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mendelian randomization

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https://www.readbyqxmd.com/read/29652757/eliminating-survivor-bias-in-two-stage-instrumental-variable-estimators
#1
Stijn Vansteelandt, Stefan Walter, Eric Tchetgen Tchetgen
Mendelian randomization studies commonly focus on elderly populations. This makes the instrumental variables analysis of such studies sensitive to survivor bias, a type of selection bias. A particular concern is that the instrumental variable conditions, even when valid for the source population, may be violated for the selective population of individuals who survive the onset of the study. This is potentially very damaging because Mendelian randomization studies are known to be sensitive to bias due to even minor violations of the instrumental variable conditions...
April 11, 2018: Epidemiology
https://www.readbyqxmd.com/read/29650766/association-of-genetic-instrumental-variables-for-lung-function-on-coronary-artery-disease-risk-a-2-sample-mendelian-randomization-study
#2
Shiu Lun Au Yeung, Maria-Carolina Borges, Debbie A Lawlor
BACKGROUND: Lung function, assessed by forced expiratory volume in 1 second (FEV1 ) and forced vital capacity (FVC), is inversely associated with coronary artery disease (CAD), but these associations could be because of confounding or reversed causality. We conducted a 2-sample Mendelian randomization study, using publicly available data from relevant genome-wide association studies, to examine the role of FEV1 or FVC on CAD. METHODS: We used the most recent genome-wide association studies on lung function to extract genetic instruments related to FEV1 and FVC (n=92 749)...
April 2018: Circulation. Genomic and precision medicine
https://www.readbyqxmd.com/read/29649275/evaluation-of-the-relationship-between-plasma-lipids-and-abdominal-aortic-aneurysm-a-mendelian-randomization-study
#3
Lu-Chen Weng, Nicholas S Roetker, Pamela L Lutsey, Alvaro Alonso, Weihua Guan, James S Pankow, Aaron R Folsom, Lyn M Steffen, Nathan Pankratz, Weihong Tang
Studies have reported that higher circulating levels of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and lower of high-density lipoprotein (HDL) cholesterol may be associated with increased risk of abdominal aortic aneurysm (AAA). Whether dyslipidemia causes AAA is still unclear and is potentially testable using a Mendelian randomization (MR) approach. We investigated the associations between blood lipids and AAA using two-sample MR analysis with SNP-lipids association estimates from a published genome-wide association study of blood lipids (n = 188,577) and SNP-AAA association estimates from European Americans (EAs) of the Atherosclerosis Risk in Communities (ARIC) study (n = 8,793)...
2018: PloS One
https://www.readbyqxmd.com/read/29643338/causal-pathways-from-blood-pressure-to-larger-qrs-amplitudes-a-mendelian-randomization-study
#4
M Yldau Van Der Ende, Tom Hendriks, Dirk J Van Veldhuisen, Harold Snieder, Niek Verweij, Pim Van Der Harst
Abnormal QRS duration and amplitudes on the electrocardiogram are indicative of cardiac pathology and are associated with adverse outcomes. The causal nature of these associations remains uncertain and could be due to QRS abnormalities being a symptom of cardiac damage rather than a factor on the causal pathway. By performing Mendelian randomization (MR) analyses using summary statistics of genome wide association study consortia with sample sizes between 20,687 and 339,224 individuals, we aimed to determine which cardiovascular risk factors causally lead to changes in QRS duration and amplitude (Sokolow-Lyon, Cornell and 12-leadsum products)...
April 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29618599/triglyceride-rich-lipoprotein-cholesterol-and-risk-of-cardiovascular-events-among-patients-receiving-statin-therapy-in-the-treating-to-new-targets-tnt-trial
#5
Antonio J Vallejo-Vaz, Rana Fayyad, S Matthijs Boekholdt, G Kees Hovingh, John J Kastelein, Shari Melamed, Philip Barter, David D Waters, Kausik K Ray
Background -Mendelian randomization data suggest genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial. Methods -Patients with coronary heart disease [CHD] and LDL-C 130-250mg/dL entered an 8-week run-in phase with atorvastatin 10mg/day (ATV10)...
April 4, 2018: Circulation
https://www.readbyqxmd.com/read/29609749/causal-effect-of-lipids-and-lipoproteins-on-atherosclerosis-lessons-from-genomic-studies
#6
REVIEW
Brian A Ference
Mendelian randomization studies demonstrate that apolipoprotein B-containing lipoproteins have both causal and cumulative effects on the risk of atherosclerotic cardiovascular disease. The clinical benefit of lipid-lowering therapies depends on both the absolute reduction in circulating apolipoprotein B-containing lipoproteins and the total duration of exposure to these particles. Because atherosclerosis seems to be caused by the retention of apolipoprotein B-containing lipoproteins rather than by the cholesterol content carried by those lipoproteins, high-density lipoprotein-mediated efflux of cholesterol from the arterial wall may not reduce the risk of atherosclerotic cardiovascular disease...
May 2018: Cardiology Clinics
https://www.readbyqxmd.com/read/29603714/sensitivity-analysis-and-power-for-instrumental-variable-studies
#7
Xuran Wang, Yang Jiang, Nancy R Zhang, Dylan S Small
In observational studies to estimate treatment effects, unmeasured confounding is often a concern. The instrumental variable (IV) method can control for unmeasured confounding when there is a valid IV. To be a valid IV, a variable needs to be independent of unmeasured confounders and only affect the outcome through affecting the treatment. When applying the IV method, there is often concern that a putative IV is invalid to some degree. We present an approach to sensitivity analysis for the IV method which examines the sensitivity of inferences to violations of IV validity...
March 31, 2018: Biometrics
https://www.readbyqxmd.com/read/29593013/relationship-of-familial-hypercholesterolemia-and-high-ldl-cholesterol-to-ischemic-stroke-the-copenhagen-general-population-study
#8
Sabina Beheshti, Christian M Madsen, Anette Varbo, Marianne Benn, Børge G Nordestgaard
Background -Familial hypercholesterolemia(FH) is a condition with very high concentrations of low-density lipoprotein(LDL) cholesterol and high risk of ischemic heart disease including myocardial infarction. However, there is limited and contradictory information on whether FH and high LDL cholesterol per se confer high risk of ischemic stroke. We tested the hypotheses that individuals in the general population with FH and/or high LDL cholesterol have higher risk of ischemic stroke. Methods -The associations of FH and high LDL cholesterol with ischemic stroke risk were tested in both causal, genetic and observational analyses using 106,412 individuals from the Copenhagen General Population Study(CGPS; 2823 ischemic strokes and 3,792 myocardial infarctions) and/or 10,372 individuals from the Copenhagen City heart Study(CCHS; 945 ischemic strokes and 1,142 myocardial infarctions)...
March 28, 2018: Circulation
https://www.readbyqxmd.com/read/29573806/differing-genetic-trend-estimates-from-traditional-and-genomic-evaluations-of-genotyped-animals-as-evidence-of-preselection-bias-in-us-holsteins
#9
Y Masuda, P M VanRaden, I Misztal, T J Lawlor
The objective of this study was to compare genetic trends from single-step genomic BLUP (ssGBLUP) and traditional BLUP models for milk production traits of US Holsteins. Phenotypes were 305-d milk, fat, and protein yields from 21,527,040 cows recorded between January 1990 and August 2015. The pedigree file included 29,651,623 animals and was limited to 3 generations back from recorded or genotyped animals. Genotypes for 764,029 animals were used, and analyses were by a 3-trait repeatability model as used in the US official genetic evaluation...
March 21, 2018: Journal of Dairy Science
https://www.readbyqxmd.com/read/29558518/risk-factors-for-type-2-diabetes-mellitus-an-exposure-wide-umbrella-review-of-meta-analyses
#10
Vanesa Bellou, Lazaros Belbasis, Ioanna Tzoulaki, Evangelos Evangelou
BACKGROUND: Type 2 diabetes mellitus (T2DM) is a global epidemic associated with increased health expenditure, and low quality of life. Many non-genetic risk factors have been suggested, but their overall epidemiological credibility has not been assessed. METHODS: We searched PubMed to capture all meta-analyses and Mendelian randomization studies for risk factors of T2DM. For each association, we estimated the summary effect size, its 95% confidence and prediction interval, and the I2 metric...
2018: PloS One
https://www.readbyqxmd.com/read/29555990/adult-height-is-associated-with-increased-risk-of-ovarian-cancer-a-mendelian-randomisation-study
#11
Suzanne C Dixon-Suen, Christina M Nagle, Aaron P Thrift, Paul D P Pharoah, Ailith Ewing, Celeste Leigh Pearce, Wei Zheng, Georgia Chenevix-Trench, Peter A Fasching, Matthias W Beckmann, Diether Lambrechts, Ignace Vergote, Sandrina Lambrechts, Els Van Nieuwenhuysen, Mary Anne Rossing, Jennifer A Doherty, Kristine G Wicklund, Jenny Chang-Claude, Audrey Y Jung, Kirsten B Moysich, Kunle Odunsi, Marc T Goodman, Lynne R Wilkens, Pamela J Thompson, Yurii B Shvetsov, Thilo Dörk, Tjoung-Won Park-Simon, Peter Hillemanns, Natalia Bogdanova, Ralf Butzow, Heli Nevanlinna, Liisa M Pelttari, Arto Leminen, Francesmary Modugno, Roberta B Ness, Robert P Edwards, Joseph L Kelley, Florian Heitz, Andreas du Bois, Philipp Harter, Ira Schwaab, Beth Y Karlan, Jenny Lester, Sandra Orsulic, Bobbie J Rimel, Susanne K Kjær, Estrid Høgdall, Allan Jensen, Ellen L Goode, Brooke L Fridley, Julie M Cunningham, Stacey J Winham, Graham G Giles, Fiona Bruinsma, Roger L Milne, Melissa C Southey, Michelle A T Hildebrandt, Xifeng Wu, Karen H Lu, Dong Liang, Douglas A Levine, Maria Bisogna, Joellen M Schildkraut, Andrew Berchuck, Daniel W Cramer, Kathryn L Terry, Elisa V Bandera, Sara H Olson, Helga B Salvesen, Liv Cecilie Vestrheim Thomsen, Reidun K Kopperud, Line Bjorge, Lambertus A Kiemeney, Leon F A G Massuger, Tanja Pejovic, Amanda Bruegl, Linda S Cook, Nhu D Le, Kenneth D Swenerton, Angela Brooks-Wilson, Linda E Kelemen, Jan Lubiński, Tomasz Huzarski, Jacek Gronwald, Janusz Menkiszak, Nicolas Wentzensen, Louise Brinton, Hannah Yang, Jolanta Lissowska, Claus K Høgdall, Lene Lundvall, Honglin Song, Jonathan P Tyrer, Ian Campbell, Diana Eccles, James Paul, Rosalind Glasspool, Nadeem Siddiqui, Alice S Whittemore, Weiva Sieh, Valerie McGuire, Joseph H Rothstein, Steven A Narod, Catherine Phelan, Harvey A Risch, John R McLaughlin, Hoda Anton-Culver, Argyrios Ziogas, Usha Menon, Simon A Gayther, Susan J Ramus, Aleksandra Gentry-Maharaj, Anna H Wu, Malcolm C Pike, Chiu-Chen Tseng, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Agnieszka Budzilowska, Iwona K Rzepecka, Penelope M Webb
BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms...
March 20, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29549348/age-at-menarche-and-adult-body-mass-index-a-mendelian-randomization-study
#12
Dipender Gill, Christopher F Brewer, Fabiola Del Greco M, Prasanthi Sivakumaran, Jack Bowden, Nuala A Sheehan, Cosetta Minelli
BACKGROUND: Pubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it difficult to infer causality. METHODS: The Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy)...
February 26, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/29547942/leveraging-lung-tissue-transcriptome-to-uncover-candidate-causal-genes-in-copd-genetic-associations
#13
Maxime Lamontagne, Jean-Christophe Bérubé, Ma'en Obeidat, Michael H Cho, Brian D Hobbs, Phuwanat Sakornsakolpat, Kim de Jong, H Marike Boezen, David Nickle, Ke Hao, Wim Timens, Maarten van den Berge, Philippe Joubert, Michel Laviolette, Don D Sin, Peter D Paré, Yohan Bossé
Causal genes of chronic obstructive pulmonary disease (COPD) remain elusive. The current study aims at integrating genome-wide association studies (GWAS) and lung expression quantitative loci (eQTL) data to map COPD candidate causal genes and gain biological insights into the recently discovered COPD susceptibility loci. Two complementary genomic datasets on COPD were studied. First, the lung eQTL dataset which included whole-genome gene expression and genotyping data from 1,038 individuals. Second, the largest COPD GWAS to date from the International COPD Genetics Consortium (ICGC) with 13,710 cases and 38,062 controls...
March 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29545162/birth-weight-gestational-age-and-late-adolescent-liver-function-using-twin-status-as-instrumental-variable-in-a-hong-kong-chinese-birth-cohort-children-of-1997
#14
Jun Xi Liu, Shiu Lun Au Yeung, Man Ki Kwok, June Yue Yan Leung, Shi Lin Lin, Lai Ling Hui, Gabriel Matthew Leung, C Mary Schooling
Birth weight (BW) is inversely associated with diabetes and liver function in Mendelian Randomization studies. Observationally, lower BW is usually also associated with poorer liver function. However, these studies could be confounded by socioeconomic position. Here we assessed if BW is associated with liver function in a unique population with little socio-economic patterning of BW, using both instrumental variable and an observational analysis. We used instrumental variable analysis (IVA) to assess the association of BW with liver function (alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, and albumin) at ~17 years with twin status as an instrumental variable in the prospective population-representative "Children of 1997" birth cohort (n = 8327)...
March 13, 2018: Preventive Medicine
https://www.readbyqxmd.com/read/29544020/thyroid-stimulating-hormone-and-bone-mineral-density-evidence-from-a-two-sample-mendelian-randomization-study-and-a-candidate-gene-association-study
#15
Nicolien A Van Vliet, Raymond Noordam, Jan B Van Klinken, Rudi G J Westendorp, J H Duncan Bassett, Graham R Williams, Diana Van Heemst
With population aging, prevalence of low bone mineral density (BMD) and associated fracture risk are increased. To determine whether low circulating thyroid stimulating hormone (TSH) levels within the normal range are causally related to BMD, we conducted a two-sample Mendelian randomization (MR) study. Furthermore, we tested whether common genetic variants in the TSH receptor (TSHR) gene and genetic variants influencing expression of TSHR (eQTLs) are associated with BMD. For both analyses, we used summary-level data of genome-wide association studies (GWAS) investigating BMD of the femoral neck (N = 32,735) and the lumbar spine (N = 28,498) in cohorts of European ancestry from the Genetic Factors of Osteoporosis (GEFOS) Consortium...
March 15, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29540730/genetic-contributions-to-the-association-between-adult-height-and-head-and-neck-cancer-a-mendelian-randomization-analysis
#16
Roberta Pastorino, Anna Puggina, Robert Carreras-Torres, Pagona Lagiou, Ivana Holcátová, Lorenzo Richiardi, Kristina Kjaerheim, Antonio Agudo, Xavier Castellsagué, Tatiana V Macfarlane, Luigi Barzan, Cristina Canova, Nalin S Thakker, David I Conway, Ariana Znaor, Claire M Healy, Wolfgang Ahrens, David Zaridze, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Eleonora Fabianova, Ioan Nicolae Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Paul Brennan, Valérie Gaborieau, James D McKay, Stefania Boccia
With the aim to dissect the effect of adult height on head and neck cancer (HNC), we use the Mendelian randomization (MR) approach to test the association between genetic instruments for height and the risk of HNC. 599 single nucleotide polymorphisms (SNPs) were identified as genetic instruments for height, accounting for 16% of the phenotypic variation. Genetic data concerning HNC cases and controls were obtained from a genome-wide association study. Summary statistics for genetic association were used in complementary MR approaches: the weighted genetic risk score (GRS) and the inverse-variance weighted (IVW)...
March 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29536507/assessing-the-causal-association-between-25-hydroxyvitamin-d-and-the-risk-of-oral-and-oropharyngeal-cancer-using-mendelian-randomization
#17
Tom Dudding, Mattias Johansson, Steven J Thomas, Paul Brennan, Richard M Martin, Nicholas J Timpson
Circulating 25-hydroxyvitamin D (25OHD) is an appealing potential intervention for cancer risk and has been associated with oral and oropharyngeal cancer risk but evidence is inconsistent. The availability of genetic variants, uncorrelated with known confounders, but predictive of 25OHD and genetic data in a large oral and oropharyngeal cancer collaboration aids causal inference when assessing this association. 5,133 oral and oropharyngeal cancer cases and 5,984 controls with genetic data were included in the study...
March 14, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29535274/role-of-blood-lipids-in-the-development-of-ischemic-stroke-and-its-subtypes-a-mendelian-randomization-study
#18
George Hindy, Gunnar Engström, Susanna C Larsson, Matthew Traylor, Hugh S Markus, Olle Melander, Marju Orho-Melander
BACKGROUND AND PURPOSE: Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR)...
March 13, 2018: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/29523638/complement-c3-and-risk-of-diabetic-microvascular-disease-a-cohort-study-of-95202-individuals-from-the-general-population
#19
Katrine Laura Rasmussen, Børge Grønne Nordestgaard, Sune Fallgaard Nielsen
BACKGROUND: Whether the complement system is involved in the development of diabetic microvascular disease is unknown. We tested the hypothesis that high concentrations of complement C3 are associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. METHODS: We studied 95202 individuals from the general population with baseline measurements of complement C3, genotyped for rs1065489, rs429608, and rs448260 determining concentrations of complement C3, and enrolled in the Copenhagen General Population Study from 2003 through 2013, following them until April 10, 2013...
March 9, 2018: Clinical Chemistry
https://www.readbyqxmd.com/read/29523632/circulating-fetuin-a-and-risk-of-type-2-diabetes-a-mendelian-randomization-analysis
#20
Janine Kröger, Karina Meidtner, Norbert Stefan, Marcela Guevara, Nicola D Kerrison, Eva Ardanaz, Dagfinn Aune, Heiner Boeing, Miren Dorronsoro, Courtney Dow, Guy Fagherazzi, Paul W Franks, Heinz Freisling, Marc J Gunter, José María Huerta, Rudolf Kaaks, Timothy J Key, Kay Tee Khaw, Vittorio Krogh, Tilman Kühn, Francesca Romana Mancini, Amalia Mattiello, Peter M Nilsson, Anja Olsen, Kim Overvad, Domenico Palli, J Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, Núria Sala, Elena Salamanca-Fernández, Ivonne Sluijs, Annemieke Mw Spijkerman, Anne Tjonneland, Konstantinos K Tsilidis, Rosario Tumino, Yvonne T van der Schouw, Nita G Forouhi, Stephen J Sharp, Claudia Langenberg, Elio Riboli, Matthias B Schulze, Nicholas J Wareham
Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian Randomization study with SNPs located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the prospective EPIC-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 cases...
March 9, 2018: Diabetes
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