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mendelian randomization

Christoph Nowak, Samira Salihovic, Andrea Ganna, Stefan Brandmaier, Taru Tukiainen, Corey D Broeckling, Patrik K Magnusson, Jessica E Prenni, Rui Wang-Sattler, Annette Peters, Konstantin Strauch, Thomas Meitinger, Vilmantas Giedraitis, Johan Ärnlöv, Christian Berne, Christian Gieger, Samuli Ripatti, Lars Lind, Nancy L Pedersen, Johan Sundström, Erik Ingelsson, Tove Fall
Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test...
October 2016: PLoS Genetics
Stephen Burgess, Jack Bowden, Tove Fall, Erik Ingelsson, Simon G Thompson
Mendelian randomization investigations are becoming more powerful and simpler to perform, due to the increasing size and coverage of genome-wide association studies and the increasing availability of summarized data on genetic associations with risk factors and disease outcomes. However, when using multiple genetic variants from different gene regions in a Mendelian randomization analysis, it is highly implausible that all the genetic variants satisfy the instrumental variable assumptions. This means that a simple instrumental variable analysis alone should not be relied on to give a causal conclusion...
September 26, 2016: Epidemiology
Amy E Taylor, Richard M Martin, Milan S Geybels, Janet L Stanford, Irene Shui, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G Giles, Fredrik Wiklund, Henrik Gronberg, Christopher A Haiman, Johanna Schleutker, Børge G Nordestgaard, Ruth C Travis, David Neal, Nora Pashayan, Kay-Tee Khaw, William Blot, Stephen Thibodeau, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Park, Radka Kaneva, Jyotsna Batra, Manuel R Teixeira, Hardev Pandha, Jenny Donovan, Marcus R Munafò
Coffee consumption has been shown in some studies to reduce the risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium...
October 14, 2016: International Journal of Cancer. Journal International du Cancer
Rachael C Aikens, Wei Zhao, Danish Saleheen, Muredach P Reilly, Stephen E Epstein, Emmi Tikkanen, Veikko Salomaa, Benjamin F Voight
Observational studies have shown that elevated systolic blood pressure (SBP) is associated with future onset of type 2 diabetes, but whether this association is causal is not known. We applied the Mendelian Randomization framework to evaluate the causal hypothesis that elevated SBP increases risk to type 2 diabetes. We utilized 28 genetic variants associated with SBP and evaluated their impact on type 2 diabetes using a European-centric meta-analysis comprising 37,293 cases and 125,686 controls. We found that elevation of SBP levels by 1 mmHg due to our genetic score was associated with a 2% increase in risk of type 2 diabetes (OR=1...
October 4, 2016: Diabetes
Stefan Coassin, Salome Friedel, Anna Köttgen, Claudia Lamina, Florian Kronenberg
OBJECTIVE: A recent observational study with almost 2 million men reported an association between low high-density lipoprotein (HDL) cholesterol and worse kidney function. The causality of this association would be strongly supported if genetic variants associated with HDL cholesterol were also associated with kidney function. APPROACH AND RESULTS: We used 68 genetic variants (single-nucleotide polymorphisms [SNPs]) associated with HDL cholesterol in genome-wide association studies including >188 000 subjects and tested their association with estimated glomerular filtration rate (eGFR) using summary statistics from another genome-wide association studies of kidney function including ≤133 413 subjects...
September 29, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Borge G Nordestgaard, Anne Langsted
Human epidemiologic and genetic evidence using the Mendelian randomization approach in large-scale studies now strongly support that elevated lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disease, that is, for myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis. The Mendelian randomization approach used to infer causality is generally not affected by confounding and reverse causation, the major problems of observational epidemiology. This approach is particularly valuable to study causality of Lp(a), as single genetic variants exist that explain 27-28% of all variation in plasma Lp(a)...
September 27, 2016: Journal of Lipid Research
S J O'Shea, J R Davies, J A Newton-Bishop
Survival from melanoma is influenced by several, well-established clinical and histopathological factors, e.g. age, Breslow thickness and microscopic ulceration. We (the Section of Epidemiology and Biostatistics, University of Leeds) have carried out research to better understand the biological basis for these observations. Preliminary results indicated a protective role for vitamin D in melanoma relapse and that higher vitamin D was associated with thinner primary melanomas. Funding from the British Skin Foundation enabled JNB to establish a study of the effects of vitamin A in melanoma...
October 2016: British Journal of Dermatology
Sonja A Swanson
No abstract text is available yet for this article.
September 20, 2016: Epidemiology
Brooke Rhead, Maria Bäärnhielm, Milena Gianfrancesco, Amanda Mok, Xiaorong Shao, Hong Quach, Ling Shen, Catherine Schaefer, Jenny Link, Alexandra Gyllenberg, Anna Karin Hedström, Tomas Olsson, Jan Hillert, Ingrid Kockum, M Maria Glymour, Lars Alfredsson, Lisa F Barcellos
OBJECTIVE: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality. METHODS: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles...
October 2016: Neurology. Genetics
Clair Brunner, Neil M Davies, Richard M Martin, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham Giles, Fredrik Wiklund, Henrik Gronberg, Christopher A Haiman, Johanna Schleutker, Børge G Nordestgaard, Ruth C Travis, David Neal, Jenny Donovan, Freddie C Hamdy, Nora Pashayan, Kay-Tee Khaw, Janet L Stanford, William J Blot, Stephen Thibodeau, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Park, Radka Kaneva, Jyotsna Batra, Manuel R Teixeira, Hardev Pandha, Luisa Zuccolo
Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium...
September 19, 2016: International Journal of Cancer. Journal International du Cancer
Yon Ho Jee, Sun Ju Lee, Keum Ji Jung, Sun Ha Jee
BACKGROUND: Previous studies have suggested that alcohol intake is associated with increased fasting serum glucose (FSG), but the nature of the relationship remains unknown. We used Mendelian randomization analysis to assess the causal effect of alcohol intake on FSG in a middle-aged Korean population. METHODS: Clinical data including FSG and alcohol intake were collected from 156,386 Koreans aged 20 years or older who took part in the Korean Cancer Prevention Study-II (KCPS-II) Biobank Cohort...
2016: PloS One
Feixiong Cheng, James L Murray, Junfei Zhao, Jinsong Sheng, Zhongming Zhao, Donald H Rubin
Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins...
September 2016: PLoS Computational Biology
Stephen Burgess, Neil M Davies, Simon G Thompson
Mendelian randomization analyses are often performed using summarized data. The causal estimate from a one-sample analysis (in which data are taken from a single data source) with weak instrumental variables is biased in the direction of the observational association between the risk factor and outcome, whereas the estimate from a two-sample analysis (in which data on the risk factor and outcome are taken from non-overlapping datasets) is less biased and any bias is in the direction of the null. When using genetic consortia that have partially overlapping sets of participants, the direction and extent of bias are uncertain...
November 2016: Genetic Epidemiology
Shan-Shan Li, Li-Hong Gao, Xiao-Ya Zhang, Jin-We He, Wen-Zhen Fu, Yu-Juan Liu, Yun-Qiu Hu, Zhen-Lin Zhang
Low serum 25-hydroxyvitamin D (25OHD) is associated with osteoporosis and osteoporotic fracture, but it remains uncertain whether these associations are causal. We conducted a Mendelian randomization (MR) study of 1,824 postmenopausal Chinese women to examine whether the detected associations between serum 25OHD and bone mineral density (BMD) and bone metabolism markers were causal. In observational analyses, total serum 25OHD was positively associated with BMD at lumbar spine (P = 0.003), femoral neck (P = 0...
2016: Scientific Reports
Caren E Smith, Oscar Coltell, Jose V Sorlí, Ramón Estruch, Miguel Ángel Martínez-González, Jordi Salas-Salvadó, Montserrat Fitó, Fernando Arós, Hassan S Dashti, Chao Q Lai, Leticia Miró, Lluís Serra-Majem, Enrique Gómez-Gracia, Miquel Fiol, Emilio Ros, Stella Aslibekyan, Bertha Hidalgo, Marian L Neuhouser, Chongzhi Di, Katherine L Tucker, Donna K Arnett, José M Ordovás, Dolores Corella
Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n ≤ 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations...
2016: Scientific Reports
Jack Bowden, Fabiola Del Greco M, Cosetta Minelli, George Davey Smith, Nuala A Sheehan, John R Thompson
BACKGROUND: MR-Egger regression has recently been proposed as a method for Mendelian randomization (MR) analyses incorporating summary data estimates of causal effect from multiple individual variants, which is robust to invalid instruments. It can be used to test for directional pleiotropy and provides an estimate of the causal effect adjusted for its presence. MR-Egger regression provides a useful additional sensitivity analysis to the standard inverse variance weighted (IVW) approach that assumes all variants are valid instruments...
September 11, 2016: International Journal of Epidemiology
Harold A Nieuwboer, René Pool, Conor V Dolan, Dorret I Boomsma, Michel G Nivard
Here we present a method of genome-wide inferred study (GWIS) that provides an approximation of genome-wide association study (GWAS) summary statistics for a variable that is a function of phenotypes for which GWAS summary statistics, phenotypic means, and covariances are available. A GWIS can be performed regardless of sample overlap between the GWAS of the phenotypes on which the function depends. Because a GWIS provides association estimates and their standard errors for each SNP, a GWIS can form the basis for polygenic risk scoring, LD score regression, Mendelian randomization studies, biological annotation, and other analyses...
October 6, 2016: American Journal of Human Genetics
Lise S Skov-Ettrup, Børge G Nordestgaard, Christina B Petersen, Janne S Tolstrup
BACKGROUND: Increasing evidence suggests that smoking influences mental health negatively. This study investigated whether high tobacco consumption is causally related to psychological distress in a Mendelian randomization design, using a variant in the nicotine acetylcholine receptor gene CHRNA3-known to influence individual tobacco consumption-as instrumental variable for tobacco consumption. METHODS: Data from 90 108 participants in the Copenhagen General Population Study was used...
August 3, 2016: Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco
Marja-Riitta Taskinen, Jan Borén
ApoC-III was discovered almost 50 years ago, but for many years, it did not attract much attention. However, as epidemiological and Mendelian randomization studies have associated apoC-III with low levels of triglycerides and decreased incidence of cardiovascular disease (CVD), it has emerged as a novel and potentially powerful therapeutic approach to managing dyslipidemia and CVD risk. The atherogenicity of apoC-III has been attributed to both direct lipoprotein lipase-mediated mechanisms and indirect mechanisms, such as promoting secretion of triglyceride-rich lipoproteins (TRLs), provoking proinflammatory responses in vascular cells and impairing LPL-independent hepatic clearance of TRL remnants...
October 2016: Current Atherosclerosis Reports
Y Zhong, S L Lin, C M Schooling
Hematocrit and hemoglobin affect viscosity, and have been considered as risk factors for ischemic heart disease (IHD), although observations are inconsistent; randomized controlled trials targeting hematocrit or hemoglobin have not been definitive. To clarify their role, the risk of IHD was assessed according to genetically determined hematocrit and hemoglobin. We applied single nucleotide polymorphisms (SNPs) strongly determining hematocrit and hemoglobin, from a genome wide association study, to a large case (64,746) control (130,681) study of coronary artery disease, CARDIoGRAMplusC4D, to obtain unconfounded estimates using instrumental variable analysis by combining the Wald estimators for each SNP taking into account any correlation between SNPs using weighted generalized linear regression...
October 2016: Preventive Medicine
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