | Van Wagoner, David R. | Vartiainen, Erkki | Viikari, Jorma | Vollenweider, Peter | Vonk, Judith M. | Waeber, Gérard | Weir, David R. | Wichmann, H.-Erich | Widen, Elisabeth | Willemsen, Gonneke | Wilson, James F. | Wright, Alan F. | Conley, Dalton | Davey-Smith, George | Franke, Lude | Groenen, Patrick J. F. | Hofman, Albert | Johannesson, Magnus | Kardia, Sharon L.R. | Krueger, Robert F. | Laibson, David | Martin, Nicholas G. | Meyer, Michelle N. | Posthuma, Danielle | Thurik, A. Roy | Timpson, Nicholas J. | Uitterlinden, André G. | van Duijn, Cornelia M. | Visscher, Peter M. | Benjamin, Daniel J. | Cesarini, David | Koellinger, Philipp D.
Science (New York, N.Y.)  2013;340(6139):1467-1471.
A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈ 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
doi:10.1126/science.1235488
PMCID: PMC3751588  PMID: 23722424

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