ORCID Profile
0000-0001-6993-6884
Current Organisation
The University of Edinburgh
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Publisher: Public Library of Science (PLoS)
Date: 29-03-2012
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
Publisher: International Global Health Society
Date: 03-09-2015
Publisher: Springer Science and Business Media LLC
Date: 17-12-2015
DOI: 10.1038/NCOMMS10257
Abstract: Nature Communications 6, Article number: 7756 (2015) Published 4 August 2015 Updated 17 December 2015 In the Results section and in the legend of Table 1 of this Article, the company deCODE genetics, Inc. is incorrectly referred to as ‘Diabetes Epidemiology: collaborative analysis of Diagnostic criteria in Europe’.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2017
DOI: 10.1038/NCOMMS14977
Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study s le. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
Publisher: International Global Health Society
Date: 12-2019
Publisher: Oxford University Press (OUP)
Date: 19-11-2034
DOI: 10.1093/IJE/DYAB124
Publisher: Springer Science and Business Media LLC
Date: 04-05-2016
DOI: 10.1038/EJHG.2016.31
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2017
DOI: 10.1101/176511
Abstract: General cognitive function is a prominent human trait associated with many important life outcomes 1,2 , including longevity 3 . The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants 4,5,6 . Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360 age range = 16 to 102). We found 9,714 genome-wide significant SNPs ( P x 10 −8 ) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function were SGCZ , ATXN1 , MAPT , AUTS2 , and P2RY6 . Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent s les. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.
Publisher: Oxford University Press (OUP)
Date: 07-03-2013
DOI: 10.1093/HMG/DDT116
Publisher: Wiley
Date: 24-05-2012
DOI: 10.1002/AJMG.B.32072
Publisher: Oxford University Press (OUP)
Date: 27-07-2012
DOI: 10.1093/HMG/DDS304
Publisher: Springer Science and Business Media LLC
Date: 31-10-2016
DOI: 10.1038/NG.3698
Publisher: F1000 Research Ltd
Date: 24-05-2021
DOI: 10.12688/WELLCOMEOPENRES.15846.2
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent in iduals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P x10 -8 ) interactions with sex on lung function, and 21 showed suggestive interactions (P x10 -6 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1 ) (P=3.15x10 -15 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP ) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6 ), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Springer Science and Business Media LLC
Date: 14-04-2015
DOI: 10.1038/MP.2015.37
Publisher: Public Library of Science (PLoS)
Date: 10-03-2009
Publisher: Springer Science and Business Media LLC
Date: 11-12-2011
DOI: 10.1038/NG.1019
Publisher: Public Library of Science (PLoS)
Date: 27-09-2011
Publisher: Springer Science and Business Media LLC
Date: 26-06-2011
DOI: 10.1038/NG.866
Publisher: Springer Science and Business Media LLC
Date: 05-06-2012
Publisher: Springer Science and Business Media LLC
Date: 06-01-2013
DOI: 10.1038/NG.2506
Publisher: Public Library of Science (PLoS)
Date: 31-10-2013
Publisher: Springer Science and Business Media LLC
Date: 21-05-2020
DOI: 10.1038/S41467-020-15706-X
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry ( N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 30-03-2011
DOI: 10.1038/EJHG.2011.21
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NCOMMS10495
Abstract: To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 in iduals. Twelve loci reached genome-wide significance ( P × 10 −8 ), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14 , IGF2BP1 , PLA2G6 , CRTC1 ) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41588-018-0297-3
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2020
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
DOI: 10.1038/NG0613-712B
Publisher: Springer Science and Business Media LLC
Date: 02-2017
DOI: 10.1038/NATURE21039
Publisher: Oxford University Press (OUP)
Date: 08-04-2010
Abstract: After performing hydrophilic interaction and weak anion exchange high-performance liquid chromatography to analyze N-glycans in the plasma of 1991 people, we identified several in iduals that differed significantly from the "normal" profile of N-glycans. By performing consensus scoring of pairwise distances between vectors containing measured glycan values, we formed six groups of in iduals with specific glyco-phenotypes. Some aberrations from the normal plasma protein patterns were found to be associated with clinical conditions (such as renal problems in people with increased monosialylated biantennary glycans, A2G2S1), while other substantial changes in N-glycan structure, such as the near complete absence of neutral glycans or antennary fucosylated tri- and tetraantennary glycans, were not associated with any observed adverse health outcomes. These results demonstrate the existence of specific altered glyco-phenotypes in some in iduals and indicate that in some cases they might represent risk factors for the development of specific diseases.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2019
DOI: 10.1038/S41588-019-0447-2
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2017
DOI: 10.1038/NG.3841
Publisher: Springer Science and Business Media LLC
Date: 13-05-2016
DOI: 10.1038/SREP25853
Abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry s les (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4 P = 6.3E–04).
Publisher: International Global Health Society
Date: 12-2012
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.1186/GM91
Publisher: Springer Science and Business Media LLC
Date: 20-05-2019
DOI: 10.1038/S41588-019-0438-3
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Elsevier BV
Date: 03-2010
Publisher: International Society of Global Health
Date: 24-11-2016
Publisher: Public Library of Science (PLoS)
Date: 19-01-2010
Publisher: American Chemical Society (ACS)
Date: 18-10-2011
DOI: 10.1021/PR2004067
Abstract: N-glycans play an essential role in biological process and are associated with age, gender, and body mass parameters in Caucasian populations, whereas no study has been reported in Chinese populations. To investigate the correlation between N-glycan structures and metabolic syndrome (MetS) components, we conducted a population-based study in 212 Chinese Han in iduals. The replication study was performed on 520 unrelated in iduals from a Croatian island Korčula. The most prominent observation was the consistent positive correlations between different forms of triantennary glycans and negative correlations between glycans containing core-fucose with MetS components including BMI, SBP, DBP, and fasting plasma glucose (FPG) simultaneously. Significant differences in a number of N-glycan traits were also detected between normal and abnormal groups of BMI, BP, and FPG, respectively. In the multivariate analysis, the level of monosialylated glycans (structure loadings = -0.776) was the most correlated with the MetS related risk factors, especially with SBP (structure loadings = 0.907). Results presented here are showing that variations in the composition of the N-glycome in human plasma could represent the alternations of human metabolism and could be potential biomarkers of MetS.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Oxford University Press (OUP)
Date: 23-04-2014
DOI: 10.1093/HMG/DDU183
Publisher: Springer Science and Business Media LLC
Date: 25-11-2016
DOI: 10.1038/NCOMMS13507
Abstract: Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP ( RPS6KA2 ) and DMRs ( VMP1, ITGB2 and TXK ) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8 + T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.
Publisher: Public Library of Science (PLoS)
Date: 07-08-2014
Publisher: Springer Science and Business Media LLC
Date: 10-06-2014
Abstract: A number of genetic and immunological studies give impetus for investigating the role of glycosylation in IBD. Experimental mouse models have helped to delineate the role of glycosylation in intestinal mucins and to explore the putative pathogenic role of glycosylation in colitis. These experiments have been extended to human studies investigating the glycosylation patterns of intestinal mucins as well as levels of glycans of serum glycoproteins and expression of glycan receptors. These early human studies have generated interesting hypotheses regarding the pathogenic role of glycans in IBD, but have generally been restricted to fairly small underpowered studies. Decreased glycosylation has been observed in the intestinal mucus of patients with IBD, suggesting that a defective inner mucus layer might lead to increased bacterial contact with the epithelium, potentially triggering inflammation. In sera, decreased galactosylation of IgG has been suggested as a diagnostic marker for IBD. Advances in glycoprofiling technology make it technically feasible and affordable to perform high-throughput glycan pattern analyses and to build on previous work investigating a much wider range of glycan parameters in large numbers of patients.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 29-11-2016
DOI: 10.1038/NG1216-1587B
Publisher: Oxford University Press (OUP)
Date: 12-01-2017
DOI: 10.1093/IJE/DYW318
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 23-11-2016
DOI: 10.1038/NCOMMS13357
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain % of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5 / C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
Publisher: Informa UK Limited
Date: 19-06-2014
DOI: 10.3109/15412555.2014.908834
Abstract: Chronic obstructive pulmonary disease (COPD) is among the leading causes of death globally, accounting for about 3 million deaths worldwide in 2011. We aimed to estimate the prevalence of COPD in Africa in the year 2010 to provide the information that could assist health policy in the region. We conducted a systematic review of Medline, EMBASE and Global Health for studies on COPD published between 1990 and 2012. We included original population based studies providing estimates of the prevalence of COPD. We considered the reported estimates in terms of the mean age of the s le, sex ratio, the year of study and the country of the study as possible covariates. RESULTS from two different types of studies, i.e., based on spirometric and non-spirometric diagnosis of COPD, were further compared. The United Nation Population Division's population figures were used to estimate the number of COPD cases in the year 2010. Our search returned 243 studies, from which only 13 met our selection criteria and only five were based on spirometry. The difference in the median prevalence of COPD in persons aged 40 years or older based on spirometry data (13.4% IQR: 9.4%-22.1%) and non-spirometry data (4.0% IQR: 2.1%-8.9%) was statistically significant (p = 0.001). There was no significant effect of the gender or the year of the study on the reported prevalence of COPD in either set of studies. The prevalence of COPD increased with age in spirometry-based studies (p = 0.017), which is a plausible finding suggesting internal consistency of spirometry-based estimates, while this trend was not observed in studies using other case definitions. When applied to the appropriate age group (40 years or more), which accounted for 196.4 million people in Africa in 2010, the estimated prevalence translates into 26.3 million (18.5-43.4 million) cases of COPD. Comparable figures for the year 2000 based on the same prevalence rates would amount to 20.0 million (14.1-33.1), suggesting an increase of 31.5% over a decade that is attributable to ageing of the African population alone. Our findings suggest that COPD is likely to already represent a very large public health problem in Africa. Moreover, rapidly ageing African population should expect a steady increase in the number of COPD cases in the next decade and beyond. The quantity and quality of available evidence does not match the size of the problem. There is a need for more research on COPD prevalence, but also incidence, mortality and risk factors in Africa. We hope this study will raise awareness of COPD in Africa and encourage further research.
Publisher: American Diabetes Association
Date: 16-04-2013
DOI: 10.2337/DB12-1077
Abstract: We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 in iduals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P & 10−3) in Punjabi Sikhs (n = 2,819 801 case subjects). We further replicated 66 SNPs (P & 10−4) through genotyping in a Punjabi Sikh s le (n = 2,894 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10−8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P & 10−3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P & 10−4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P & 10−5 to & 10−7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 in iduals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2016
DOI: 10.1038/NG.3552
Publisher: Elsevier BV
Date: 09-2014
Publisher: Croatian Medical Journals
Date: 12-2008
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2500
Publisher: Springer Science and Business Media LLC
Date: 12-10-2022
DOI: 10.1038/S41586-022-05275-Y
Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge s le sizes 1 . Here, using data from a genome-wide association study of 5.4 million in iduals of erse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-s le estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller s le sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/NATURE17671
Publisher: Springer Science and Business Media LLC
Date: 15-08-2022
DOI: 10.1038/S41467-022-32264-6
Abstract: We investigated thrombocytopenic, thromboembolic and hemorrhagic events following a second dose of ChAdOx1 and BNT162b2 using a self-controlled case series analysis. We used a national prospective cohort with 2.0 million(m) adults vaccinated with two doses of ChAdOx or 1.6 m with BNT162b2. The incidence rate ratio (IRR) for idiopathic thrombocytopenic purpura (ITP) 14–20 days post-ChAdOx1 second dose was 2.14, 95% confidence interval (CI) 0.90–5.08. The incidence of ITP post-second dose ChAdOx1 was 0.59 (0.37–0.89) per 100,000 doses. No evidence of an increased risk of CVST was found for the 0–27 day risk period (IRR 0.83, 95% CI 0.16 to 4.26). However, few (≤5) events arose within this risk period. It is perhaps noteworthy that these events all clustered in the 7–13 day period (IRR 4.06, 95% CI 0.94 to 17.51). No other associations were found for second dose ChAdOx1, or any association for second dose BNT162b2 vaccination. Second dose ChAdOx1 vaccination was associated with increased borderline risks of ITP and CVST events. However, these events were rare thus providing reassurance about the safety of these vaccines. Further analyses including more cases are required to determine more precisely the risk profile for ITP and CVST after a second dose of ChAdOx1 vaccine.
Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1038/NATURE14618
Publisher: Elsevier BV
Date: 02-2014
Publisher: Public Library of Science (PLoS)
Date: 04-01-2011
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: Elsevier BV
Date: 02-2017
Publisher: Public Library of Science (PLoS)
Date: 11-01-2011
Publisher: Public Library of Science (PLoS)
Date: 27-04-2017
Publisher: American Medical Association (AMA)
Date: 08-2012
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-06-2013
Abstract: Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 s les, Rietveld et al. (p. 1467 , published online 30 May see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2022
DOI: 10.1007/S44197-022-00049-1
Abstract: An epidemiological transition in the prevalence of peripheral artery disease (PAD) is taking place especially in low- and middle-income countries (LMICs) where an ageing population and adoption of western lifestyles are associated with an increase in PAD. We discuss the limited evidence which suggests that infection, potentially mediated by inflammation, may be a risk factor for PAD, and show by means of an ecological analysis that country-level prevalence of the major endemic infections of HIV, tuberculosis and malaria are associated with the prevalence of PAD. While further research is required, we propose that scientists and health authorities pay more attention to the interplay between communicable and non-communicable diseases, and we suggest that limiting the occurrence of endemic infections might have some effect on slowing the epidemiological transition in PAD.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Oxford University Press (OUP)
Date: 04-04-2013
DOI: 10.1093/AJE/KWS473
Publisher: Springer Science and Business Media LLC
Date: 04-08-2015
DOI: 10.1038/NCOMMS8756
Abstract: More than 100 loci have been identified for age at menarche by genome-wide association studies however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1 / LAMB2 / TNRC6A/TACR3/PRKAG1 ) are associated with age at menarche (minor allele frequencies 0.08–4.6% effect sizes 0.08–1.25 years per allele P × 10 −8 ). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P =9.4 × 10 −13 ) and FAAH2 (rs5914101, P =4.9 × 10 −10 ). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche ( P =2.8 × 10 −11 ), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the ‘missing heritability’ of this complex trait.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2012
DOI: 10.1038/EJHG.2012.17
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
Publisher: Public Library of Science (PLoS)
Date: 10-07-2014
Publisher: Elsevier BV
Date: 04-2015
Publisher: Public Library of Science (PLoS)
Date: 17-04-2014
Publisher: Springer Science and Business Media LLC
Date: 08-2010
DOI: 10.1038/NATURE09270
Publisher: Public Library of Science (PLoS)
Date: 10-05-2012
Publisher: Springer Science and Business Media LLC
Date: 29-07-2019
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-03-2016
Abstract: Coronary heart disease is a tale of two forms of plasma cholesterol. In contrast to the well-established effects of “bad” cholesterol (LDL-C), the role of “good” cholesterol (HDL-C) is mysterious. Elevated HDL-C correlates with a lower risk of heart disease, yet drugs that raise HDL-C levels do not reduce risk. Zanoni et al. found that some people with exceptionally high levels of HDL-C carry a rare sequence variant in the gene encoding the major HDL-C receptor, scavenger receptor BI. This variant destroys the receptor's ability to take up HDL-C. Interestingly, people with this variant have a higher risk of heart disease despite having high levels of HDL-C. Science , this issue p. 1166
Publisher: Public Library of Science (PLoS)
Date: 20-10-2011
Publisher: Elsevier BV
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 31-03-2022
DOI: 10.1038/S41588-022-01016-Z
Abstract: We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a s le of ~3 million in iduals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI’s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2013
DOI: 10.1038/NG.2610
Publisher: Springer Science and Business Media LLC
Date: 06-02-2017
DOI: 10.1038/NG.3787
Publisher: Wiley
Date: 06-2015
DOI: 10.1002/WPS.20222
Publisher: Public Library of Science (PLoS)
Date: 22-09-2011
Publisher: Public Library of Science (PLoS)
Date: 03-09-2013
Publisher: International Global Health Society
Date: 12-2017
Publisher: International Global Health Society
Date: 12-2017
Publisher: International Global Health Society
Date: 12-2017
Publisher: International Global Health Society
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 24-04-2014
Publisher: Impact Journals, LLC
Date: 12-08-2020
Publisher: International Global Health Society
Date: 06-2016
Publisher: Springer Science and Business Media LLC
Date: 31-10-2019
DOI: 10.1038/S41467-019-12283-6
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients ( F ROH ) for .4 million in iduals, we show that F ROH is significantly associated ( p 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.
Publisher: American Diabetes Association
Date: 06-08-2010
DOI: 10.2337/DC10-1150
Abstract: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in in iduals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. Via meta-analysis of data from 14 cohorts comprising ∼48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value & .0028 (0.05 of 18 tests) as statistically significant. Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: −0.009 mmol/l glucose [−0.013 to −0.005], P & 0.0001 and −0.011 pmol/l [ln] insulin [−0.015 to −0.007], P = 0.0003). No interactions met our multiple testing–adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Elsevier BV
Date: 11-2016
Publisher: Springer Science and Business Media LLC
Date: 19-07-2017
DOI: 10.1038/S41467-017-00031-7
Abstract: Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass ( n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide ( p 5 × 10 −8 ) or suggestively genome wide ( p 2.3 × 10 −6 ). Replication in 63,475 (47,227 of European ancestry) in iduals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3 , IRS1 , and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN , ADAMTSL3 , and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
Publisher: Oxford University Press (OUP)
Date: 14-08-2013
DOI: 10.1093/HMG/DDT399
Abstract: Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic in iduals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595 risk allele = A risk allele frequency (RAF) = 0.080 P = 2.55 × 10(-13) odds ratio (OR) = 1.17], GPSM1 [rs11787792 risk allele = A RAF = 0.874 P = 1.74 × 10(-10) OR = 1.15] and SLC16A13 (rs312457 risk allele = G RAF = 0.078 P = 7.69 × 10(-13) OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.
Publisher: Croatian Medical Journals
Date: 12-2013
Publisher: Public Library of Science (PLoS)
Date: 29-06-2016
Publisher: Elsevier BV
Date: 11-2021
Publisher: Elsevier BV
Date: 07-2010
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Springer Science and Business Media LLC
Date: 15-06-2014
DOI: 10.1038/NG.3011
Publisher: Springer Science and Business Media LLC
Date: 22-06-2014
DOI: 10.1038/NG.3014
Publisher: Elsevier BV
Date: 09-2016
Publisher: Springer Science and Business Media LLC
Date: 28-09-2015
DOI: 10.1038/NG.3412
Publisher: American Medical Association (AMA)
Date: 06-2021
Publisher: Proceedings of the National Academy of Sciences
Date: 31-10-2016
Abstract: In iduals with more education tend to live longer. Genetic variants have been discovered that predict educational attainment. We tested whether a “polygenic score” based on these genetic variants could make predictions about people’s lifespan. We used data from three cohort studies (including ,000 participants) to examine the link between offspring polygenic score for education and parental longevity. Across the studies, we found that participants with more education-linked genetic variants had longer-living parents compared with those with the lowest genetic education scores, those with the highest scores had parents who lived on average 6 months longer. This finding suggests the hypothesis that part of the ultimate explanation for the extended longevity of better-educated people is an underlying, quantifiable, genetic propensity.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2017
DOI: 10.1038/S41598-017-11852-3
Abstract: Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-in idual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2008
DOI: 10.1038/NG.269
Publisher: Elsevier BV
Date: 06-2013
Publisher: International Global Health Society
Date: 12-2015
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 26-10-2021
Publisher: IEEE
Date: 11-2013
Publisher: Public Library of Science (PLoS)
Date: 18-09-2014
Publisher: Cold Spring Harbor Laboratory
Date: 11-10-2017
DOI: 10.1101/198234
Abstract: High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1038/MP.2014.188
Abstract: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts ( N =53 949) in which the participants had undertaken multiple, erse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P =3.93 × 10 −9 , MIR2113 rs17522122, P =2.55 × 10 −8 , AKAP6 rs10119, P =5.67 × 10 −9 , APOE/TOMM40 ). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 ( P =1 × 10 −6 ). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study ( N =6617) and the Health and Retirement Study ( N =5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort ( N =5487 P =1.5 × 10 −17 ). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40 , APOE , ABCG1 and MEF2C .
Publisher: Springer Science and Business Media LLC
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 13-04-2011
DOI: 10.1186/1471-2458-11-S3-S28
Abstract: Oxygen therapy is recommended for all of the 1.5 – 2.7 million young children who consult health services with hypoxemic pneumonia each year, and the many more with other serious conditions. However, oxygen supplies are intermittent throughout the developing world. Although oxygen is well established as a treatment for hypoxemic pneumonia, quantitative evidence for its effect is lacking. This review aims to assess the utility of oxygen systems as a method for reducing childhood mortality from pneumonia. Aiming to improve priority setting methods, The Child Health and Nutrition Research Initiative (CHNRI) has developed a common framework to score competing interventions into child health. That framework involves the assessment of 12 different criteria upon which interventions can be compared. This report follows the proposed framework, using a semi-systematic literature review and the results of a structured exercise gathering opinion from experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies), to assess and score each criterion as their “collective optimism” towards each, on a scale from 0 to 100%. A rough estimate from an analysis of the literature suggests that global strengthening of oxygen systems could save lives of up to 122,000 children from pneumonia annually. Following 12 CHNRI criteria, the experts expressed very high levels of optimism (over 80%) for answerability, low development cost and low product cost high levels of optimism (60-80%) for low implementation cost, likelihood of efficacy, deliverability, acceptance to end users and health workers and moderate levels of optimism (40-60%) for impact on equity, affordability and sustainability. The median estimate of potential effectiveness of oxygen systems to reduce the overall childhood pneumonia mortality was ~20% (interquartile range: 10-35%, min. 0%, max. 50%). However, problems with oxygen systems in terms of affordability, sustainability and impact on equity are noted in both expert opinion scores and on review. Oxygen systems are likely to be an effective intervention in combating childhood mortality from pneumonia. However, a number of gaps in the evidence base exist that should be addressed to complete the investment case and research addressing these issues merit greater funding attention.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2011
DOI: 10.1186/1471-2458-11-S3-S27
Abstract: Staphylococcus aureus is a commensal of human skin and nares. It is also one of the leading nosocomial pathogens in both developed and developing countries and is responsible for a wide range of life threatening infections, especially in patients who are immunocompromised, post-surgery, undergoing haemodialysis and those who are treated with catheters and ventilators. Over the past two decades, the incidence of nosocomial staphylococcal infections has increased dramatically. Currently there are at least seven vaccine and immunotherapy candidates against S. aureus in the developmental phase targeting both active and passive immunization. We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging vaccines against Staphylococcus aureus relevant to several criteria of interest: answerability cost of development, production and implementation efficacy and effectiveness deliverability, affordability and sustainability maximum potential impact on disease burden reduction acceptability to the end users and health workers and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies) to participate. The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to sensitive nature of their involvement in such exercises. They answered questions from CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. The panel of experts expressed low levels of optimism (score around or below 50%) on the criteria of answerability, efficacy, maximum disease burden reduction potential, low cost of production, low cost of implementation and affordability moderate levels of optimism (scores around 60 to 80%) that these vaccines could be developed at a low cost, and thus on the deliverability, sustainability and impact on equity and high levels of optimism (scores above 80%) regarding acceptable of such a product to both the end-users and health workers. While assessing the candidates for passive immunization against S.aureus, the experts were poorly optimistic regarding low production cost, low implementation cost, efficacy, deliverability, sustainability, affordability and equity moderately optimistic regarding answerability and acceptability to health workers and end-users. They were of the opinion that these interventions would have only a modest impact (3 to 5%) on the burden of childhood pneumonia. . In order to provide an effective vaccine against S. aureus , a number of unresolved issues in vaccine development relating to optimal antigenic target identification, criteria for acceptable efficacy, identification of target population, commercial development limitations, optimal timing of immunization strategy, storage, cold chain requirements and cost need to be addressed properly. There is still a great deal unknown about the complex interaction between S. aureus and the human host. However, given the nature of S. aureus and the lessons learned from the recent failure of two emerging vaccines, it is clear that a multi-component vaccine is essential. Combating only one virulence factor is not sufficient in the human host but finding the right combination of factors will be very challenging.
Publisher: Cold Spring Harbor Laboratory
Date: 22-02-2017
DOI: 10.1101/110833
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150,134 European ancestry in iduals and sought significant evidence for independent replication in a further 228,245 in iduals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9 and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12,607 in iduals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in BP regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
DOI: 10.1161/HYPERTENSIONAHA.117.09438
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry in iduals and sought significant evidence for independent replication in a further 228 245 in iduals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 in iduals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2013
DOI: 10.1038/NG.2554
Publisher: Springer Science and Business Media LLC
Date: 06-10-2013
DOI: 10.1038/NG.2795
Publisher: Springer Science and Business Media LLC
Date: 06-10-2013
DOI: 10.1038/NG.2797
Publisher: Wiley
Date: 31-05-2013
DOI: 10.1002/AJMG.B.32168
Publisher: Elsevier BV
Date: 08-2022
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2019
DOI: 10.1101/712398
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality 1,2 . We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
Publisher: Public Library of Science (PLoS)
Date: 07-05-2013
Publisher: Springer Science and Business Media LLC
Date: 13-04-2011
DOI: 10.1186/1471-2458-11-S3-S29
Abstract: Meningococcal meningitis is a major cause of disease worldwide, with frequent epidemics particularly affecting an area of sub-Saharan Africa known as the “meningitis belt”. Neisseria meningitidis group A (MenA) is responsible for major epidemics in Africa. Recently W-135 has emerged as an important pathogen. Currently, the strategy for control of such outbreaks is emergency use of meningococcal (MC) polysaccharide vaccines, but these have a limited ability to induce herd immunity and elicit an adequate immune response in infant and young children. In recent times initiatives have been taken to introduce meningococcal conjugate vaccine in these African countries. Currently there are two different types of MC conjugate vaccines at late stages of development covering serogroup A and W-135: a multivalent MC conjugate vaccine against serogroup A,C,Y and W-135 and a monovalent conjugate vaccine against serogroup A. We aimed to perform a structured assessment of these emerging meningococcal vaccines as a means of reducing global meningococal disease burden among children under 5 years of age. We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In the first stage we systematically reviewed the literature related to emerging MC vaccines relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. For MenA conjugate vaccine the experts showed very high level of optimism (~ 90% or more) for 7 out of the 12 criteria. The experts felt that the likelihood of efficacy on meningitis was very high (~ 90%). Deliverability, acceptability to health workers, end users and the effect on equity were all seen as highly likely (~ 90%). In terms of the maximum potential impact on meningitis disease burden, the median potential effectiveness of the vaccines in reduction of overall meningitis mortality was estimated to be 20% (interquartile range 20-40% and min. 8%, max 50 %). For the multivalent meningococcal vaccines the experts had similar optimism for most of the 12 CHNRI criteria with slightly lower optimism in answerability and low development cost criteria. The main concern was expressed over the cost of product, its affordability and cost of implementation. With increasing recognition of the burden of meningococcal meningitis, especially during epidemics in Africa, it is vitally important that strategies are taken to reduce the morbidity and mortality attributable to this disease. Improved MC vaccines are a promising investment that could substantially contribute to reduction of child meningitis mortality world-wide.
Publisher: Public Library of Science (PLoS)
Date: 31-01-2013
Publisher: Public Library of Science (PLoS)
Date: 06-06-2013
Publisher: Public Library of Science (PLoS)
Date: 10-03-2011
Publisher: Public Library of Science (PLoS)
Date: 19-07-2012
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
DOI: 10.1038/NCOMMS11008
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry in iduals, we identify six novel loci ( FAM150B-ACP1 , LINC00340 , FBN1 , DIS3L-MAP2K1 , ARID2-SNAT1 and SLC14A2 ) associated with refractive error. In Asian populations, three genome-wide significant loci AREG , GABRR1 and PDE10A also exhibit strong interactions with education ( P .5 × 10 −5 ), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2022
DOI: 10.1101/2022.05.11.22274314
Abstract: Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. In idual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2016
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
DOI: 10.1038/S41467-018-04362-X
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486 age 16–102) and find 148 genome-wide significant independent loci ( P 5 × 10 −8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent s les. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2018
Publisher: Cold Spring Harbor Laboratory
Date: 07-11-2019
DOI: 10.1101/831321
Abstract: Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous in iduals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P 5×10 −8 ). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippoc us and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippoc us morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (r g = 0.26 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1038/NG.2385
Publisher: Public Library of Science (PLoS)
Date: 10-2015
Publisher: Springer Science and Business Media LLC
Date: 27-06-2010
DOI: 10.1038/NG.609
Publisher: Springer Science and Business Media LLC
Date: 09-2014
DOI: 10.1038/NATURE13673
Publisher: Springer Science and Business Media LLC
Date: 13-04-2011
DOI: 10.1186/1471-2458-11-S3-S31
Abstract: Measles was responsible for an estimated 100,000 deaths worldwide in 2008. Despite being a vaccine-preventable disease, measles remains a major cause of morbidity and mortality in young children. Although a safe and effective injectable measles vaccine has been available for over 50 years it has not been possible to achieve the uniformly high levels of coverage (required to achieve measles eradication) in most parts of the developing world. Aerosolised measles vaccines are now under development with the hope of challenging the delivery factors currently limiting the coverage of the existing vaccine. We used a modified CHNRI methodology for setting priorities in health research investments to assess the strengths and weaknesses of this emerging intervention to decrease the burden of childhood pneumonia. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging aerosol vaccines against measles relevant to several criteria of interest. Although there are a number of different aerosol vaccine approaches under development, for the purpose of this exercise, all were considered as one intervention. The criteria of interest were: answerability cost of development, production and implementation efficacy and effectiveness deliverability, affordability and sustainability maximum potential impact on disease burden reduction acceptability to the end users and health workers and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to the sensitive nature of their involvement in such exercises. They answered questions from the CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. The panel of experts expressed mixed feelings about an aerosol measles vaccine. The group expressed low levels of optimism regarding the criteria of likelihood of efficacy and low cost of development (scores around 50%) moderate levels of optimism regarding answerability, low cost of production, low cost of implementation and affordability (score around 60%) and high levels of optimism regarding deliverability, impact on equity and acceptability to health workers and end-users (scores over 80%). Finally, the experts felt that this intervention will have a modest but nevertheless important impact on reduction of burden of disease due to childhood pneumonia (median: 5%, interquartile range 1-15%, minimum 0%, maximum 45%). Aerosol measles vaccine is at an advanced stage of development, with evidence of good immunogenicity. This new intervention will be presented as a feasible candidate strategy in the c aign for global elimination of measles. It also presents an unique opportunity to decrease the overall burden of disease due to severe pneumonia in young children.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2021
Publisher: Springer Science and Business Media LLC
Date: 19-03-2020
DOI: 10.1038/S42003-020-0802-Y
Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 in iduals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11 / FBLN2 rs2630445, RBP3 rs11204213) others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2011
DOI: 10.1186/1471-2458-11-S3-S30
Abstract: Respiratory Syncytial Virus (RSV) is the leading cause of acute lower respiratory infections (ALRI) in children. It is estimated to cause approximately 33.8 million new episodes of ALRI in children annually, 96% of these occurring in developing countries. It is also estimated to result in about 53,000 to 199,000 deaths annually in young children. Currently there are several vaccine and immunoprophylaxis candidates against RSV in the developmental phase targeting active and passive immunization. We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging vaccines against RSV relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to the sensitive nature of their involvement in such exercises. They answered questions from the CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. In the case of candidate vaccines for active immunization of infants against RSV, the experts expressed very low levels of optimism for low product cost, affordability and low cost of development moderate levels of optimism regarding the criteria of answerability, likelihood of efficacy, deliverability, sustainability and acceptance to end users for the interventions and high levels of optimism regarding impact on equity and acceptance to health workers. While considering the candidate vaccines targeting pregnant women, the panel expressed low levels of optimism for low product cost, affordability, answerability and low development cost moderate levels of optimism for likelihood of efficacy, deliverability, sustainability and impact on equity high levels of optimism regarding acceptance to end users and health workers. The group also evaluated immunoprophylaxis against RSV using monoclonal antibodies and expressed no optimism towards low product cost very low levels of optimism regarding deliverability, affordability, sustainability, low implementation cost and impact on equity moderate levels of optimism against the criteria of answerability, likelihood of efficacy, acceptance to end-users and health workers and high levels of optimism regarding low development cost. They felt that either of these vaccines would have a high impact on reducing burden of childhood ALRI due to RSV and reduce the overall childhood ALRI burden by a maximum of about 10%. Although monoclonal antibodies have proven to be effective in providing protection to high-risk infants, their introduction in resource poor settings might be limited by high cost associated with them. Candidate vaccines for active immunization of infants against RSV hold greatest promise. Introduction of a low cost vaccine against RSV would reduce the inequitable distribution of burden due to childhood ALRI and will most likely have a high impact on morbidity and mortality due to severe ALRI.
Publisher: International Global Health Society
Date: 06-2017
Publisher: Public Library of Science (PLoS)
Date: 05-06-2009
Publisher: Oxford University Press (OUP)
Date: 17-03-2017
Abstract: The use of the emerging "omics" technologies for large scale population screening is promising in terms of predictive, preventive and personalized medicine. For Parkinson's disease, it is essential that an accurate diagnosis is obtained and disease progression can be monitored. Immunoglobulin G (IgG) has the ability to exert both anti-inflammatory and pro-inflammatory effects, and the N-glycosylation of the fragment crystallizable portion of IgG is involved in this process. This study aimed to determine whether the IgG glycome could be a candidate biomarker for Parkinson's disease. Ninety-four community-based in iduals with Parkinson's disease and a sex-, age- and ethnically-matched cohort of 102 in iduals with mixed phenotypes, representative of a "normally" aged Caucasian controls, were investigated. Plasma IgG glycans were analyzed by ultra-performance liquid chromatography. Overall, seven glycan peaks and 11 derived traits had statistically significant differences (P < 8.06 × 10-4) between Parkinson's disease cases and healthy controls. Out of the seven significantly different glycan peaks, four were selected by Akaike's Information Criterion to be included in the logistic regression model, with a sensitivity of 87.2% and a specificity of 92.2%. The study suggested that there may be a reduced capacity for the IgG to inhibit Fcγ-RIIIa binding, which would allow an increased ability for the IgG to cause antibody-dependent cell cytotoxicity and a possible state of low-grade inflammation in in iduals with Parkinson's disease.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2021
Publisher: Elsevier BV
Date: 11-2009
Publisher: Public Library of Science (PLoS)
Date: 19-08-2011
Publisher: Springer Science and Business Media LLC
Date: 28-09-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2009
Publisher: Public Library of Science (PLoS)
Date: 22-08-2013
Publisher: International Global Health Society
Date: 15-04-2022
Publisher: Oxford University Press (OUP)
Date: 19-12-2013
DOI: 10.1093/HMG/DDT620
Publisher: Public Library of Science (PLoS)
Date: 23-08-2017
Publisher: Springer Science and Business Media LLC
Date: 22-12-2017
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: Oxford University Press (OUP)
Date: 27-02-2013
DOI: 10.1093/HMG/DDT104
Publisher: Springer Science and Business Media LLC
Date: 09-02-2014
DOI: 10.1038/NG.2897
Publisher: Springer Science and Business Media LLC
Date: 09-2022
DOI: 10.1038/S41588-022-01165-1
Abstract: Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 in iduals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2010
DOI: 10.1038/NG.714
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: International Global Health Society
Date: 11-2017
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Igor Rudan.