119 results on '"Alexandra I. F. Blakemore"'
Search Results
2. Tracking physical activity using smart phone apps: assessing the ability of a current app and systematically collecting patient recommendations for future development.
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Jennifer Murphy, T. Uttamlal, Kelly Ann Schmidtke, Ivo Vlaev, David Taylor, Mian Ahmad, S. Alsters, P. Purkayastha, Samantha Scholtz, Ramin Ramezani, A. R. Ahmed, H. Chahal, Ara Darzi, and Alexandra I. F. Blakemore
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- 2020
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3. Relationship between BMI and emotion-handling capacity in an adult Finnish population: The Northern Finland Birth Cohort 1966.
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Nurul Hanis Ramzi, Andrianos M Yiorkas, Sylvain Sebert, Sirkka Keinänen-Kiukaanniemi, Leena Ala-Mursula, Rauli Svento, Jari Jokelainen, Juha Veijola, Juha Auvinen, Jouko Miettunen, Terence M Dovey, Marjo-Riitta Järvelin, and Alexandra I F Blakemore
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Medicine ,Science - Abstract
BACKGROUND:Alexithymia, a difficulty in identifying and expressing emotions, has been associated with obesity and eating disorders in small-scale cross-sectional studies. Here, we assess the relationship between body mass index (BMI) and alexithymia in a large cohort of free-living Finnish adults over a 15-year period. METHODS:Participants were drawn from the Northern Finnish Birth Cohort 1966 (NFBC1966). The 20-Item Toronto Alexithymia Scale (TAS-20) was used as a measure of alexithymia and was completed at the age of 31 years (31y: n = 4841), and 46 years (46y: n = 5404). BMI was recorded at both time points. Where data at both time points were available (n = 3274), the relationship between changes in BMI and TAS-20 over this time period was also investigated. RESULTS:BMI was significantly and positively associated with TAS-20 score (p
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- 2018
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4. Inferring combined CNV/SNP haplotypes from genotype data.
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Shu-Yi Su, Julian E. Asher, Marjo-Riitta Järvelin, Philippe Froguel, Alexandra I. F. Blakemore, David J. Balding, and Lachlan J. M. Coin
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- 2010
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5. Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis
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Alexandra I. F. Blakemore, Anthony A. James, Marinos Kyriakopoulos, Susanne Marwedel, Mitra S Sato, Clare Borsay, Anna C. Need, and Armandina Almanza Gutierrez
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0301 basic medicine ,Proband ,Genetics ,Mutation ,Psychosis ,business.industry ,medicine.disease ,medicine.disease_cause ,Developmental disorder ,03 medical and health sciences ,Psychiatry and Mental health ,030104 developmental biology ,0302 clinical medicine ,Intellectual disability ,Medicine ,Missense mutation ,Family history ,business ,Exome ,030217 neurology & neurosurgery ,Biological Psychiatry ,Genetics (clinical) - Abstract
Objective To identify genes underlying childhood onset psychosis. Methods Patients with onset of psychosis at age 13 or younger were identified from clinics across England, and they and their parents were exome sequenced and analysed for possible highly penetrant genetic contributors. Results We report two male childhood onset psychosis patients of different ancestries carrying hemizygous very rare possibly damaging missense variants (p.Arg846His and p.Pro145Ser) in the L1CAM gene. L1CAM is an X-linked Mendelian disease gene in which both missense and loss of function variants are associated with syndromic forms of intellectual disability and developmental disorder. Conclusions This is the first study reporting a possible extension of the phenotype of L1CAM variant carriers to childhood onset psychosis. The family history and presence of other significant rare genetic variants in the patients suggest that there may be genetic interactions modulating the presentation.
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- 2020
6. Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism.
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Suzanne I M Alsters, Anthony P Goldstone, Jessica L Buxton, Anna Zekavati, Alona Sosinsky, Andrianos M Yiorkas, Susan Holder, Robert E Klaber, Nicola Bridges, Mieke M van Haelst, Carel W le Roux, Andrew J Walley, Robin G Walters, Michael Mueller, and Alexandra I F Blakemore
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Medicine ,Science - Abstract
Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.
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- 2015
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7. famCNV: copy number variant association for quantitative traits in families.
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Hariklia Eleftherohorinou, Johanna C. Andersson-Assarsson, Robin G. Walters, Julia S. El-Sayed Moustafa, Lachlan J. M. Coin, Peter Jacobson, Lena M. S. Carlsson, Alexandra I. F. Blakemore, Philippe Froguel, Andrew J. Walley, and Mario Falchi
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- 2011
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8. How do lipids influence risk of violence, self-harm and suicidality in people with psychosis? A systematic review
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Danielle Adewusi, Alexandra I. F. Blakemore, Veena Kumari, and Piyal Sen
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Adult ,Male ,medicine.medical_specialty ,Psychosis ,Violence ,Suicidal Ideation ,03 medical and health sciences ,0302 clinical medicine ,sex ,Medicine ,Humans ,Psychiatry ,suicide ,Triglycerides ,business.industry ,Aggression ,aggression ,cholesterol ,General Medicine ,medicine.disease ,030227 psychiatry ,schizophrenia ,Lipoproteins, LDL ,Psychiatry and Mental health ,Suicide ,Harm ,Cholesterol ,Psychotic Disorders ,Schizophrenia ,Low cholesterol ,Female ,medicine.symptom ,business ,Self-Injurious Behavior ,030217 neurology & neurosurgery - Abstract
Objectives:Low cholesterol has been linked with violent and suicidal behaviour in people with schizophrenia. This association, if consistently present, may be a promising biological marker that could assist clinicians in decision making regarding risk and treatment. We conducted a systematic review to assess whether there is a reliable association between lipid profile (total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides) and aggression, self-harm or suicide in people with schizophrenia, and whether effects are similar in males and females.Method:Relevant databases were searched to identify primary research studies (up to November 2020) that (1) involved adults (some samples also included 16- to 18-year olds) with a confirmed diagnosis of schizophrenia, schizoaffective disorder or psychosis; and (2) included a standardised assessment of verbal aggression, physical aggression against objects, physical aggression against self (including suicide) or others. The search yielded 23 studies eligible for inclusion following a quality appraisal.Results:Suicidality was the most commonly assessed subtype of aggression (20 studies). For suicidality, about half the studies, including the study with the largest sample size, found a link with total cholesterol. An association between low total cholesterol and violence towards others was found in six of nine studies that investigated this. The evidence for a link with violence was the strongest for total cholesterol, followed by low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, and the weakest for triglycerides. Only a few studies investigated sex differences and yielded mixed evidence. Studies focussed on self-harm as well as involving females in forensic settings were lacking.Conclusion:There is encouraging evidence of an association between low total cholesterol and aggression towards others as well as suicidality in schizophrenia. Future studies should systematically explore this association in people with schizophrenia who have a significant history of violence, suicidality and self-harm, both inpatients and community, and also investigate underlying mechanisms.
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- 2021
9. Multiple measures of adiposity are associated with mean leukocyte telomere length in the northern Finland birth cohort 1966.
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Jessica L Buxton, Shikta Das, Alina Rodriguez, Marika Kaakinen, Alexessander Couto Alves, Sylvain Sebert, Iona Y Millwood, Jaana Laitinen, Paul F O'Reilly, Marjo-Riitta Jarvelin, and Alexandra I F Blakemore
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Medicine ,Science - Abstract
Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.
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- 2014
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10. Who will benefit from bariatric surgery for diabetes? A protocol for an observational cohort study
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Ahmed R. Ahmed, Julia Kenkre, Tricia Tan, Sanjay Purkayastha, Stephen R. Bloom, A Toby Prevost, Khalefah Malallah, Alexandra I. F. Blakemore, and Research Trainees Coordinating Centre
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Adult ,medicine.medical_specialty ,Gastric Bypass ,Bariatric Surgery ,030209 endocrinology & metabolism ,medicine.disease_cause ,Obesity, Bariatric Surgery, Diabetes Mellitus, Type 2 ,1117 Public Health and Health Services ,03 medical and health sciences ,0302 clinical medicine ,Medicine, General & Internal ,Diabetes mellitus ,General & Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,Obesity ,Prospective Studies ,adult surgery ,Trial registration ,nutrition & dietetics ,Protocol (science) ,Science & Technology ,Adult patients ,business.industry ,Gastric bypass surgery ,general diabetes ,Remission Induction ,Type 2 Diabetes Mellitus ,1103 Clinical Sciences ,General Medicine ,medicine.disease ,Surgery ,Obesity, Morbid ,Diabetes and Endocrinology ,Observational Studies as Topic ,Treatment Outcome ,Diabetes Mellitus, Type 2 ,Medicine ,business ,Life Sciences & Biomedicine ,Cohort study ,1199 Other Medical and Health Sciences - Abstract
IntroductionType 2 diabetes mellitus (T2DM) and obesity are pandemic diseases that lead to a great deal of morbidity and mortality. The most effective treatment for obesity and T2DM is bariatric or metabolic surgery; it can lead to long-term diabetes remission with 4 in 10 of those undergoing surgery having normal blood glucose on no medication 1 year postoperatively. However, surgery carries risks and, additionally, due to resource limitations, there is a restricted number of patients who can access this treatment. Moreover, not all those who undertake surgery respond equally well metabolically. The objective of the current research is to prospectively investigate predictors of T2DM response following metabolic surgery, including those directly involved in its aetiopathogenesis such as fat distribution and genetic variants. This will inform development of a clinically applicable model to help prioritise this therapy to those predicted to have remission.Methods and analysisA prospective multicentre observational cohort study of adult patients with T2DM and obesity undergoing Roux-en-Y gastric bypass surgery. Patients will be comprehensively assessed before surgery to determine their clinical, metabolic, psychological, genetic and fat distribution profiles. A multivariate logistic regression model will be used to assess the value of the factors derived from the preoperative assessment in terms of prediction of diabetes remission.Ethics and disseminationFormal ethics review was undertaken with a favourable opinion (UK HRA RES reference number 18/LO/0931). The dissemination plan is to present the results at conferences, in peer-reviewed journals as well as to lay media and to patient organisations.Trial registration detailsClinicalTrials.gov, Identifier: NCT03842475.
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- 2021
11. Secondary analyses of global datasets:do obesity and physical activity explain variation in diabetes risk across populations?
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Nader Lessan, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, and Budour Alkaf
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Male ,Diabetes risk ,Epidemiology ,Endocrinology, Diabetes and Metabolism ,Physical activity ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,Review Article ,Type 2 diabetes ,Biology ,Global Health ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Diabetes mellitus ,medicine ,Humans ,risk factors ,Obesity ,030212 general & internal medicine ,Risk factor ,Exercise ,Nutrition and Dietetics ,medicine.disease ,Variation (linguistics) ,Risk factors ,Diabetes Mellitus, Type 2 ,Homogeneous ,Female ,epidemiology ,Sedentary Behavior ,Demography - Abstract
Copyright © 2021 The Author(s). Type 2 diabetes rates vary significantly across geographic regions. These differences are sometimes assumed to be entirely driven by differential distribution of environmental triggers, including obesity and insufficient physical activity (IPA). In this review, we discuss data which conflicts with this supposition. We carried out a secondary analysis of publicly available data to unravel the relative contribution of obesity and IPA towards diabetes risk across different populations. We used sex-specific, age-standardized estimates from Non-Communicable Disease Risk Factor Collaboration (NCD-RisC) on diabetes (1980–2014) and obesity (1975–2016) rates, in 200 countries, and from WHO on IPA rates in 168 countries in the year 2016. NCD-RisC and WHO organized countries into nine super-regions. All analyses were region- and sex-specific. Although obesity has been increasing since 1975 in every part of the world, this was not reflected in a proportional increase in diabetes rates in several regions, including Central and Eastern Europe, and High-income western countries region. Similarly, the association of physical inactivity with diabetes is not homogeneous across regions. Countries from different regions across the world could have very similar rates of diabetes, despite falling on opposite ends of IPA rate spectrum. The combined effect of obesity and IPA on diabetes risk was analyzed at the worldwide and country level. The overall findings highlighted the larger impact of obesity on disease risk; low IPA rates do not seem to be protective of diabetes, when obesity rates are high. Despite that, some countries deviate from this overall observation. Sex differences were observed across all our analyses. Overall, data presented in this review indicate that different populations, while experiencing similar environmental shifts, are apparently differentially subject to diabetes risk. Sex-related differences observed suggest that males and females are either subject to different risk factor exposures or have different responses to them. The work presented in this paper is part of a PhD project by the first author (Budour Alkaf); internal funding by Imperial College London Diabetes Centre is gratefully acknowledged. The authors are also grateful for The Medical Research Council, UK (grant numbers: MR/M013138/1, MRC/BBSRC MR/S03658X/1 (JPI HDHL H2020)) for their financial support during the authors time when conducting this piece of work and writing this paper.
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- 2021
12. Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.
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Robin G Walters, Lachlan J M Coin, Aimo Ruokonen, Adam J de Smith, Julia S El-Sayed Moustafa, Sebastien Jacquemont, Paul Elliott, Tõnu Esko, Anna-Liisa Hartikainen, Jaana Laitinen, Katrin Männik, Danielle Martinet, David Meyre, Matthias Nauck, Claudia Schurmann, Rob Sladek, Gudmar Thorleifsson, Unnur Thorsteinsdóttir, Armand Valsesia, Gerard Waeber, Flore Zufferey, Beverley Balkau, François Pattou, Andres Metspalu, Henry Völzke, Peter Vollenweider, Kári Stefansson, Marjo-Riitta Järvelin, Jacques S Beckmann, Philippe Froguel, and Alexandra I F Blakemore
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Medicine ,Science - Abstract
The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.
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- 2013
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13. Long-term unemployment is associated with short telomeres in 31-year-old men: an observational study in the northern Finland birth cohort 1966.
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Leena Ala-Mursula, Jessica L Buxton, Ellen Ek, Markku Koiranen, Anja Taanila, Alexandra I F Blakemore, and Marjo-Riitta Järvelin
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Medicine ,Science - Abstract
Life stress resulting from early-life experiences and domestic stress is linked with shorter leukocyte telomere length (LTL), but evidence on employment-related stress is scarce. We explored whether unemployment in early adulthood is associated with shorter LTL, a potential biomarker of premature aging.We used data from 5620 men and women belonging to the Northern Finland Birth Cohort 1966. Individually registered unemployment days in 1995-97 were compared with data on biological, behavioral and socioeconomic health predictors and existing medical conditions obtained by surveys and clinical examinations at follow-up in 1997-98. Mean LTL at follow-up was measured by multiplex quantitative real-time PCR. We calculated odds ratios and their 95% confidence intervals (CI) of belonging to the sex-stratified shortest decile of standardized relative mean LTL according to the categories of: 0,
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- 2013
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14. Are C-reactive protein associated genetic variants associated with serum levels and retinal markers of microvascular pathology in Asian populations from Singapore?
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Rajkumar Dorajoo, Ruoying Li, Mohammad Kamran Ikram, Jianjun Liu, Philippe Froguel, Jeannette Lee, Xueling Sim, Rick Twee-Hee Ong, Wan Ting Tay, Chen Peng, Terri L Young, Alexandra I F Blakemore, Ching Yu Cheng, Tin Aung, Paul Mitchell, Jie Jin Wang, Caroline C Klaver, Eric Boerwinkle, Ronald Klein, David S Siscovick, Richard A Jensen, Vilmundur Gudnason, Albert Vernon Smith, Yik Ying Teo, Tien Yin Wong, E-Shyong Tai, Chew-Kiat Heng, and Yechiel Friedlander
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Medicine ,Science - Abstract
C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations.Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry.Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10(-8)) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058).Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease.
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- 2013
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15. Increased adiposity is protective for breast and prostate cancer: a Mendelian randomisation study using up to 132,413 breast cancer cases and 85,907 prostate cancer cases
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Fotios Drenos, Andrianos M. Yiorkas, Hasnat A Amin, Alexandra I. F. Blakemore, Heather Cooke, and Pimpika Kaewsri
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Oncology ,medicine.medical_specialty ,business.industry ,Cancer ,Odds ratio ,medicine.disease ,Body fat percentage ,Prostate cancer ,Breast cancer ,Internal medicine ,medicine ,Risk factor ,business ,Prospective cohort study ,Body mass index - Abstract
BackgroundBreast and prostate cancer are the first and second most common types of cancer in women and men, respectively. A recent campaign by Cancer Research UK emphasised obesity as being a causal risk factor for cancer, although previously published evidence is heterogenous. We aimed to explore the causal effect of adiposity on breast and prostate cancer risk in the UK Biobank (UKB), a large prospective cohort study, and published data.MethodsWe used Mendelian randomisation (MR) to assess the causal effect of body mass index (BMI), body fat percentage (BFP), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) on breast and prostate cancer risk.ResultsWe obtained estimates (odds ratios, OR, per SD unit increase) of the causal effect of the adiposity measures on breast and prostate cancer risk. BMI and HC decrease the risk of breast cancer (OR 0.776 [95% CIs 0.661-0.91] and OR 0.781 [95% CIs 0.649-0.94], respectively). WC, BFP, and BMI decrease the risk of prostate cancer (OR 0.602 [95% CIs 0.439-0.825], OR 0.629 [95% CIs 0.414-0.956], and OR 0.695 [95% CIs 0.553-0.874], respectively). The protective effect of adiposity on prostate cancer risk is enhanced in men who are exposed to potentially hazardous substances at work, and the association between BMI and breast cancer is confounded by variables associated with general health.ConclusionsIn conclusion, increasing adiposity is causally protective for breast and prostate cancer and the effects in prostate cancer may, at least partly, be due to the safe storage of chemicals in adipose cells. It is necessary to explore the mechanisms through which adiposity may protect against or be a risk factor for cancer, to identify how the latter can be minimised without sacrificing the former, and to base public health campaigns around sound evidence.HIGHLIGHTSPreviously published evidence regarding the effect of adiposity on prostate and breast cancer risk is heterogenousIncreasing BMI and hip circumference decrease the risk of breast cancer in womenIncreasing waist circumference, body fat percentage, and BMI decrease the risk of prostate cancerThe protective effect of adiposity on prostate cancer is stronger in men who are exposed to carcinogens at workPublic health campaigns need to target the negative aspects of adiposity whilst preserving the positive aspects
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- 2020
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16. Tracking physical activity using smart phone apps: assessing the ability of a current app and systematically collecting patient recommendations for future development
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David Taylor, Ramin Ramezani, Ivo Vlaev, T. Uttamlal, Jennifer Murphy, Ahmed R. Ahmed, Ara Darzi, P. Purkayastha, Mian Ahmad, Samantha Scholtz, Suzanne I. M. Alsters, Harvinder Chahal, Alexandra I. F. Blakemore, Kelly Ann Schmidtke, and National Institute of Health Research
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Male ,Cardiovascular ,Health informatics ,Oral and gastrointestinal ,0302 clinical medicine ,Physical activity monitoring ,030212 general & internal medicine ,Cancer ,Data Collection ,Health Policy ,Smartphone app ,Middle Aged ,Mobile Applications ,3. Good health ,Computer Science Applications ,Stroke ,lcsh:R858-859.7 ,Smartphone ,Psychology ,Inclusion (education) ,Research Article ,Information Systems ,Adult ,Adolescent ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Physical activity ,030209 endocrinology & metabolism ,Health Informatics ,lcsh:Computer applications to medicine. Medical informatics ,Young Adult ,03 medical and health sciences ,Clinical Research ,Humans ,Obesity ,Set (psychology) ,Exercise ,Metabolic and endocrine ,Aged ,Nutrition ,Medical education ,Descriptive statistics ,business.industry ,Prevention ,1103 Clinical Sciences ,United Kingdom ,Good Health and Well Being ,Mobile phone ,Facilitator ,0806 Information Systems ,Surgery ,Tracking (education) ,business ,RD ,Medical Informatics - Abstract
Background Within the United Kingdom’s National Health System (NHS), patients suffering from obesity may be provided with bariatric surgery. After receiving surgery many of these patients require further support to continue to lose more weight or to maintain a healthy weight. Remotely monitoring such patients’ physical activity and other health-related variables could provide healthworkers with a more ‘ecologically valid’ picture of these patients’ behaviours to then provide more personalised support. The current study assesses the feasibility of two smartphone apps to do so. In addition, the study looks at the barriers and facilitators patients experience to using these apps effectively. Methods Participants with a BMI > 35 kg/m2 being considered for and who had previously undergone bariatric surgery were recruited. Participants were asked to install two mobile phone apps. The ‘Moves’ app automatically tracked participants’ physical activity and the ‘WLCompanion’ app prompted participants to set goals and input other health-related information. Then, to learn about participants’ facilitators and barriers to using the apps, some participants were asked to complete a survey informed by the Theoretical Domains Framework. The data were analysed using regressions and descriptive statistics. Results Of the 494 participants originally enrolled, 274 participants data were included in the analyses about their activity pre- and/or post-bariatric surgery (ages 18–65, M = 44.02, SD ± 11.29). Further analyses were performed on those 36 participants whose activity was tracked both pre- and post-surgery. Participants’ activity levels pre- and post-surgery did not differ. In addition, 54 participants’ survey responses suggested that the main facilitator to their continued use of the Moves app was its automatic nature, and the main barrier was its battery drain. Conclusions The current study tracked physical activity in patients considered for and who had previously undergone bariatric surgery. The results should be interpreted with caution because of the small number of participants whose data meet the inclusion criteria and the barriers participants encountered to using the apps. Future studies should take note of the barriers to develop more user-friendly apps. Trial registration ClinicalTrials.gov- NCT01365416 on the 3rd of June 2011.
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- 2020
17. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
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Joris Deelen, Antonia Trichopoulou, Sara Hägg, Kim Overvad, Elisabete Weiderpass, Iryna O. Fedko, Rudolf Kaaks, Nicola D. Kerrison, Kirsi H. Pietiläinen, Ida Surakka, Veikko Salomaa, Svetlana Stoma, Jaakko Kaprio, Alessandra Allione, Cornelia M. van Duijn, Nicholas G. Martin, Veryan Codd, Olle Melander, Nilesh J. Samani, Josine E. Verhoeven, Anne Tjønneland, Natalia Pervjakova, Domenico Palli, Adam S. Butterworth, Nicholas J. Wareham, María Dolores Chirlaque, P. Eline Slagboom, Massimo Mangino, Pascal P. Arp, Christopher P. Nelson, Brenda W.J.H. Penninx, Jessica L. Buxton, Pietro Ferrari, Tao Jiang, Iiris Hovatta, Taylor K. Loe, N. Charlotte Onland-Moret, Salvatore Panico, Peter Jones, Heiner Boeing, Timothy J. Key, Luca A. Lotta, Miguel Rodríguez-Barranco, Diana van Heemst, Chen Li, Robert A. Scott, Sarah E. Medland, Giuseppe Matullo, Alexessander Couto Alves, Rosario Tumino, Jouke-Jan Hottenga, Ken K. Ong, Vittorio Krogh, Gonneke Willemsen, Andres Metspalu, Eva Albrecht, Elina Sillanpää, Johan G. Eriksson, Najaf Amin, Dale R. Nyholt, Reedik Mägi, Eros Lazzerini Denchi, Peter M. Nilsson, André G. Uitterlinden, Antonio Agudo, Yuri Milaneschi, Ashley van der Spek, Alessia Russo, Linda Broer, Federico Canzian, Marian Beekman, Grant W. Montgomery, Sophie C Warner, Guy Fagherazzi, Markus Perola, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Robert Karlsson, Tim D. Spector, Paul W. Franks, H. Eka D. Suchiman, Claudia Langenberg, Liher Imaz, Nancy L. Pedersen, Scott D. Gordon, Stephen E. Hamby, J. Ramón Quirós, Yvonne T. van der Schouw, Concha Moreno, Christian Gieger, Pekka Jousilahti, Dorret I. Boomsma, Marc J. Gunter, Benjamin Miraglio, Gianluca Severi, John Danesh, UNIVERSITY OF OULU, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, APH - Methodology, Sociology and Social Gerontology, Li, Chen [0000-0002-6423-6325], Ong, Kenneth [0000-0003-4689-7530], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, University of Helsinki, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, HUS Abdominal Center, Department of Medicine, Endokrinologian yksikkö, Clinicum, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, HUS Helsinki and Uusimaa Hospital District, Department of Psychology and Logopedics, Genetics, SLEEPWELL Research Program, Department of Public Health, Mind and Matter, Internal Medicine, and Epidemiology
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Netherlands Twin Register (NTR) ,Limfomes ,LOCI ,Genome-wide association study ,Disease ,VARIANTS ,DISEASE ,0302 clinical medicine ,Leukocytes ,telomere length ,GWAS ,Genetics(clinical) ,Càncer ,Mendelian randomisation ,Thyroid cancer ,Genetics (clinical) ,11 Medical and Health Sciences ,Cancer ,Genetics ,Genetics & Heredity ,RISK ,0303 health sciences ,Telòmer ,age-related disease ,biological aging ,Humans ,Nucleotides ,Genome-Wide Association Study ,Telomere ,meta-analyysi ,genomiikka ,Genomics ,CANCER ,3. Good health ,030220 oncology & carcinogenesis ,MENDELIAN RANDOMIZATION ,Medical genetics ,Biomarker (medicine) ,HEART ,Lymphomas ,Life Sciences & Biomedicine ,Medical Genetics ,medicine.medical_specialty ,GENES ,DATABASE ,Age-related Disease ,Biological Aging ,Mendelian Randomisation ,Telomere Length ,Biology ,Article ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Mendelian randomization ,medicine ,Journal Article ,030304 developmental biology ,Medicinsk genetik ,Science & Technology ,06 Biological Sciences ,medicine.disease ,Genòmica ,ikääntyminen ,1182 Biochemistry, cell and molecular biology ,telomeerit ,biological - Abstract
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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- 2020
18. Variation at the Klotho gene locus does not affect cognitive function in up to 335,074 British Caucasians in the UK Biobank
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Hasnat A Amin, Fotios Drenos, and Alexandra I. F. Blakemore
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0303 health sciences ,business.industry ,Haplotype ,Cognition ,Locus (genetics) ,Biobank ,Cognitive health ,03 medical and health sciences ,0302 clinical medicine ,Prospective memory ,Medicine ,10. No inequality ,business ,Klotho ,030217 neurology & neurosurgery ,030304 developmental biology ,Demography - Abstract
The proportion of older adults in Western populations is increasing and there is, therefore, a need to define factors affecting maintenance of physical and cognitive health in old age. Variations in the Klotho (KL) gene, and specifically the KL-VS haplotype, have been identified by several authors as potentially influencing cognitive function and decline. We have attempted to verify the reported associations between KL variants, including the KL-VS haplotype, and cognitive function in up to 335,074 British Caucasian participants aged 40-79 years from the UK Biobank. We do not find evidence that KL-VS affects cognitive function or its decline with increasing age. We examined a further 244 KL variants and found that rs117650866 was associated with Prospective Memory, but could not replicate this in follow-up samples. In conclusion, there is insufficient evidence in the UK Biobank to support the concept that KL variants affect cognitive function or its rate of decline.
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- 2019
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19. Small deletion variants have stable breakpoints commonly associated with alu elements.
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Adam J de Smith, Robin G Walters, Lachlan J M Coin, Israel Steinfeld, Zohar Yakhini, Rob Sladek, Philippe Froguel, and Alexandra I F Blakemore
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Medicine ,Science - Abstract
Copy number variants (CNVs) contribute significantly to human genomic variation, with over 5000 loci reported, covering more than 18% of the euchromatic human genome. Little is known, however, about the origin and stability of variants of different size and complexity. We investigated the breakpoints of 20 small, common deletions, representing a subset of those originally identified by array CGH, using Agilent microarrays, in 50 healthy French Caucasian subjects. By sequencing PCR products amplified using primers designed to span the deleted regions, we determined the exact size and genomic position of the deletions in all affected samples. For each deletion studied, all individuals carrying the deletion share identical upstream and downstream breakpoints at the sequence level, suggesting that the deletion event occurred just once and later became common in the population. This is supported by linkage disequilibrium (LD) analysis, which has revealed that most of the deletions studied are in moderate to strong LD with surrounding SNPs, and have conserved long-range haplotypes. Analysis of the sequences flanking the deletion breakpoints revealed an enrichment of microhomology at the breakpoint junctions. More significantly, we found an enrichment of Alu repeat elements, the overwhelming majority of which intersected deletion breakpoints at their poly-A tails. We found no enrichment of LINE elements or segmental duplications, in contrast to other reports. Sequence analysis revealed enrichment of a conserved motif in the sequences surrounding the deletion breakpoints, although whether this motif has any mechanistic role in the formation of some deletions has yet to be determined. Considered together with existing information on more complex inherited variant regions, and reports of de novo variants associated with autism, these data support the presence of different subgroups of CNV in the genome which may have originated through different mechanisms.
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- 2008
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20. Associations of Leukocyte Telomere Length With Aerobic and Muscular Fitness in Young Adults
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Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Jessica L. Buxton, Dylan M. Williams, Marko T. Kantomaa, and Tuija Tammelin
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0301 basic medicine ,Gerontology ,INDICATORS ,Male ,Epidemiology ,Original Contributions ,Trunk structure ,Physical fitness ,CAPABILITY ,Body Mass Index ,telomere length ,Leukocytes ,Medicine ,European commission ,Biological sciences ,health care economics and organizations ,Finland ,media_common ,Public, Environmental & Occupational Health ,2. Zero hunger ,NORTHERN FINLAND ,aerobic fitness ,handgrip strength ,BIRTH COHORT ,Hand Strength ,Age Factors ,11 Medical And Health Sciences ,University hospital ,3. Good health ,CARDIOVASCULAR-DISEASE ,biological aging ,GRIP STRENGTH ,Female ,HEALTH ,Northern Finland Birth Cohorts ,sports ,Life Sciences & Biomedicine ,Adult ,CAPACITY ,03 medical and health sciences ,Sex Factors ,media_common.cataloged_instance ,Humans ,Muscle Strength ,European union ,01 Mathematical Sciences ,Science & Technology ,business.industry ,MORTALITY ,Telomere Homeostasis ,Muscle endurance ,Mental health ,030104 developmental biology ,PHYSICAL-ACTIVITY ,Cross-Sectional Studies ,Physical Fitness ,Physical Endurance ,business ,biological - Abstract
Decline in both telomere length and physical fitness over the life course may contribute to increased risk of several chronic diseases. The relationship between telomere length and aerobic and muscular fitness is not well characterized. We examined whether there are cross-sectional associations of mean relative leukocyte telomere length (LTL) with objective measures of aerobic fitness, muscle strength, and muscle endurance, using data on 31-year-old participants of the Northern Finland Birth Cohort 1966 (n = 4,952-5,205, varying by exposure-outcome analysis). Aerobic fitness was assessed by means of heart rate measurement following a standardized submaximal step test; muscular fitness was assessed by means of a maximal isometric handgrip strength test and a test of lower-back trunk muscle endurance. Longer LTL was associated with higher aerobic fitness and better trunk muscle endurance in models including adjustment for age, sex, body mass index, socioeconomic position, diet, smoking, alcohol consumption, physical activity level, and C-reactive protein. In a sex-stratified analysis, LTL was not associated with handgrip strength in either men or women. LTL may relate to aspects of physical fitness in young adulthood, but replication of these findings is required, along with further studies to help assess directions and causality in these associations. This work was supported financially by the following institutions: the Academy of Finland (grants 104781, 120315, 129269, 1114194, and 12926); University Hospital Oulu, Biocenter, University of Oulu (grant 75617); the European Commission (grant QLG1-CT-2000-01643); the National Heart, Lung, and Blood Institute, US National Institutes of Health (grant 5R01HL087679-02); the National Institute of Mental Health, US National Institutes of Health (grant 5R01MH63706:02); the Medical Research Council, United Kingdom (grants G0500539 and G0600705); the Wellcome Trust, United Kingdom (grant GR069224); and Diabetes UK (grant 08/0003775). J.L.B. was supported by a Wellcome Trust Fellowship (grant WT088431MA). D.M.W. and M.R.J. were supported by the European Union’s Horizon 2020 research and innovation program under grant agreement DynaHEALTH (grant 633595).
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- 2017
21. Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation
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Wieland Kiess, Josée Dupuis, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, George Dedoussis, Frida Renström, Carolina Medina-Gomez, Tamara B. Harris, Cramer Christensen, Audrey Y. Chu, Nicola L. Beer, Emil V. R. Appel, Niels Grarup, Fredrik Karpe, Mark I. McCarthy, Yuning Chen, Veikko Salomaa, Sylvain Sebert, Richard A. Jensen, Joel N. Hirschhorn, Lars Lind, Jocelyn E. Manning Fox, Caroline Hayward, Patrick E. MacDonald, Matti Uusitupa, Stavroula Kanoni, Carola Marzi, Kenneth Rice, Leslie A. Lange, Ken Sin Lo, Jennifer L. Asimit, Nisa M. Maruthur, Leonard Lipovich, James S. Floyd, Rona J. Strawbridge, Magdalena Zoledziewska, Anne Raimondo, Robert Sladek, Alexandra I. F. Blakemore, Hugoline G. de Haan, Danish Saleheen, Ji Chen, Neil Robertson, Ching-Yu Cheng, Heiner Boeing, Min A. Jhun, Marjo-Riitta Järvelin, Anubha Mahajan, Rainer Rauramaa, Satu Männistö, Paul M. Ridker, Ivan Brandslund, Hester M. den Ruijter, Tien Yin Wong, Alison D. Murray, Jaakko Tuomilehto, Xueling Sim, Igor Rudan, Martijn van de Bunt, Jin Li, Marit E. Jørgensen, Marie-France Hivert, Archie Campbell, Salman M. Tajuddin, Pekka Jousilahti, Lawrence F. Bielak, Juan P. Fernandez, Eleanor Wheeler, Alan B. Zonderman, Anne Clark, Lori L. Bonnycastle, Kurt Lohman, Peter Kovacs, Jung-Jin Lee, Jennifer Wessel, Wesam A Alhejily, Gerard Pasterkamp, John M. Starr, Ping An, Matthias Blüher, Jian'an Luan, Hanieh Yeghootkar, Jakob Stokholm, Michael Roden, Blair H. Smith, Johanna Jakobsdottir, Franco Giulianini, Andrianos M. Yiorkas, Hidetoshi Kitajima, Michael A. Province, Aliki-Eleni Farmaki, Kerrin S. Small, Juha Saltevo, Robert A. Scott, Alena Stančáková, Gaëlle Marenne, Asif Rasheed, Ruth J. F. Loos, David J. Porteous, Cecilia M. Lindgren, Inês Barroso, Gail Davies, Anna L. Gloyn, Shuai Wang, Paul Redmond, Xiuqing Guo, Ele Ferrannini, Mariaelisa Graff, Cornelia M. van Duijn, Juha Auvinen, David R. Weir, Kay-Tee Kaw, Tarunveer S. Ahluwalia, Olov Rolandsson, Wei Zhao, Paul Elliott, Torben Hansen, Abbas Dehghan, Bram P. Prins, Michiel L. Bots, Alison Pattie, Jun Liu, Gonçalo R. Abecasis, Maria Karaleftheri, Claudia Langenberg, Jan-Håkan Jansson, Marja Vääräsmäki, James S. Pankow, Rebecca S. Fine, Jaana Lindström, Ozren Polasek, Vinicius Tragante, Soren K. Thomsen, Jana K. Rundle, Najaf Amin, Saima Afaq, Jennifer A. Smith, Anne U. Jackson, Eirini Marouli, Weihua Zhang, Tim D. Spector, Paul W. Franks, Serena Sanna, Mark J. Caulfield, Heikki A. Koistinen, Jaspal S. Kooner, Tea Skaaby, Francis S. Collins, Eva Rabing Brix Petersen, Arfan Ikram, Sander W. van der Laan, Johanna Kuusisto, Jette Bork-Jensen, Daniel I. Chasman, Michele K. Evans, Emmanouil Tsafantakis, A. I. Tarasov, Ian J. Deary, Hans Bisgaard, Dennis O. Mook-Kanamori, Helen R. Warren, Kent D. Taylor, Andrew D. Morris, Eleftheria Zeggini, Sharon L.R. Kardia, Emma Ahlqvist, Gert J. de Borst, Torben Jørgensen, Antonella Mulas, Man Li, Betina H. Thuesen, Yuan Shi, Timo A. Lakka, Jie Yao, Tapani Ebeling, Natasha H. J. Ng, Sai Chen, Leena Kinnunen, Antje Körner, Klaus Bønnelykke, Lorraine Southam, Anette P. Gjesing, Ilonca Vaartjes, Heather M. Highland, Göran Hallmans, Anke Tönjes, Markku Laakso, Lenore J. Launer, Josef Coresh, Oscar H. Franco, Yongmei Liu, Beverley Balkau, Leena Moilanen, Karl-Heinz Herzig, James G. Wilson, Jennifer A. Brody, Renée de Mutsert, Alisa K. Manning, Anne E. Justice, Matthias B. Schulze, Sandosh Padmanabhan, Jose C. Florez, Shuang Feng, Heather M. Stringham, Bruce M. Psaty, Erwin P. Bottinger, Hannu Puolijoki, Vilmundur Gudnason, Leif Groop, Nicholas J. Wareham, Karina Meidtner, Andrew P. Morris, Taulant Muka, Benoit Hastoy, Panos Deloukas, Pirjo Komulainen, Ayse Demirkan, Francesco Cucca, Stefan Gustafsson, Eric Boerwinkle, Patrik Rorsman, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Allan Linneberg, Tiinamaija Tuomi, Dan E. Arking, Steve Franks, Jonathan Marten, Mark Walker, Ruifang Li-Gao, Kai Savonen, Michael Stumvoll, Andreas Fritsche, E-Shyong Tai, Mark O. Goodarzi, Matt J. Neville, Oluf Pedersen, Eero Kajantie, Ching-Ti Liu, Michael Boehnke, Aaron Leong, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, John C. Chambers, John Danesh, Sirkka Keinänen-Kiukaanniemi, Giorgio Pistis, Karen L. Mohlke, Folkert W. Asselbergs, James B. Meigs, Tibor V. Varga, Erica L. Kleinbrink, Andrew T. Hattersley, Nathan A. Bihlmeyer, Harald Grallert, Albert V. Smith, Konstantin Strauch, Jerome I. Rotter, and Frits R. Rosendaal
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medicine.medical_specialty ,G6PC2 ,pathways ,Adipose tissue ,Type 2 diabetes ,Biology ,effector transcript ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Diabetes mellitus ,Internal medicine ,0502 economics and business ,medicine ,Glucose homeostasis ,genetics ,050207 economics ,030304 developmental biology ,Glycemic ,0303 health sciences ,050208 finance ,Pancreatic islets ,05 social sciences ,tissue ,Genomics ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,chemistry ,glycemic traits ,Glycated hemoglobin ,type 2 diabetes ,030217 neurology & neurosurgery - Abstract
SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia
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- 2019
22. New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders
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Jessica D. Faul, Ilja M. Nolte, Alexandra I. F. Blakemore, Raha Pazoki, Marjo-Riitta Järvelin, Andrew C. Heath, Adrian Rothenfluh, Nicholas G. Martin, Catharina A. Hartman, Paul Blakeley, Michael Boehnke, Paul M. Matthews, Dan E. Arking, Jennifer A. Smith, Yuri Milaneschi, James F. Wilson, Alena Stančáková, Laura J. Scott, Jie Yao, Paul Elliott, Sharon L.R. Kardia, Peter K. Joshi, Niki Dimou, Leo-Pekka Lyytikäinen, Tim D. Spector, Ozren Polasek, Pim van der Harst, Sylvane Desrivières, Bing Yu, Brenda W.J.H. Penninx, Katherine A. Kentistou, Michael Kühne, Mika Kähönen, Hideaki Suzuki, Ioanna Tzoulaki, Daniel Levy, Congying Chu, Johan G. Eriksson, Minna Männikkö, Markku Laakso, Anne U. Jackson, Sebastian E. Baumeister, Hans J. Grabe, Massimo Mangino, Albertine J. Oldehinkel, Evangelos Evangelou, Caroline Hayward, Niek Verweij, Penelope A. Lind, Lorenz Risch, Harold Snieder, Andrianos M. Yiorkas, Andrew R. Butts, David Conen, Toni-Kim Clarke, Harry Campbell, Fotios Koskeridis, Johanna Kuusisto, Alexis C. Wood, Karen L. Mohlke, Mia-Maria Perälä, Jerome I. Rotter, Gunter Schumann, Wei Zhao, Terho Lehtimäki, Ibrahim Karaman, Olli T. Raitakari, Rozenn N. Lemaitre, David J. Porteous, Michael R. Brown, Xiuqing Guo, Igor Rudan, Juha Auvinen, David R. Weir, Christopher P. Nelson, Traci M. Bartz, Peter S. Braund, Bruce M. Psaty, Alanna C. Morrison, Alexander Teumer, Nilesh J. Samani, Georg Homuth, Jennifer A. Brody, Joshua Elliott, John Whitfield, He Gao, Andrew M. McIntosh, Georgios Ntritsos, Samuli Tuominen, Sébastien Thériault, Chunyu Liu, Juha Veijola, Stefanie Aeschbacher, Jimmy D. Bell, Scott M. Ratliff, Jagadish Vangipurapu, Qiang Luo, Jari Lahti, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Academic Medical Center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Digital Health, Imperial College Healthcare NHS Trust- BRC Funding, Health Data Research Uk, National Institute for Health Research, Medical Research Council (MRC), and UK DRI Ltd
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Male ,LOCI ,Social Sciences ,Genome-wide association study ,physiopathology [Brain] ,VARIANTS ,genetics [Mental Disorders] ,Cardiovascular ,Oral and gastrointestinal ,genetics [Genes] ,Behavioral Neuroscience ,Alcohol Use and Health ,Substance Misuse ,0302 clinical medicine ,ddc:150 ,PARKINSONS-DISEASE ,DEPENDENCE ,Epidemiology ,Psychology ,2.1 Biological and endogenous factors ,risk factors ,genetics [Schizophrenia] ,genetics ,genetics [Genetic Predisposition to Disease] ,Aetiology ,610 Medicine & health ,Cancer ,Genetics ,RISK ,0303 health sciences ,Psychology, Biological ,Psychology, Experimental ,Mental Disorders ,Brain ,Single Nucleotide ,Middle Aged ,Serious Mental Illness ,Biobank ,Magnetic Resonance Imaging ,Multidisciplinary Sciences ,Stroke ,physiology [Genes] ,Alcoholism ,Mental Health ,Schizophrenia ,Meta-analysis ,genetics [Polymorphism, Single Nucleotide] ,Science & Technology - Other Topics ,Female ,Life Sciences & Biomedicine ,Biotechnology ,EXPRESSION ,Adult ,medicine.medical_specialty ,Social Psychology ,Alcohol Drinking ,Quantitative Trait Loci ,genetics [White People] ,Experimental and Cognitive Psychology ,Neuroimaging ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,Article ,White People ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,Aged ,European Continental Ancestry Group ,Genes ,Genome-Wide Association Study ,GENOME-WIDE ASSOCIATION ,Polymorphism ,METAANALYSIS ,030304 developmental biology ,Genetic association ,Science & Technology ,genetics [Quantitative Trait Loci] ,Human Genome ,Neurosciences ,CONSUMPTION ,medicine.disease ,Genetic architecture ,Brain Disorders ,Good Health and Well Being ,genetics [Alcoholism] ,genetics [Alcohol Drinking] ,Neurosciences & Neurology ,HIGH-DENSITY-LIPOPROTEIN ,030217 neurology & neurosurgery - Abstract
H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. I.K. was supported by the EU PhenoMeNal project (Horizon 2020, grant no. 654241) and the UK Dementia Research Institute, which is supported by the MRC, the Alzheimer’s Society and Alzheimer’s Research UK. S. Thériault was supported by the Canadian Institutes of Health Research and Université Laval (Quebec City, Canada). L.R. was supported by Forschungs- und Förder-Stiftung INOVA, Vaduz, Liechtenstein. D.C. holds a McMaster University Department of Medicine Mid-Career Research Award. M.B. is supported by NIH grant R01-DK062370. P.v.d.H. was supported by ICIN-NHI and Marie Skłodowska-Curie GF (call: H2020-MSCA-IF-2014; Project ID: 661395). C.H. was supported by a core MRC grant to the MRCHGU QTL in Health and Disease research programme. N.V. was supported by Marie Skłodowska-Curie GF (grant no. 661395) and ICIN-NHI. Q.L. is partially supported by the National Natural Sciences Foundation of China (No. 81873909), Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01) and ZJLab. P.E. acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141), the Medical Research Council (MRC) and Public Health England (PHE) Centre for Environment and Health (MR/L01341X/1) and Health Data Research (HDR) UK. P.E. is supported by a UK Dementia Research Institute (DRI) professorship, UK DRI at Imperial College London, funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK. This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology; LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders; grant no. 695313), ERANID (Understanding the interplay between cultural, biological and subjective factors in drug use pathways; PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics; MR/N027558/1), the FP7 projects IMAGEMEND (grant no. 602450; IMAging GEnetics for MENtal Disorders) and MATRICS (grant no. 603016), the Innovative Medicine Initiative Project EU-AIMS (grant. no115300-2), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions; MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; and Forschungsnetz AERIAL 01EE1406A and 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2 and SFB 940/2), the Medical Research Foundation and Medical Research Council (MR/R00465X/1), the Human Brain Project (HBP SGA 2). Further support was provided by grants from ANR (project AF12-NEUR0008-01-WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1); and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence.
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- 2019
23. Limitations of the DiaRem Score in Predicting Remission of Diabetes Following Roux-En-Y Gastric Bypass (RYGB) in an ethnically Diverse Population from a Single Institution in the UK
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Tricia Tan, George Tharakan, Harvinder Chahal, Alexander D. Miras, Ahmed R. Ahmed, Alexandra I. F. Blakemore, Olivia Szepietowski, Rebecca Scott, and Sanjay Purkayastha
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Male ,Original Contributions ,Endocrinology, Diabetes and Metabolism ,0302 clinical medicine ,OBESE-PATIENTS ,Health Status Indicators ,Medicine ,030212 general & internal medicine ,Single institution ,Diabetes remission ,education.field_of_study ,Nutrition and Dietetics ,Remission Induction ,Diabetes ,Middle Aged ,Prognosis ,Roux-en-Y anastomosis ,Obesity, Morbid ,DiaRem ,1117 Public Health And Health Services ,Cohort ,Female ,Life Sciences & Biomedicine ,Adult ,medicine.medical_specialty ,Population ,Gastric bypass ,Gastric Bypass ,Black People ,030209 endocrinology & metabolism ,White People ,03 medical and health sciences ,Asian People ,RYGB ,Internal medicine ,Diabetes mellitus ,Humans ,education ,Retrospective Studies ,Bariatric surgery ,Science & Technology ,business.industry ,Type 2 Diabetes Mellitus ,1103 Clinical Sciences ,Ethnically diverse ,medicine.disease ,Surgery ,Diabetes Mellitus, Type 2 ,business - Abstract
Purpose This study aimed to determine the predictive power of the DiaRem score following Roux-en-Y gastric bypass to identify patients who would have diabetes remission at 1 year in an ethnically diverse population. Methods We performed a retrospective review of 262 patients with type 2 diabetes mellitus who underwent RYGB at the Imperial Weight Centre, UK, from 2007 to 2014. Data was collected on the parameters required to calculate the DiaRem score as well as pre- and post-surgical weight and the ethnicity of the subjects. Results The studied cohort was ethnically diverse (61.3 % Caucasian, 10.3 % Asian, 5.3 % black, 2.6 % mixed and 20.6 % other). At 1-year post-surgery, there were significant reductions in mean weight (133.4 to 94.3 kg) and BMI (46.7 to 33.3 kg/m2). The mean HbA1c decreased from 8.2 to 6.1 %, and 32.5 % of the cohort underwent either partial or complete remission. 67.8 % of the patients that were classified in group 1 of the DiaRem score (most likely to have remission) had complete remission. However, 22.9 % of the patients predicted to have the least chance of remission had either partial or complete remission. Conclusions In this ethnically diverse cohort, the DiaRem score remains a useful tool to predict diabetes remission in those that have a low DiaRem score (high chance for remission) but was more limited in its predictive power in those with a high DiaRem score (least likely to have remission). Caution must be used in the application of this model in populations other than the US white Caucasian population used to derive the score.
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- 2016
24. Guidelines for the follow-up of patients undergoing bariatric surgery
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Su Sethi, Iris MacMillan, Mary O'Kane, Manisha Sharma, Carly A Hughes, Jacqueline Joyce, Tamara Puplampu, Julian H. Barth, Sean Woodcock, Alexandra I. F. Blakemore, Kenneth Clare, and Helen M Parretti
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Service (business) ,Terms of reference ,medicine.medical_specialty ,Shared care ,Project commissioning ,business.industry ,Endocrinology, Diabetes and Metabolism ,Nice ,030209 endocrinology & metabolism ,Surgery ,03 medical and health sciences ,Patient safety ,0302 clinical medicine ,Weight loss ,Medicine ,030212 general & internal medicine ,medicine.symptom ,business ,computer ,Reference group ,computer.programming_language - Abstract
Summary Bariatric surgery can facilitate weight loss and improvement in medical comorbidities. It has a profound impact on nutrition, and patients need access to follow-up and aftercare. NICE CG189 Obesity emphasized the importance of a minimum of 2 years follow-up in the bariatric surgical service and recommended that following discharge from the surgical service, there should be annual monitoring as part of a shared care model of chronic disease management. NHS England Obesity Clinical Reference Group commissioned a multi-professional subgroup, which included patient representatives, to develop bariatric surgery follow-up guidelines. Terms of reference and scope were agreed upon. The group members took responsibility for different sections of the guidelines depending on their areas of expertise and experience. The quality of the evidence was rated and strength graded. Four different shared care models were proposed, taking into account the variation in access to bariatric surgical services and specialist teams across the country. The common features include annual review, ability for a GP to refer back to specialist centre, submission of follow-up data to the national data base to NBSR. Clinical commissioning groups need to ensure that a shared care model is implemented as patient safety and long-term follow-up are important.
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- 2016
25. 25-Hydroxyvitamin D Concentration and Leukocyte Telomere Length in Young Adults: Findings From the Northern Finland Birth Cohort 1966
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Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Saranya Palaniswamy, Dylan M. Williams, Jessica L. Buxton, Sylvain Sebert, Elina Hyppönen, Wellcome Trust, Williams, Dylan M, Palaniswamy, Saranya, Sebert, Sylvain, Buxton, Jessica L, Blakemore, Alexandra IF, Hyppönen, Elina, and Jarvelin, Marjo-Riitta
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Male ,Gerontology ,Epidemiology ,Original Contributions ,vitamin D ,VITAMIN-D STATUS ,Northern finland ,Body Mass Index ,0302 clinical medicine ,telomere length ,Leukocytes ,Medicine ,European commission ,Prospective Studies ,030212 general & internal medicine ,Young adult ,Finland ,Public, Environmental & Occupational Health ,Adiposity ,media_common ,RISK ,2. Zero hunger ,WOMEN ,ASSOCIATION ,11 Medical And Health Sciences ,Telomere ,University hospital ,3. Good health ,C-Reactive Protein ,CARDIOVASCULAR-DISEASE ,biological aging ,MENDELIAN RANDOMIZATION ,Female ,Northern Finland Birth Cohorts ,Birth cohort ,Life Sciences & Biomedicine ,Adult ,030209 endocrinology & metabolism ,Young Adult ,D DEFICIENCY ,03 medical and health sciences ,Humans ,media_common.cataloged_instance ,European union ,METAANALYSIS ,01 Mathematical Sciences ,Calcifediol ,Science & Technology ,business.industry ,MORTALITY ,Telomere Homeostasis ,Mental health ,BODY-MASS INDEX ,Cross-Sectional Studies ,Chronic disease ,030228 respiratory system ,business ,Body mass index ,biological ,030217 neurology & neurosurgery ,Demography - Abstract
Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m)2) with mean relative leukocyte telomere length (LTL) using data gathered on 5,096 participants from Northern Finland Birth Cohort 1966 at age 31 years (1997). 25(OH)D was not associated with LTL in either basic or confounder/mediator-adjusted models. BMI was inversely associated with LTL after adjustment for potential confounding by age, sex, socioeconomic position, physical activity, diet, smoking, alcohol intake, and use of oral contraceptives (per 1-unit increase in BMI, mean difference in LTL = −0.4%, 95% confidence interval: −0.6, −0.2). The BMI-LTL association was also independent of 25(OH)D and was attenuated slightly, but remained, after adjustment for C-reactive protein, a marker of low-grade inflammation (mean difference in LTL = −0.3%, 95% confidence interval −0.6, −0.1). These findings suggest that vitamin D status is unlikely to be an important determinant of LTL, at least by young adulthood. Inflammation may partly mediate associations of adiposity with LTL. This work was supported financially by the following institutions: the Academy of Finland (grants 104781, 120315, 129269, 1114194, 24300796, and 12926); University Hospital Oulu and Biocenter Oulu, University of Oulu (grant 75617); the European Commission (grant QLG1-CT-2000- 01643); the National Heart, Lung, and Blood Institute, US National Institutes of Health (grant 5R01HL087679-02); the National Institute of Mental Health, US National Institutes of Health (grant 5R01MH63706:02); the Medical Research Council (grants G0500539, G0600705, G0601653, and K014536); the Wellcome Trust (grant GR069224); and Diabetes UK (grant 08/0003775). J.L.B. was supported by a Wellcome Trust Fellowship grant (WT088431MA). D.M.W., S.S., and M.-R.J. were supported by the European Union’s Horizon 2020 research and innovation program under grant agreement DynaHEALTH (633595).
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- 2016
26. Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders
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Raha Pazoki, Michael R. Brown, Albertine J. Oldehinkel, Evangelos Evangelou, Bruce M. Psaty, Caroline Hayward, Penelope A. Lind, Harry Campbell, Sylvane Desrivières, Leo-Pekka Lyytikäinen, Harold Snieder, Niek Verweij, Igor Rudan, Rozenn N. Lemaitre, Andrianos M. Yiorkas, David Conen, Ozren Polasek, Mia-Maria Perälä, Jennifer A. Smith, Christopher P. Nelson, Wei Zhao, Ilja M. Nolte, Michael Kühne, Mika Kähönen, Jessica D. Faul, Sharon L.R. Kardia, Peter K. Joshi, Ibrahim Karaman, Paul M. Matthews, Adrian Rothenfluh, Jari Lahti, Alexandra I. F. Blakemore, John Whitfield, Alexander Teumer, James F. Wilson, Alena Stančáková, Marjo-Riitta Järvelin, David R. Weir, Peter S. Braund, Andrew M. McIntosh, Scott M. Ratliff, Nicholas G. Martin, Hideaki Suzuki, Georgios Ntritsos, Niki Dimou, Bing Yu, Andrew R. Butts, Alanna C. Morrison, Gunter Schumann, Michael Boehnke, Paul Elliott, Samuli Tuominen, Paul Blakeley, Xiuqing Guo, Massimo Mangino, Yuri Milaneschi, Brenda W.J.H. Penninx, Daniel Levy, Juha Auvinen, Jie Yao, Hans J. Grabe, David J. Porteous, Laura J. Scott, Lorenz Risch, Katherine A. Kentistou, Jagadish Vangipurapu, Stefanie Aeschbacher, Terho Lehtimäki, Markku Laakso, Jimmy D. Bell, Fotios Koskeridis, Anne U. Jackson, Karen L. Mohlke, Catharina A. Hartman, Ioanna Tzoulaki, Sebastian E. Baumeister, Dan E. Arking, Alexis C. Wood, Sébastien Thériault, Johanna Kuusisto, Pim van der Harst, Chunyu Liu, Juha Veijola, Georg Homuth, Jennifer A. Brody, Traci M. Bartz, Andrew C. Heath, He Gao, Toni-Kim Clarke, Jerome I. Rotter, Tim D. Spector, Congying Chu, Johan G. Eriksson, Minna Männikkö, Olli T. Raitakari, Nilesh J. Samani, and Joshua Elliott
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Genetics ,0303 health sciences ,Genome-wide association study ,Biology ,medicine.disease ,Excessive alcohol consumption ,Genetic architecture ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Schizophrenia ,Trait ,medicine ,Functional significance ,Functional studies ,Alcohol consumption ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.
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- 2018
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27. A neurobiological pathway to smoking in adolescence: TTC12-ANKK1-DRD2 variants and reward response
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Jürgen Gallinat, Sylvane Desrivières, Uli Bromberg, Pimphen Charoen, Arun L.W. Bokde, Christine Macare, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Tobias Banaschewski, Francesca Ducci, Gunter Schumann, Barbara Ruggeri, Tomáš Paus, Hugh Garavan, Marcus R. Munafò, Filippo Casoni, Herta Flor, Christian Büchel, Gursharan Kalsi, Juha Veijola, Marika Kaakinen, Andreas Heinz, Jean-Luc Martinot, Jessica L. Buxton, Penny A. Gowland, Yuning Zhang, Vincent Frouin, Matthew Hill, Tianye Jia, Bernd Ittermann, Patricia J. Conrod, Mark Lathrop, Jan Peters, Macare, C., Ducci, F., Zhang, Y., Ruggeri, B., Jia, T., Kaakinen, M., Kalsi, G., Charoen, P., Casoni, F., Peters, J., Bromberg, U., Hill, M., Buxton, J., Blakemore, A., Veijola, J., Buchel, C., Banaschewski, T., Bokde, A. L. W., Conrod, P., Flor, H., Frouin, V., Gallinat, J., Garavan, H., Gowland, P. A., Heinz, A., Ittermann, B., Lathrop, M., Martinot, J. -L., Paus, T., Desrivieres, S., Munafo, M., Jarvelin, M. -R., and Schumann, G.
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0301 basic medicine ,Male ,Striatum ,Protein-Serine-Threonine Kinase ,Brain and Behaviour ,chemistry.chemical_compound ,DOPAMINE ,0302 clinical medicine ,Medicine ,Pharmacology (medical) ,Risk taking ,Pharmacology & Pharmacy ,Cotinine ,11 Medical and Health Sciences ,media_common ,Psychiatry ,ANKK1 ,BIRTH COHORT ,SERUM COTININE ,Tobacco and Alcohol ,Dopaminergic ,fMRI ,Smoking ,Brain ,ASSOCIATION ,HUMAN BRAIN ,Protein-Serine-Threonine Kinases ,Anticipation ,Magnetic Resonance Imaging ,17 Psychology and Cognitive Sciences ,Psychiatry and Mental health ,ADDICTION ,Neurology ,Meta-analysis ,Female ,Life Sciences & Biomedicine ,Human ,Clinical psychology ,Adolescent ,media_common.quotation_subject ,Clinical Neurology ,Genetic Association Studie ,Protein Serine-Threonine Kinases ,Article ,03 medical and health sciences ,Genetic ,Reward ,Genetics ,Humans ,Meta-analysi ,Association (psychology) ,IMAGEN Consortium ,Biological Psychiatry ,Genetic Association Studies ,Pharmacology ,VULNERABILITY ,Science & Technology ,business.industry ,Receptors, Dopamine D2 ,Protein ,Addiction ,Neurosciences ,Genetic Variation ,Proteins ,Anticipation, Psychological ,NICOTINE DEPENDENCE ,Behavior, Addictive ,030104 developmental biology ,chemistry ,Adolescent Behavior ,IMAGEN-ALSPAC-NFBC ,Neurology (clinical) ,Neurosciences & Neurology ,CIGARETTE-SMOKING ,business ,030217 neurology & neurosurgery ,biological - Abstract
The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (N = 14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (p = 5.0 × 10−4) and higher plasma cotinine levels (p = 7.0 × 10−5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (n = 1,263) and with higher DRD2 gene expression in the striatum (p = 0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking.
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- 2018
28. Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype Is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension
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Anna Murray, Francesca Frau, Dennis O. Mook-Kanamori, Samuel E. Jones, Andrianos M. Yiorkas, Michael N. Weedon, Rachel M. Freathy, Andrew R. Wood, Andrew T. Hattersley, Ewan R. Pearson, Harald Staiger, Hanieh Yaghootkar, Robin N Beaumont, Caroline Hayward, Marcus A. Tuke, Alexandra I. F. Blakemore, Hans-Ulrich Häring, Norbert Stefan, Renée de Mutsert, Anubha Mahajan, Archie Campbell, Timothy M. Frayling, Jessica Tyrrell, Jürgen Machann, Karla V. Allebrandt, Yingjie Ji, Jimmy D. Bell, Naeimeh Atabaki-Pasdar, Katherine S. Ruth, E. Louise Thomas, and Paul W. Franks
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0301 basic medicine ,Male ,Endocrinology, Diabetes and Metabolism ,LOCI ,Adipose tissue ,Type 2 diabetes ,Body fat percentage ,0302 clinical medicine ,11 Medical and Health Sciences ,Adiposity ,INSULIN-RESISTANCE ,ASSOCIATION ,Middle Aged ,Magnetic Resonance Imaging ,Hypertension ,Female ,Life Sciences & Biomedicine ,Adult ,medicine.medical_specialty ,Intra-Abdominal Fat ,Heart Diseases ,METABOLICALLY-OBESE ,030209 endocrinology & metabolism ,Endocrinology & Metabolism ,03 medical and health sciences ,Insulin resistance ,BETA-CELL FUNCTION ,Internal medicine ,GLYCEMIC TRAITS ,Internal Medicine ,medicine ,Humans ,Obesity ,METAANALYSIS ,NORMAL-WEIGHT ,Aged ,Science & Technology ,IDENTIFICATION ,business.industry ,Waist-Hip Ratio ,medicine.disease ,BODY-MASS INDEX ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Metabolic syndrome ,business ,Body mass index ,Genome-Wide Association Study - Abstract
Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such “favourable adiposity” alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined magnetic resonance imaging (MRI) data with genome-wide association studies (GWAS) of body fat % and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity, but a favourable metabolic profile. Consistent with previous studies, individuals carrying more “favourable adiposity” alleles had higher body fat % and higher BMI, but lower risk of type 2 diabetes, heart disease and hypertension. These individuals also had higher subcutaneous fat, but lower liver fat and lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14 and IRS1, whilst the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified “favourable adiposity” alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglyceride in metabolically low risk depots. Diabetes UK RD Lawrence fellowship, European Research Council, Wellcome Trust and Royal Society grant, European Regional Development Fund, Medical Research Council, German Federal Ministry of Education and Research, German Research Foundation, Innovative Medicines Initiative Joint Undertaking, European Union's Seventh Framework Programme, Dutch Science Organisation, Scottish Government Health Directorates, Scottish Funding Council and Medical Research Council UK and the Wellcome Trust.
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- 2018
29. The prognostic significance and relationship with body composition of CCR7-positive cells in colorectal cancer
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Stella C. Knight, Hafid O. Al-Hassi, John T. Jenkins, Alexandra I. F. Blakemore, David Bernardo, Morgan Moorghen, George Malietzis, and Gui Han Lee
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Oncology ,medicine.medical_specialty ,Pathology ,Tumor microenvironment ,Multivariate analysis ,business.industry ,Lymphovascular invasion ,Colorectal cancer ,C-C chemokine receptor type 7 ,General Medicine ,medicine.disease ,Immune system ,Internal medicine ,Carcinoma ,Medicine ,Immunohistochemistry ,Surgery ,business - Abstract
Background and Objectives The host local immune response (LIR) to cancer is a determinant of cancer outcome. Regulation of this local response is largely achieved through chemokine synthesis from the tumor microenvironment such as C-Chemokine-Receptor-7 (CCR7). We examined the LIR measured as CCR7 expression, in colorectal cancers (CRC) and explored relationships with body composition (BC) and survival. Methods A study of paraffin-embedded tissue specimens was carried out in 116 patients with non-metastatic CRC. CCR7 expression was determined by immunohistochemistry. Analysis of computer tomography scans was used to calculate BC parameters. Survival analyses and multivariate regression models were used. Results High CCR7+ cell density within the tumor stroma and at the margin was significantly associated with increased age, the presence of lymphovascular invasion, higher tumor stage, lymph node metastasis, high Klintrup-Makinen immune score, and myosteatosis. High CCR7+ cell density in the tumor margin was significantly associated with shorter disease-free (DFS) and overall survival (OS) (P
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- 2015
30. Genetic Determinants of Leucocyte Telomere Length in Children: a Neglected and Challenging Field
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Maria G. Stathopoulou, Philippe Froguel, Alexandros M. Petrelis, Jessica L. Buxton, Sophie Visvikis-Siest, and Alexandra I. F. Blakemore
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2. Zero hunger ,Telomere-binding protein ,Genetics ,0303 health sciences ,Epidemiology ,business.industry ,Genome-wide association study ,Locus (genetics) ,Disease ,Environmental exposure ,Bioinformatics ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Genetic epidemiology ,Pediatrics, Perinatology and Child Health ,Medicine ,business ,Body mass index ,030217 neurology & neurosurgery ,030304 developmental biology ,Genetic association - Abstract
BACKGROUND: Telomere length is associated with a large range of human diseases. Genome-wide association studies (GWAS) have identified genetic variants that are associated with leucocyte telomere length (LTL). However, these studies are limited to adult populations. Nevertheless, childhood is a crucial period for the determination of LTL, and the assessment of age-specific genetic determinants, although neglected, could be of great importance. Our aim was to provide insights and preliminary results on genetic determinants of LTL in children. METHODS: Healthy children (n = 322, age range = 6.75-17 years) with available GWAS data (Illumina Human CNV370-Duo array) were included. The LTL was measured using multiplex quantitative real-time polymerase chain reaction. Linear regression models adjusted for age, gender, parental age at child's birth, and body mass index were used to test the associations of LTL with polymorphisms identified in adult GWAS and to perform a discovery-only GWAS. RESULTS: The previously GWAS-identified variants in adults were not associated with LTL in our paediatric sample. This lack of association was not due to possible interactions with age or gene × gene interactions. Furthermore, a discovery-only GWAS approach demonstrated six novel variants that reached the level of suggestive association (P ≤ 5 × 10(-5)) and explain a high percentage of children's LTL. CONCLUSIONS: The study of genetic determinants of LTL in children may identify novel variants not previously identified in adults. Studies in large-scale children populations are needed for the confirmation of these results, possibly through a childhood consortium that could better handle the methodological challenges of LTL genetic epidemiology field.
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- 2015
31. New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals
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Anne-Claire Vergnaud, Tibor V. Varga, Melissa A. Richard, Jaakko Tuomilehto, Louise V. Wain, Leif Groop, Reedik Mägi, Danish Saleheen, Olle Melander, Marcus Dörr, He Zhang, Alena Stančáková, Michael Boehnke, Claudia Langenberg, Paul Elliott, Adam S. Butterworth, Andrianos M. Yiorkas, Yingchang Lu, Tea Skaaby, George Dedoussis, Xiuqing Guo, Robin Young, Cristiano Fava, Timo A. Lakka, Igor Rudan, Riccardo E. Marioni, Helen R. Warren, Ioanna Tzoulaki, Myriam Fornage, Bruce M. Psaty, Tõnu Esko, Najaf Amin, Vilmundur Gudnason, Ozren Polasek, Yongmei Liu, Panos Deloukas, Paul M. Ridker, Vinicius Tragante, John M. C. Connell, Mark J. Caulfield, Jette Bork-Jensen, Giovanni Malerba, Eric Boerwinkle, Alanna C. Morrison, Todd L. Edwards, Teresa Ferreira, Torben Hansen, Aldi T. Kraja, He Gao, Alaitz Poveda, Praveen Surendran, Christopher Newton-Cheh, Christian Theil Have, Cramer Christensen, Daniel I. Chasman, Paul W. Franks, Ian J. Deary, Xueling Sim, Evangelos Evangelou, Roby Joehanes, Daniel R. Witte, Cristina Menni, Niels Grarup, Weihua Zhang, Eleftheria Zeggini, Anubha Mahajan, Nora Franceschini, Fredrik Karpe, Lars Lind, Rainer Rauramaa, Oluf Pedersen, Pim van der Harst, Jeanette M. Stafford, Alisa K. Manning, Lori L. Bonnycastle, Rudolf A. de Boer, Kenneth Rice, Nicholas J. Wareham, Tiinamaija Tuomi, Charles Kooperberg, Alexandra I. F. Blakemore, Kathleen Stirrups, Marjo-Riitta Järvelin, Michael A. Province, Marit E. Jørgensen, Allan Linneberg, Veikko Salomaa, Albert V. Smith, Cornelia M. van Duijn, Hao Mei, Mark I. McCarthy, Nilesh J. Samani, Anna F. Dominiczak, Joanna M. M. Howson, Erik Ingelsson, Colin N. A. Palmer, Markku Laakso, Karen L. Mohlke, Folkert W. Asselbergs, Sarah E. Harris, Ayush Giri, Daniel Levy, Anne Mari Käräjämäki, Michael R. Barnes, Aliki-Eleni Farmaki, Muhammad Riaz, Lorraine Southam, Karl-Heinz Herzig, Caroline Hayward, Nigel W. Rayner, John Danesh, Ruth J. F. Loos, Jennifer A. Smith, Ivan Brandslund, Neil Poulter, Jerome I. Rotter, Peter S. Sever, Chunyu Liu, John M. Starr, Stefan Weiss, Georg Ehret, Cecilia M. Lindgren, Walter Palmas, Fotios Drenos, Jaspal S. Kooner, Göran Hallmans, Megan L. Grove, Patricia B. Munroe, Andrew P. Morris, Aki S. Havulinna, James P. Cook, John C. Chambers, Cristen J. Willer, Claudia P. Cabrera, Sharon L.R. Kardia, Peter van der Meer, James G. Wilson, Louis Little, Sandosh Padmanabhan, Oksa Heikki, Franco Giulianini, Giovanni Gambaro, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Ehret, Georg Benedikt, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, British Heart Foundation, Imperial College Healthcare NHS Trust- BRC Funding, Epidemiology, Medical Informatics, Medical Oncology, Internal Medicine, and Gastroenterology & Hepatology
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0301 basic medicine ,Candidate gene ,Cardiac & Cardiovascular Systems ,Databases, Factual ,Neuronal ,Association Studies ,Genome-wide association study ,Blood Pressure ,030204 cardiovascular system & hematology ,VARIANTS ,Lymphocyte Homing ,DISEASE ,Antiporters ,Cell Adhesion Molecules, Neuronal/genetics ,0302 clinical medicine ,Genotype ,Receptors ,Missense mutation ,Settore MED/14 - NEFROLOGIA ,FUNCTIONAL VARIATION ,CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group† ,genetics ,Exome ,Genetics (clinical) ,Genetics ,Genetics & Heredity ,ddc:616 ,Antiporters/genetics ,Microfilament Proteins ,blood pressure ,Single Nucleotide ,sample size ,Phenotype ,COMPARATIVE RISK-ASSESSMENT ,exome ,genotype ,Cell Adhesion Molecules, Neuronal ,Genome-Wide Association Study ,Humans ,Polymorphism, Single Nucleotide ,Receptors, Lymphocyte Homing ,Genetic Loci ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,SCAVENGER RECEPTOR ,Understanding Society Scientific Group ,Blood Pressure/genetics ,Neuronal/genetics ,Locus (genetics) ,Biology ,Gene Expression and Regulation ,1102 Cardiovascular Medicine And Haematology ,03 medical and health sciences ,Databases ,Microfilament Proteins/genetics ,SYSTEMATIC ANALYSIS ,Journal Article ,GENOME-WIDE ASSOCIATION ,Polymorphism ,COMMON ,Receptors, Lymphocyte Homing/genetics ,Factual ,Genetic association ,0604 Genetics ,Science & Technology ,FAT DISTRIBUTION ,GLOBAL BURDEN ,Minor allele frequency ,030104 developmental biology ,Cardiovascular System & Hematology ,Cardiovascular System & Cardiology ,Cell Adhesion Molecules ,Lymphocyte Homing/genetics - Abstract
Background— Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results— Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant ( P − 8 ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP ), rs7437940 ( AFAP1 ), rs13303 (missense, STAB1 ), and rs1055144 ( 7p15.2 ). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L ) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency DBH ) was genome-wide significant. Conclusions— We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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- 2017
32. Determinants of post-prandial plasma bile acid kinetics in human volunteers
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Tim J. van den Broek, Andrianos M. Yiorkas, Alexandra I. F. Blakemore, Suzan Wopereis, Milena Rundle, Jarlei Fiamoncini, Hannelore Daniel, Kurt Gedrich, Thomas Clavel, Ilias Lagkouvardos, Gary Frost, Ben van Ommen, Sanne I Alsters, Guus Roeselers, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Medicine, Imperial College London, Brunel University, Partenaires INRAE, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Division of Diabetes, Endocrinology & Metabolism, Imperial College London-Department of Medicine, Netherlands Organisation for Applied Scientific Research, Danone Nutricia Research, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), TUM School of Life Sciences Weihenstephan, and RWTH Aachen University
- Subjects
0301 basic medicine ,Enterohepatic circulation ,Male ,Unclassified drug ,Taurine ,Physiology ,Deoxycholic acid ,Genomic DNA ,Glycoursodeoxycholic acid ,Biomedical Innovation ,postprandial ,Taurodeoxycholic acid ,chemistry.chemical_compound ,0302 clinical medicine ,Life ,Chenodeoxycholic acid ,Cholic acid ,Bile acid synthesis ,Quantitative analysis ,Taurochenodeoxycholic acid ,Glycodeoxycholic acid ,Bile acid ,Postprandial ,Gastroenterology ,Glycocholic acid ,Fasting ,Middle Aged ,Postprandial Period ,3. Good health ,Clinical trial ,Phenotype ,Blood ,Ursodeoxycholic acid ,Randomized controlled trial ,Female ,Tauroursodeoxycholic acid ,Healthy Living ,medicine.medical_specialty ,medicine.drug_class ,Metabolic Clearance Rate ,Weight reduction ,Glycine ,SLCO1A2 ,Oral glucose tolerance test ,Biology ,oral glucose tolerance test ,Bile acid blood level ,Bile Acids and Salts ,03 medical and health sciences ,Diet restriction ,mixed-meal tolerance test ,Physiology (medical) ,Internal medicine ,Weight Loss ,medicine ,Humans ,Liquid chromatography-mass spectrometry ,bile acids ,Glycochenodeoxycholic acid ,Postprandial state ,Hepatology ,Feces microflora ,Dietary intake ,Whole exome sequencing ,Taurolitocholic acid ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Genome analysis ,Taurocholic acid ,Sex difference ,Mixed-meal tolerance test ,Bile acids ,Solute carrier organic anion transporter 1A2 ,Kinetics ,030104 developmental biology ,Endocrinology ,MSB - Microbiology and Systems Biology ,chemistry ,Gene expression ,ELSS - Earth, Life and Social Sciences ,Controlled study ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,030217 neurology & neurosurgery - Abstract
Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women (n = 72, 62 ± 8 yr, mean ± SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed-meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography-tandem mass spectrometry combined with whole genome exome sequencing and fecal microbiota profiling. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma BA profiles. Fasting and postprandial BA profiles revealed high interindividual variability, and three main patterns in postprandial BA response were identified using multivariate analysis. Although the women enrolled were postmeno-pausal, effects of sex difference in BA response were evident. Exome data revealed the contribution of preselected genes to the observed interindividual variability. In particular, a variant in the SLCO1A2 gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases. Fecal microbiota analysis did not reveal evidence for a significant influence of bacterial diversity and/or composition on plasma BA profiles. The analysis of plasma BA profiles in response to two different dietary challenges revealed a high interindividual variability, which was mainly determined by genetics and sex difference of host with minimal effects of the microbiota. NEW & NOTEWORTHY Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma bile acid (BA) profiles. Despite high interindividual variability, three main patterns in postprandial BA response were identified using multivariate analysis. A variant in the SLCO1A2 gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases in response to both the oral glucose tolerance test and the mixed-meal tolerance test. © 2017, American Physiological Society. All rights reserved. Chemicals/CAS: chenodeoxycholic acid, 474-25-9; cholic acid, 32500-01-9, 361-09-1, 81-25-4; deoxycholic acid, 83-44-3; glycine, 56-40-6, 6000-43-7, 6000-44-8; glycochenodeoxycholic acid, 640-79-9; glycocholic acid, 475-31-0; glycodeoxycholic acid, 16409-34-0, 360-65-6; taurine, 107-35-7; taurochenodeoxycholic acid, 516-35-8; taurocholic acid, 145-42-6, 59005-70-8, 81-24-3; taurodeoxycholic acid, 1180-95-6, 516-50-7; tauroursodeoxycholic acid, 14605-22-2; ursodeoxycholic acid, 128-13-2, 2898-95-5; Bile Acids and Salts
- Published
- 2017
33. Telomere Length in Circulating Leukocytes is Associated with Lung Function and Disease
- Author
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Alexessander Couto Alves, Kirsi H. Pietiläinen, Cornelia M. van Duijn, Pamela A. F. Madden, Massimo Mangino, Iiris Hovatta, Stefan Karrasch, Alexandra I. F. Blakemore, Anjali K. Henders, Marjo-Riitta Järvelin, Ben A. Oostra, Seppo Sarna, Annette Peters, Eco J. C. de Geus, H.-Erich Wichmann, Ana Viñuela, Nilesh J. Samani, Christopher P. Nelson, Linda Broer, Elina Sillanpää, Ida Surakka, Christian Gieger, Konstantin Strauch, Jessica L. Buxton, Markku Peltonen, Taina Rantanen, Sarianna Sipilä, Holger Schulz, Eva Albrecht, Nicholas G. Martin, Veryan Codd, Patrik K. E. Magnusson, Jaakko Kaprio, Melanie Waldenberger, Nancy L. Pedersen, Najaf Amin, Gonneke Willemsen, Dale R. Nyholt, Rudolf A. Jörres, Joachim Heinrich, Dorret I. Boomsma, Juergen Behr, Manuel A. R. Ferreira, Hell M. Backmand, Päivi Piirilä, Tim D. Spector, Aila Rissanen, Tellervo Korhonen, Rudolf M. Huber, Sara Hägg, Epidemiology, Clinical Genetics, Public Health, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes
- Subjects
Lung Diseases ,Male ,Pulmonary and Respiratory Medicine ,Spirometry ,Netherlands Twin Register (NTR) ,Vital capacity ,Vital Capacity ,ennenaikainen vanheneminen ,Disease ,Cohort Studies ,Pathogenesis ,Pulmonary Disease, Chronic Obstructive ,Telomere Homeostasis ,SDG 3 - Good Health and Well-being ,Forced Expiratory Volume ,astma ,Leukocytes ,Humans ,COPD ,Medicine ,keuhkoahtaumatauti ,Aged ,Asthma ,telomeeri ,medicine.diagnostic_test ,premature aging ,business.industry ,Smoking ,Case-control study ,ta3141 ,Middle Aged ,Telomere ,spirometria ,medicine.disease ,biologinen ikä ,biological age ,3. Good health ,respiratory tract diseases ,Europe ,Case-Control Studies ,Immunology ,Regression Analysis ,Female ,business - Abstract
Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
- Published
- 2014
34. A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism
- Author
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Julia M. Keogh, Richard J. Ellis, Mehul T. Dattani, Robin G. Walters, Susan E. Holder, I. Sadaf Farooqi, Stephen O'Rahilly, Mieke M. van Haelst, Giles S.H. Yeo, U. L. Fairbrother, Carolin Purmann, Philippe Froguel, Angela F. Brady, Elana Henning, Adam J. de Smith, Alexandra I. F. Blakemore, University of Groningen, Other departments, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
- Subjects
Male ,Molecular Sequence Data ,RECOMBINATION ,DEFINE ,Biology ,Hyperphagia ,Young Adult ,Hypogonadotropic hypogonadism ,Genetics ,medicine ,Humans ,RNA, Small Nucleolar ,Amino Acid Sequence ,Obesity ,BREAKPOINTS ,Small nucleolar RNA ,Molecular Biology ,Genotyping ,Gene ,Genetics (clinical) ,Chromosomes, Human, Pair 15 ,Hypogonadism ,Breakpoint ,Chromosome ,Chromosome Mapping ,CLUSTER ,General Medicine ,Articles ,medicine.disease ,Phenotype ,GENE ,DEFICIENCY ,PRADER-WILLI-SYNDROME ,Sequence Alignment ,Comparative genomic hybridization ,ALU ELEMENTS - Abstract
Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight in humans. We report a 19-year-old male with hyperphagia and severe obesity, mild learning difficulties and hypogonadism, in whom diagnostic tests for Prader-Willi syndrome (PWS) had been negative. We carried out detailed clinical and metabolic phenotyping of this patient and investigated the genetic basis of this obesity syndrome using Agilent 185 k array comparative genomic hybridization (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification and long-range PCR, followed by breakpoint sequencing which enabled precise localization of the deletion. We identified a approximately 187 kb microdeletion at chromosome 15q11-13 that encompasses non-coding small nucleolar RNAs (including HBII-85 snoRNAs) which were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism and growth failure. We have identified a novel deletion on chromosome 15q11-13 in an individual with hyperphagia, obesity, hypogonadism and other features associated with PWS, which is normally caused by deficiency of several paternally expressed imprinted transcripts within chromosome 15q11-13, a region that includes multiple protein-coding genes as well as several non-coding snoRNAs. These findings provide direct evidence for the role of a particular family of non-coding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction.
- Published
- 2016
35. Quantified-Self for Obesity: Physical Activity Behaviour Sensing to Improve Health Outcomes
- Author
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David, Taylor, Jennifer, Murphy, Mian, Ahmad, Sanjay, Purkayastha, Samantha, Scholtz, Ramin, Ramezani, Ivaylo, Vlaev, Alexandra I F, Blakemore, and Ara, Darzi
- Subjects
Adult ,Male ,Patient Outcome Assessment ,Self Care ,Treatment Outcome ,Bariatric Surgery ,Humans ,Female ,Obesity ,Smartphone ,Actigraphy ,Exercise ,Exercise Therapy - Abstract
Physical activity levels in bariatric patients have not been well documented, despite their importance in maintaining weight loss following surgery. This study investigated the feasibility of tracking physical activity using a smartphone app with minimal user interaction. Thus far, we have obtained good quality data from 255 patients at various points in their weight loss journey. Preliminary analyses indicate little change in physical activity levels following surgery with pre-surgery patients reaching an average of 16 minutes per day and post-surgery patients achieving a daily average of 21 minutes. Further analyses using machine-learning techniques will be conducted to determine whether physical activity is a critical factor in distinguishing between successful and unsuccessful weight loss outcomes and in the resolution of comorbid conditions in patients with similar clinical profiles.
- Published
- 2016
36. Body composition of the host influences dendritic cell phenotype in patients treated for colorectal cancer
- Author
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Hafid O. Al-Hassi, John T. Jenkins, David Bernardo, Stella C. Knight, Robin H. Kennedy, Morgan Moorghen, Alexandra I. F. Blakemore, Gui Han Lee, George Malietzis, Biotechnology and Biological Sciences Research Cou, Biotechnology and Biological Sciences Research Council, and London North West Healthcare NHS Trust (LNWH)
- Subjects
0301 basic medicine ,Adult ,Male ,Myeloid ,CD36 ,C-C chemokine receptor type 7 ,Peripheral blood mononuclear cell ,Body composition ,Dendritic cells ,03 medical and health sciences ,Antigen ,Medicine ,Cytotoxic T cell ,Humans ,Oncology & Carcinogenesis ,Aged ,CD40 ,biology ,business.industry ,hemic and immune systems ,1103 Clinical Sciences ,General Medicine ,Dendritic cell ,Middle Aged ,Flow Cytometry ,Colorectal cancer ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Immunology ,Myopenia ,biology.protein ,Female ,business ,Colorectal Neoplasms ,Tomography, X-Ray Computed - Abstract
Dendritic cells (DCs) are antigen-presenting cells that can acquire tumour antigens and initiate cytotoxic T cell reactions. Obesity has been proposed as a cause for tumours escaping immune surveillance, but few studies investigate the impact of other body composition parameters. We examined the relationship of DC phenotype with computer tomography (CT)-defined parameters in patients with colorectal cancer (CRC). DCs were identified within peripheral blood mononuclear cells by flow cytometry as HLA-DR positive and negative for markers of other cell lineages in 21 patients. Analysis of CT scans was used to calculate lumbar skeletal muscle index (LSMI) and mean muscle attenuation (MA). Positive correlation between the LSMI and expression of CD40 in all DCs (r = 0.45; p = 0.04) was demonstrated. The MA was positively correlated with scavenger receptor CD36 [all DCs (r = 0.60; p = 0.01) and myeloid DCs (r = 0.63; p
- Published
- 2016
37. Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity
- Author
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Julian E. Asher, David Meyre, Philippe Froguel, Robert Sladek, Mario Falchi, Christian Dina, Andrew Walley, Lachlan J. M. Coin, Lena M. S. Carlsson, Hariklia Eleftherohorinou, Leonardo Bottolo, Robin G. Walters, Eleni Hadjigeorgiou, Adam J. de Smith, Alexandra I. F. Blakemore, Johanna C. Andersson-Assarsson, Peter Jacobson, Jessica L. Buxton, Julia S. El-Sayed Moustafa, Sophie Visvikis-Siest, Alexessander Couto Alves, and Lars Sjöström
- Subjects
Adult ,Context (language use) ,Minisatellite Repeats ,Biology ,law.invention ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,law ,Genetics ,Guanine Nucleotide Exchange Factors ,Humans ,Genetic Predisposition to Disease ,Copy-number variation ,Child ,Molecular Biology ,Gene ,Genetics (clinical) ,Polymerase chain reaction ,Sequence Deletion ,030304 developmental biology ,Genetic association ,0303 health sciences ,Association Studies Articles ,Chromosome ,General Medicine ,Dietary Fats ,Phenotype ,Obesity, Morbid ,3. Good health ,Variable number tandem repeat ,Adipose Tissue ,Gene Expression Regulation ,Case-Control Studies ,030217 neurology & neurosurgery ,Chromosomes, Human, Pair 8 - Abstract
Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P(empirical)= 8.9 × 10(-8) and P= 3.1 × 10(-3), respectively) which we estimate explains ~0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (P(combined)= 1.6 × 10(-3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (P(empirical)= 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.
- Published
- 2012
38. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis
- Author
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Norman Klopp, Chih-Mei Chen, Erik Melén, Dirkje S. Postma, Klaus Bønnelykke, Gerard H. Koppelman, Ivan Curjuric, Massimo Mangino, Nicholas J. Timpson, Alexandra I. F. Blakemore, Stephen B. Montgomery, Marjo-Riitta Järvelin, Anneli Pouta, Dorret I. Boomsma, Melanie C. Matheson, Albert Hofman, Matthias Wjst, Hans Bisgaard, Natalija Novak, Deborah Jarvis, Grant W. Montgomery, Frank Geller, Beate St Pourcain, Craig E. Pennell, Manuel A. R. Ferreira, Andre Franke, Alexessander Couto Alves, Frank D. Mentch, Vincent W. V. Jaddoe, Marie Standl, Nicole M. Warrington, Jouke-Jan Hottenga, Jessica L. Buxton, Peter N. Le Souëf, Bjarke Feenstra, Peter D. Sly, Bo L. Chawes, Martina Mueller-Nurasyid, Angela Simpson, Philip J. Thompson, Jacob P. Thyssen, Patrick G. Holt, Eskil Kreiner-Møller, David L. Duffy, Thomas Illig, Johan C. de Jongste, Bo Jacobsson, Joachim Heinrich, Mads Melbye, Wenche Nystad, H-Erich Wichmann, Medea Imboden, Wendy L. McArdle, Carla M. T. Tiesler, Susan M. Ring, Jeff Murray, Lavinia Paternoster, Torkil Menné, Marjan Kerkhof, John Henderson, Ronny Myhre, Lyle J. Palmer, George Davey Smith, Eva Albrecht, Pamela A. F. Madden, Marika Kaakinen, Hansjoerg Baurecht, Nicole Probst-Hensch, Cecilia Kim, Cornelia M. van Duijin, Panos Deloukas, Patrick M. A. Sleiman, Christian Gieger, John A. Curtin, Adnan Custovic, Daniel Glass, Cilla Söderhäll, Annika Sääf, Elke Rodriguez, Nicholas G. Martin, Stephan Weidinger, Tim D. Spector, Adaikalavan Ramasamy, John P. Kemp, Heather A. Boyd, Elisabeth Thiering, David P. Strachan, Anna-Liisa Hartikainen, Hakon Hakonarson, Allan Linneberg, Ralf J. P. van der Valk, Pirro G. Hysi, David M. Evans, Rain Jögi, Ellen A. Nohr, Liesbeth Duijts, Katharina Heim, Veronique Bataille, Fernando Rivadeneira, Maria M. Groen-Blokhuis, Andrew C. Heath, David Ellinghaus, Michael E. March, Holger Prokisch, Regina Foelster-Holst, André G. Uitterlinden, Emmanouil T. Dermitzakis, Juha Pekkanen, Henriette A. Smit, Medical Research Council (MRC), Dermitzakis, Emmanouil, Montgomery, Stephen, Biological Psychology, EMGO+ - Mental Health, Pediatrics, Surgery, Internal Medicine, Epidemiology, Erasmus MC other, Public Health, Groningen Research Institute of Pharmacy, Faculteit Medische Wetenschappen/UMCG, and Groningen Research Institute for Asthma and COPD (GRIAC)
- Subjects
Male ,Genetics of Overweight Young Adults (GOYA) Consortium ,Netherlands Twin Register (NTR) ,Epidemiology ,Cell Differentiation/genetics Chromosomes, Human, Pair 11/genetics Chromosomes, Human, Pair 20/genetics Chromosomes, Human, Pair 5 Cytokines/genetics DNA-Binding Proteins/genetics Dermatitis, Atopic/*genetics/immunology Epidermis/immunology Female *Genetic Loci Genetic Predisposition to Disease *Genome-Wide Association Study Humans Intermediate Filament Proteins/genetics Kinesin/genetics Male Polymorphism, Single Nucleotide Risk Transcription Factors/genetics ,Chromosomes, Human, Pair 20 ,Kinesins ,Genome-wide association study ,Filaggrin Proteins ,VARIANTS ,Chromosomes, Human, Pair 11/genetics ,medicine.disease_cause ,Genome-wide association studies ,DISEASE ,030207 dermatology & venereal diseases ,0302 clinical medicine ,Intermediate Filament Proteins ,Epidermis/immunology ,ddc:576.5 ,GENETICS & HEREDITY ,Genetics ,0303 health sciences ,education.field_of_study ,PSORIASIS ,Cytokines/genetics ,Cell Differentiation ,Kinesin ,11 Medical And Health Sciences ,Atopic dermatitis ,3. Good health ,DNA-Binding Proteins ,DIFFERENTIATION ,Chromosomes, Human, Pair 5 ,Cytokines ,Female ,Dermatitis, Atopic/genetics/immunology ,Life Sciences & Biomedicine ,Kinesin/genetics ,Filaggrin ,EXPRESSION ,Risk ,Cell Differentiation/genetics ,Population ,Transcription Factors/genetics ,Single-nucleotide polymorphism ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Australian Asthma Genetics Consortium (AAGC) ,Article ,MECHANISMS ,Dermatitis, Atopic ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,medicine ,FILAGGRIN ,Humans ,SPERMATOGENESIS ,Genetic Predisposition to Disease ,EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium ,education ,030304 developmental biology ,Science & Technology ,Chromosomes, Human, Pair 11 ,Odds ratio ,06 Biological Sciences ,Immune dysregulation ,medicine.disease ,Chromosomes, Human, Pair 20/genetics ,Genetic Loci ,Intermediate Filament Proteins/genetics ,Immunology ,ASTHMA ,Epidermis ,CELLULAR MOTILITY ,DNA-Binding Proteins/genetics ,Genome-Wide Association Study ,Transcription Factors ,Developmental Biology - Abstract
Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.
- Published
- 2012
39. Analysis with the exome array identifies multiple new independent variants in lipid loci
- Author
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George Dedoussis, Stavroula Kanoni, Bengt Sennblad, Patricia B. Munroe, Alice Stanton, Peter S. Braund, John C. Chambers, Angela Matchan, Eleftheria Zeggini, Olov Rolandsson, Céline Besse, Melanie Waldenberger, Tibor V. Varga, Panos Deloukas, Emmanouil Tsafantakis, Kathleen Stirrups, Maciej Tomaszewski, Martina Müller-Nurasyid, Anne Boland, John M. C. Connell, Robert A. Scott, Harald Grallert, Aliki-Eleni Farmaki, Neil R Poulter, Lorraine Southam, Martin D. Tobin, Maria Sabater-Lleal, Alexessander Couto Alves, Helen R. Warren, Rona J. Strawbridge, Nicholas G. D. Masca, Weihua Zhang, Lazaros Lataniotis, Denis C. Shields, Nigel W. Rayner, Stefan A. Escher, Angela Silveira, Christian Gieger, Dorota Pasko, Nicholas J. Wareham, Stephen Franks, Sirkka Keinänen-Kiukaanniemi, Konstantin Strauch, Paul W. Franks, Mark I. McCarthy, Nilesh J. Samani, Nikman An Hashim, Frida Renström, Maria Karaleftheri, Jan-Håkan Jansson, Hanieh Yaghootkar, Jaspal S. Kooner, Peter S. Sever, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Annette Peters, Anders Hamsten, Anna F. Dominiczak, Colin N. A. Palmer, Mark J. Caulfield, Timothy M. Frayling, Medical Research Council (MRC), National Institute for Health Research, and MRC
- Subjects
0301 basic medicine ,Genome-wide association study ,LDL-CHOLESTEROL ,BLOOD-LIPIDS ,RARE ,Gene Frequency ,Exome ,Child ,Genetics (clinical) ,Genetics & Heredity ,Genetics ,HERITABILITY ,Association Studies Articles ,11 Medical And Health Sciences ,General Medicine ,Middle Aged ,Lipids ,CORONARY-ARTERY-DISEASE ,LOW-FREQUENCY ,Wellcome Trust Case Control Consortium ,lipids (amino acids, peptides, and proteins) ,Life Sciences & Biomedicine ,TRAITS ,Adult ,Biochemistry & Molecular Biology ,Adolescent ,European Continental Ancestry Group ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,Humans ,GENOME-WIDE ASSOCIATION ,Molecular Biology ,Allele frequency ,METAANALYSIS ,Triglycerides ,Aged ,Science & Technology ,TRANSPORTER ,Cholesterol, HDL ,Lipid metabolism ,Cholesterol, LDL ,06 Biological Sciences ,Heritability ,Lipid Metabolism ,Genetic architecture ,Minor allele frequency ,030104 developmental biology ,Genome-Wide Association Study - Abstract
It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF
- Published
- 2015
40. Chromosome 19p13.3 deletion in a patient with macrocephaly, obesity, mental retardation, and behavior problems
- Author
-
Mieke M. van Haelst, Alexandra I. F. Blakemore, Susan E. Holder, Richard J. Ellis, Stewart J. Payne, Philippe Froguel, Sugera K. Hashim, Adam J. de Smith, Other departments, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
- Subjects
Pediatrics ,medicine.medical_specialty ,Adolescent ,Gene Dosage ,Biology ,Behavior disorder ,CAYMAN ATAXIA ,Intellectual Disability ,Genetics ,medicine ,Humans ,Obesity ,Genetics (clinical) ,Comparative Genomic Hybridization ,Mental Disorders ,Macrocephaly ,Chromosome ,Nutritional status ,Exons ,Microdeletion syndrome ,medicine.disease ,Megalencephaly ,Developmental disorder ,Female ,Chromosome Deletion ,medicine.symptom ,Chromosomes, Human, Pair 19 - Published
- 2011
41. Investigation of the HIN200 Locus in UK SLE Families Identifies Novel Copy Number Variants
- Author
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Timothy W. Behrens, Adam J. de Smith, Lachlan J. M. Coin, Alexandra I. F. Blakemore, Maria Michelle Fernando, David L. Morris, Jonathan Mangion, Timothy J. Vyse, Philippe Froguel, and Robert R. Graham
- Subjects
Genetics ,Systemic lupus erythematosus ,Lupus erythematosus ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,medicine.disease ,Human genetics ,immune system diseases ,medicine ,SNP ,Copy-number variation ,International HapMap Project ,skin and connective tissue diseases ,Genetics (clinical) - Abstract
We undertook a candidate locus study of the HIN200 gene cluster on 1q21-23 in UK systemic lupus erythematosus (SLE) families. To date, despite mounting evidence demonstrating the importance of these proteins in autoimmune disease, cancer, apoptosis, inflammation, and cell cycle arrest, there has been a dearth of data with respect to the genetic characterisation of the HIN200 locus in SLE or any other disease. We typed 83 single nucleotide polymorphisms (SNPs) across 317 kb of the HIN200 cluster in 428 UK SLE families and sought replication from a European-American lupus cohort. We do not find strong evidence of SNP association in either cohort. Interestingly, we do observe a trend for association with certain HIN200 SNPs and serologic subphenotypes in UK SLE that parallels the association of lupus antibodies with the orthologous murine locus. Furthermore, we find the HIN200 locus to be unexpectedly complex in terms of genetic structural organisation. We have identified a number of copy number variants (CNVs) in this region in healthy French males, HapMap samples, and UK SLE families. In summary, candidate interferon signalling genes show evidence of common CNV in human SLE and healthy subjects. The impact of these CNVs in health and disease remains to be determined. © 2011 The Authors Annals of Human Genetics
- Published
- 2011
42. Investigation of Mendelian forms of obesity holds out the prospect of personalized medicine
- Author
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Philippe Froguel and Alexandra I. F. Blakemore
- Subjects
Genetics ,business.industry ,General Neuroscience ,Single-nucleotide polymorphism ,Biology ,medicine.disease ,Bioinformatics ,Phenotype ,Obesity ,General Biochemistry, Genetics and Molecular Biology ,symbols.namesake ,History and Philosophy of Science ,Polymorphism (computer science) ,medicine ,Mendelian inheritance ,symbols ,SNP ,Personalized medicine ,business ,Gene - Abstract
Mendelian forms of obesity are already known to account for approximately 5% of the severely obese but are currently underinvestigated. In contrast, there has been much recent concentration on genome-wide single nucleotide polymorphism (SNP) associations in obesity, with particular emphasis given to the role of the fat mass and obesity associated (FTO) gene. Unfortunately, despite the enormous resources devoted to this work, none of the SNP markers in the ∼30 genes discovered to have associations with common obesity have meaningful predictive power. This is very different from the situation for Mendelian obesity, where mutations have very clear effects on phenotype. Study of Mendelian obesity has also added significantly to our understanding of mechanisms of appetite regulation, with all known causative genes being active in the brain and most forming part of the leptin-melanocortin signaling pathway. Investigation of genomic structural variation has also recently revealed deletions causing obesity, sometimes with concomitant neurocognitive dysfunction. Advances in next-generation sequencing are expected to uncover additional highly penetrant causes of obesity. Screening for Mendelian forms of obesity is rarely carried out but holds considerable promise for improved clinical care of these high-risk patients.
- Published
- 2010
43. cnvHap: an integrative population and haplotype–based multiplatform model of SNPs and CNVs
- Author
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Alexandra I. F. Blakemore, Robin G. Walters, Lachlan J. M. Coin, David J. Balding, Julian E. Asher, Adam J. de Smith, Julia S. El-Sayed Moustafa, Robert Sladek, and Philippe Froguel
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Genetics ,education.field_of_study ,Databases, Factual ,Haplotype ,Population ,Chromosome Mapping ,Reproducibility of Results ,Genome-wide association study ,Single-nucleotide polymorphism ,Cell Biology ,Nucleic acid amplification technique ,Biology ,Polymorphism, Single Nucleotide ,Biochemistry ,Haplotypes ,Chromosomes, Human, Pair 1 ,Missing heritability problem ,mental disorders ,Humans ,education ,Nucleic Acid Amplification Techniques ,Molecular Biology ,Genotyping ,Biotechnology ,Genetic association - Abstract
Although genome-wide association studies have uncovered single-nucleotide polymorphisms (SNPs) associated with complex disease, these variants account for a small portion of heritability. Some contribution to this 'missing heritability' may come from copy-number variants (CNVs), in particular rare CNVs; but assessment of this contribution remains challenging because of the difficulty in accurately genotyping CNVs, particularly small variants. We report a population-based approach for the identification of CNVs that integrates data from multiple samples and platforms. Our algorithm, cnvHap, jointly learns a chromosome-wide haplotype model of CNVs and cluster-based models of allele intensity at each probe. Using data for 50 French individuals assayed on four separate platforms, we found that cnvHap correctly detected at least 14% more deleted and 50% more amplified genotypes than PennCNV or QuantiSNP, with an 82% and 115% improvement for aberrations containing
- Published
- 2010
44. Copy number variation at 1q21.1 associated with neuroblastoma
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Kai Wang, Cecilia Kim, Kristina A. Cole, Jill E. Lynch, Jonathan P. Bradfield, Alexandra I. F. Blakemore, Patrick McGrady, Maura Diamond, Kristopher R. Bosse, Katlyn Pecor, Hakon Hakonarson, Marci Laudenslager, Sharon J. Diskin, Hongzhe Li, Cuiping Hou, Edward F. Attiyeh, John M. Maris, Cynthia Winter, Andrew Wood, Wendy B. London, Marcella Devoto, Yael P. Mosse, Tamim H. Shaikh, Struan F.A. Grant, Elizabeth A. Geiger, E. Rappaport, and Joseph T. Glessner
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Genotype ,Gene Dosage ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Gene dosage ,White People ,Article ,Neuroblastoma ,Fetus ,medicine ,Humans ,Genetic Predisposition to Disease ,RNA, Messenger ,Copy-number variation ,Child ,In Situ Hybridization, Fluorescence ,Genetics ,Multidisciplinary ,Breakpoint ,Genetic Variation ,Reproducibility of Results ,Chromosome Breakage ,medicine.disease ,Chromosomes, Human, Pair 1 ,Chromosome breakage ,Genome-Wide Association Study - Abstract
Copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) are two important potential sources of phenotypic variation in humans. Until now, only SNPs have been associated with cancer, but the increasing recognition that germline DNA dosage is a critical component of human diversity raises the possibility that CNVs might also influence susceptibility to this cancer. Diskin et al. now report that a common CNV at chromosome 1q21.1 is associated with the childhood cancer neuroblastoma, and that a transcript within this CNV, the previously unknown neuroblastoma breakpoint family gene NBPF23, is involved in the early stages of tumorigenesis. Copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) are two important potential sources of phenotypic variation in humans; however, only SNPs have been associated with cancer. Here, a CNV at 1q21.1 is shown to be associated with neuroblastoma, and a transcript within this CNV, NBPF23, is implicated in early tumorigenesis of the disease. Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility1,2. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at ∼550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent–offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes3,4 and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.
- Published
- 2009
45. Combined effects of MC4R and FTO common genetic variants on obesity in European general populations
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Philippe Froguel, Anna-Liisa Hartikainen, Fanny Stutzmann, Christine Cavalcanti-Proença, Anneli Pouta, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Jaana Laitinen, Sylviane Vol, Michel Marre, Emmanuelle Durand, David Meyre, Stéphane Cauchi, Beverley Balkau, Paul Elliott, Tuija Tammelin, and Arturo Gonzalez-Izquierdo
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Adult ,Male ,medicine.medical_specialty ,Diabetes risk ,Adolescent ,Genotype ,Population ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO ,Type 2 diabetes ,Polymorphism, Single Nucleotide ,Childhood obesity ,Body Mass Index ,Cohort Studies ,Gene Frequency ,Risk Factors ,Internal medicine ,Drug Discovery ,Prevalence ,medicine ,Humans ,Obesity ,Child ,education ,Allele frequency ,Alleles ,Finland ,Genetics (clinical) ,Aged ,education.field_of_study ,business.industry ,Incidence ,Genetic Variation ,Proteins ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,Endocrinology ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Receptor, Melanocortin, Type 4 ,Molecular Medicine ,Female ,France ,business ,Body mass index - Abstract
Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20-24% of the populations), subjects with three or four risk alleles (7-10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (approximately 1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm(3) (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.
- Published
- 2009
46. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk
- Author
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Jean-Claude Chèvre, Jacques Weill, Claire Levy-Marchal, Barbara Heude, Torben Hansen, Katleen Lemaire, Paul Elliott, Marion Marchand, Stéphane Lobbens, Christian Dina, Philippe Froguel, Oluf Pedersen, Jérôme Delplanque, Ghislain Rocheleau, Andrew Walley, Torben Jørgensen, Jean Tichet, Aimo Ruokonen, Knut Borch-Johnsen, Thomas Sparsø, François Pattou, Robert Sladek, Christine Cavalcanti-Proença, Sophie Visvikis-Siest, Alexandra I. F. Blakemore, M. R. Järvelin, Amélie Bonnefond, Maithé Tauber, Michel Marre, Anna-Liisa Hartikainen, Emmanuelle Durand, Beverley Balkau, Frans Schuit, Johan Holmkvist, Stéphane Cauchi, Nabila Bouatia-Naji, Samy Hadjadj, Guillaume Charpentier, Franck De Graeve, David Meyre, Martine Vaxillaire, and University of Groningen
- Subjects
Blood Glucose ,Receptors, Melatonin ,melatonin ,Type 2 diabetes ,polymorphism ,Cohort Studies ,MELLITUS ,Glucokinase ,Glucose homeostasis ,Child ,GENE-EXPRESSION ,INSULIN-RESISTANCE ,Fasting ,cohort ,Middle Aged ,medicine.anatomical_structure ,DISEASES ,Adult ,medicine.medical_specialty ,MELATONIN ,Adolescent ,Biology ,Melatonin receptor ,Polymorphism, Single Nucleotide ,insulin-resistance ,diseases ,Islets of Langerhans ,Insulin resistance ,Meta-Analysis as Topic ,Diabetes mellitus ,Internal medicine ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,COHORT ,RNA, Messenger ,GENOME-WIDE ASSOCIATION ,Adaptor Proteins, Signal Transducing ,Receptor, Melatonin, MT2 ,Pancreatic islets ,Chromosomes, Human, Pair 11 ,Gene Expression Profiling ,Reproducibility of Results ,medicine.disease ,gene-expression ,POLYMORPHISM ,Endocrinology ,Melatonin receptor 1B ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,genome-wide association ,Insulin Resistance ,Genome-Wide Association Study ,mellitus - Abstract
In genome-wide association (GWA) data from 2,151 nondiabetic French subjects, we identified rs1387153, near MTNR1B (which encodes the melatonin receptor 2 (MT2)), as a modulator of fasting plasma glucose (FPG; P = 1.3 x 10(-7)). In European populations, the rs1387153 T allele is associated with increased FPG (beta = 0.06 mmol/l, P = 7.6 x 10(-29), N = 16,094), type 2 diabetes (T2D) risk (odds ratio (OR) = 1.15, 95% CI = 1.08-1.22, P = 6.3 x 10(-5), cases N = 6,332) and risk of developing hyperglycemia or diabetes over a 9-year period (hazard ratio (HR) = 1.20, 95% CI = 1.06-1.36, P = 0.005, incident cases N = 515). RT-PCR analyses confirm the presence of MT2 transcripts in neural tissues and show MT2 expression in human pancreatic islets and beta cells. Our data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway. ispartof: Nature Genetics vol:41 issue:1 pages:89-94 ispartof: location:United States status: published
- Published
- 2009
47. Is Obesity Our Genetic Legacy?
- Author
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Alexandra I. F. Blakemore and Philippe Froguel
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Candidate gene ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Context (language use) ,Disease ,Environment ,Biochemistry ,Evolution, Molecular ,Endocrinology ,Internal medicine ,Humans ,Medicine ,Obesity ,Exercise ,Genetic association ,Extreme obesity ,business.industry ,Biochemistry (medical) ,Feeding Behavior ,Syndrome ,medicine.disease ,business ,Candidate Disease Gene ,Evidence synthesis - Abstract
To design rational management regimes and identify novel therapeutic targets, it is essential to understand the biological drivers of the current epidemic of obesity. This review describes our current knowledge of genetic factors in obesity, drawing functional parallels in the underlying neuroendocrine mechanisms and suggesting promising new directions for research.Published literature, addressing both the current knowledge of genetics of monogenic and syndromic forms of extreme obesity, and the emerging literature on genetic factors associated with more common forms of obesity are analyzed.The current genetic evidence in obesity underlines the importance of neuroendocrine mechanisms of appetite regulation. Monogenic forms of disease explain 6% of children with extreme obesity, having hyperphagia associated with defects in the leptin-melanocortin pathway, as a central feature. Candidate gene association studies indicate that more subtle variations of the same genes also contribute to common forms of obesity. Well-powered genome-wide association studies recently identified FTO as a strong contributor to both childhood and adult obesity, demonstrating the power of such hypothesis-free analysis to provide new insights into the underlying pathogenic mechanisms of a common complex disease.Although there has been some very heartening recent progress in elucidating genetic mechanisms underlying obesity, we are still a long way from explaining the high heritability of adiposity. Investigations of different forms of variation, such as copy number polymorphism, may extend our understanding of this condition.
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- 2008
48. Human genes involved in copy number variation: mechanisms of origin, functional effects and implications for disease
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A J de Smith, Robin G. Walters, Philippe Froguel, and Alexandra I. F. Blakemore
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Genetics ,Natural selection ,Gene Dosage ,Population genetics ,Disease ,Copy Number Variation and Inherited Disease ,Biology ,Gene dosage ,Evolution, Molecular ,Phenotype ,Evolutionary biology ,Genetic predisposition ,Animals ,Humans ,Human genome ,Copy-number variation ,Molecular Biology ,Gene ,Genetics (clinical) - Abstract
Copy number variants (CNVs) overlap over 7000 genes, many of which are pivotal in biological pathways. The implications of this are profound, with consequences for evolutionary studies, population genetics, gene function and human phenotype, including elucidation of genetic susceptibility to major common diseases, the heritability of which has thus far defied full explanation. Even though this research is still in its infancy, CNVs have already been associated with a number of monogenic, syndromic and complex diseases: the development of high throughput and high resolution techniques for CNV screening is likely to bring further new insights into the contribution of copy number variation to common diseases. Amongst genes overlapped by CNVs, significant enrichments for certain gene ontology categories have been identified, including those related to immune responses and interactions with the environment. Genes in both of these categories are thought to be important in evolutionary adaptation and to be particular targets of natural selection. Thus, a full appreciation of copy number variation may be important for our understanding of human evolution.
- Published
- 2008
49. Leptin Receptor Genotype at Gln223Arg is Associated With Body Composition, BMD, and Vertebral Fracture in Postmenopausal Danish Women
- Author
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Una L. Fairbrother, Philippe Froguel, Claus Christiansen, Andrew Walley, László B. Tankó, and Alexandra I. F. Blakemore
- Subjects
medicine.medical_specialty ,Genotype ,Denmark ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Population ,Receptors, Cell Surface ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Bone remodeling ,Bone Density ,Internal medicine ,medicine ,Humans ,Orthopedics and Sports Medicine ,education ,Aged ,DNA Primers ,Femoral neck ,Aged, 80 and over ,education.field_of_study ,Leptin receptor ,Base Sequence ,business.industry ,Leptin ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,Body Composition ,Receptors, Leptin ,Spinal Fractures ,Population study ,Female ,Menopause ,business - Abstract
Leptin is emerging as a key regulator of bone remodeling. In a population-based study of 1306 postmenopausal Danish women, nonsynonymous LEPR SNPs were associated with risk of adiposity, BMD, and vertebral fracture. Smoking exacerbates this LEPR-associated fracture risk. Introduction: Nonsynonymous single nucleotide polymorphisms (SNPs) in the human LEPR gene have been associated with adiposity in a number of studies, but there have been no large-scale studies of their implica- tions for BMD and osteoporotic fracture risk in postmenopausal women. Materials and Methods: We carried out a population-based study of 1430 women. Three well-known non- synonymous leptin receptor (LEPR) SNPs (Lys109Arg, Gln223Arg, and Lys656Asn) were genotyped for qualitative and quantitative association analysis. Phenotype characteristics of main interest were DXA mea- sures of body fat and lean tissue mass, BMD, and radiographic vertebral fractures. Results: Gln223Arg associated with risk of vertebral fracture (overall OR 1.76; OR in smokers 2.31; p 0.0004), in addition to BMD of the femoral neck and total hip (p 0.036 and 0.008, respectively). Heterozygote carriers showed lower BMD at both sites. Gln223Arg was also associated with adiposity (p 0.001 for total fat mass). For adiposity, the at-risk allele was G (resulting in an arginine at position 223). Conclusions: Variation in LEPR seemed to contribute to the variation in BMD and fracture risk in Danish postmenopausal women; the heterozygous genotype was associated with increased risk of manifest osteopo- rosis. Further studies are needed to replicate these data and to clarify the mechanisms involved. J Bone Miner Res 2007;22:544-550. Published online on January 22, 2007; doi: 10.1359/JBMR.070114
- Published
- 2007
50. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index
- Author
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Virpi Lindi, Clare S. Murray, Liming Liang, Wieland Kiess, Philippe Froguel, Tarunveer S. Ahluwalia, Hakon Hakonarson, Dorret I. Boomsma, Pitkänen Niina Pitkänen, Romy Gaillard, Mandy Geserick, John A. Curtin, Shana E. McCormack, Niinikoski Harri, Jens-Christian Holm, Vicente Gilsanz, Ville Huikari, Maties Torrent, Nicholas J. Timpson, George Dedoussis, Angela Simpson, Struan F.A. Grant, Klaus Bønnelykke, Anubha Mahajan, George McMahon, Raimo Joro, Christel M. Middeldorp, Johan G. Eriksson, Vilor-Tejedor Natalia Vilor-Tejedor, Gerard H. Koppelman, Frank Geller, Amélie Bonnefond, Hanna Maaria Lakka, Jinyan Huang, Craig E. Pennell, Johannes Waage, Jane Wardle, Torben Hansen, Olli T. Raitakari, John A. Shepherd, Lisbeth Carstensen, Andrea Kelly, Katja Pahkala, Jordi Sunyer, Claire M. A. Haworth, Per Magnus, Juan R. González, Babette S. Zemel, Mads Melbye, Steve Franks, Carla M. T. Tiesler, Roland Pfäffle, Momoko Horikoshi, Susan M. Ring, Adnan Custovic, Claudia Flexeder, Claire Monnereau, Heidi J. Kalkwarf, Janine F. Felix, Julie A. Marsh, Thorkild I. A. Sørensen, André G. Uitterlinden, Mustafa Atalay, Jouke-Jan Hottenga, Mark I. McCarthy, Joel N. Hirschhorn, Niels Grarup, Lude Franke, Diana L. Cousminer, Timo A. Lakka, Robert Plomin, Ronny Myhre, Albert Hofman, Baoshan Ma, Eskil Kreiner-Møller, Jesús Vioque, Vincent W. V. Jaddoe, Hans Bisgaard, Bjarke Feenstra, Sylvain Sebert, Evie Stergiakouli, Eleftheria Zeggini, Joachim Heinrich, Bo Jacobsson, Tune H. Pers, Dirkje S. Postma, Elina Hyppönen, Loic Yengo, Haja N. Kadarmideen, Alana Cavadino, Jonathan P. Bradfield, Elisabeth Thiering, Ralf J. P. van der Valk, George Davey Smith, Alexandra I. F. Blakemore, Christine Power, Marjo-Riitta Järvelin, Wei Ang, Ioanna Ntalla, Sharon E. Oberfield, Fernando Rivadeneira, Rebecca K. Vinding, Alexandra M. Lewin, Mika Kähönen, Verena Sengpiel, Maria M. Groen-Blokhuis, Anna-Liisa Hartikainen, Antje Körner, Oluf Pedersen, Joyce B. J. van Meurs, Alessandra Chesi, Widén Elisabeth Widén, Terho Lehtimäki, Thomas S. Price, Frank D. Mentch, Joan M. Lappe, Leo-Pekka Lyytikäinen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Early Growth Genetics (EGG) Consortium, Bone Mineral Density in Childhood Study (BMDCS), Early Genetics and Lifecourse Epidemiology (EAGLE) consortium, Felix, Janine F, Bradfield, Jonathan P, Monnereau, Claire, van der Valk, Ralf JP, Hypponen, Elina, Jaddoe, Vincent WV, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Erasmus MC other, Epidemiology, Pediatrics, Child and Adolescent Psychiatry / Psychology, Internal Medicine, and Public Health
- Subjects
0301 basic medicine ,Netherlands Twin Register (NTR) ,Male ,ADAM23 ,Genome-wide association study ,VARIANTS ,ENVIRONMENTAL-FACTORS ,Body Mass Index ,Child ,Genetics (clinical) ,2. Zero hunger ,Genetics ,education.field_of_study ,Association Studies Articles ,General Medicine ,INSIGHTS ,Child, Preschool ,Female ,childhood obesity ,EXPRESSION ,Adult ,Risk ,Adolescent ,Population ,body mass index ,Single-nucleotide polymorphism ,Biology ,ta3111 ,Polymorphism, Single Nucleotide ,Childhood obesity ,White People ,03 medical and health sciences ,Young Adult ,children ,SDG 3 - Good Health and Well-being ,medicine ,Humans ,Obesity ,Allele ,education ,Molecular Biology ,METAANALYSIS ,Genetic association ,FAT DISTRIBUTION ,ta3121 ,medicine.disease ,ta3123 ,GENE ,030104 developmental biology ,Genetic Loci ,WEIGHT ,Body mass index ,Genome-Wide Association Study - Abstract
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Refereed/Peer-reviewed
- Published
- 2015
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