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A unified framework for joint-tissue transcriptome-wide association and Mendelian randomization analysis.
Zhou D, Jiang Y, Zhong X, Cox NJ, Liu C, Gamazon ER
(2020) Nat Genet 52: 1239-1246
MeSH Terms: Animals, Gene Expression Profiling, Genetic Association Studies, Humans, Lipoproteins, LDL, Mendelian Randomization Analysis, Mice, Models, Genetic, Multifactorial Inheritance, Predictive Value of Tests
Show Abstract · Added October 7, 2020
Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation method PrediXcan as a special case and outperforms other single-tissue approaches (the Bayesian sparse linear mixed model and Dirichlet process regression). MR-JTI models variant-level heterogeneity (primarily due to horizontal pleiotropy, addressing a major challenge of transcriptome-wide association study interpretation) and performs causal inference with type I error control. We make explicit the connection between the genetic architecture of gene expression and of complex traits and the suitability of Mendelian randomization as a causal inference strategy for transcriptome-wide association studies. We provide a resource of imputation models generated from GTEx and PsychENCODE panels. Analysis of biobanks and meta-analysis data, and extensive simulations show substantially improved statistical power, replication and causal mapping rate for JTI relative to existing approaches.
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10 MeSH Terms
Association of Genetic Risk of Obesity with Postoperative Complications Using Mendelian Randomization.
Robinson JR, Carroll RJ, Bastarache L, Chen Q, Mou Z, Wei WQ, Connolly JJ, Mentch F, Sleiman P, Crane PK, Hebbring SJ, Stanaway IB, Crosslin DR, Gordon AS, Rosenthal EA, Carrell D, Hayes MG, Wei W, Petukhova L, Namjou B, Zhang G, Safarova MS, Walton NA, Still C, Bottinger EP, Loos RJF, Murphy SN, Jackson GP, Kullo IJ, Hakonarson H, Jarvik GP, Larson EB, Weng C, Roden DM, Denny JC
(2020) World J Surg 44: 84-94
MeSH Terms: Adult, Body Mass Index, Female, Humans, Logistic Models, Male, Mendelian Randomization Analysis, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Postoperative Complications, Retrospective Studies, Risk Factors
Show Abstract · Added March 24, 2020
BACKGROUND - The extent to which obesity and genetics determine postoperative complications is incompletely understood.
METHODS - We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity-risk single-nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components.
RESULTS - Individuals with overweight or obese BMI (≥25 kg/m) had increased risk of incisional hernia (odds ratio [OR] 1.7-5.5, p < 3.1 × 10), and people with obesity (BMI ≥ 30 kg/m) had increased risk of postoperative infection (OR 1.2-2.3, p < 2.5 × 10). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8-2.5], p = 1.4 × 10) and postoperative infection (OR 1.6 [95% CI 1.4-1.9], p = 3.1 × 10). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures.
CONCLUSIONS - Clinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection.
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13 MeSH Terms
MR-PheWAS: exploring the causal effect of SUA level on multiple disease outcomes by using genetic instruments in UK Biobank.
Li X, Meng X, Spiliopoulou A, Timofeeva M, Wei WQ, Gifford A, Shen X, He Y, Varley T, McKeigue P, Tzoulaki I, Wright AF, Joshi P, Denny JC, Campbell H, Theodoratou E
(2018) Ann Rheum Dis 77: 1039-1047
MeSH Terms: Adult, Arthritis, Autoimmune Diseases, Biological Specimen Banks, Celiac Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Gout, Humans, Hypertension, Male, Mendelian Randomization Analysis, Middle Aged, Multimorbidity, Myocardial Infarction, Prognosis, Risk Assessment, United Kingdom, Uric Acid
Show Abstract · Added March 14, 2018
OBJECTIVES - We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank.
METHODS - We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage.
RESULTS - Our PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus () that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy.
CONCLUSIONS - Elevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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20 MeSH Terms
PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.
Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, Hartwig FP, Horta BL, Hyppönen E, Power C, Moldovan M, van Iperen E, Hovingh GK, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Liu T, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott R, Luan J, Bobak M, Malyutina S, Pająk A, Kubinova R, Tamosiunas A, Pikhart H, Husemoen LL, Grarup N, Pedersen O, Hansen T, Linneberg A, Simonsen KS, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Kirchner HL, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, LifeLines Cohort study group, Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dörr M, Lerch MM, Völker U, Völzke H, Ward J, Pell JP, Smith DJ, Meade T, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Balkau B, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Ridker PM, Chasman DI, Reiner AP, Lange LA, Ritchie MD, Asselbergs FW, Casas JP, Keating BJ, Preiss D, Hingorani AD, UCLEB consortium, Sattar N
(2017) Lancet Diabetes Endocrinol 5: 97-105
MeSH Terms: Blood Glucose, Case-Control Studies, Cholesterol, LDL, Cohort Studies, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Genetic Variation, Humans, Mendelian Randomization Analysis, Proprotein Convertase 9, Randomized Controlled Trials as Topic
Show Abstract · Added March 14, 2018
BACKGROUND - Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.
METHODS - In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.
FINDINGS - Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m, -0·09 to 0·30).
INTERPRETATION - PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.
FUNDING - British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.
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11 MeSH Terms
Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses.
Khankari NK, Shu XO, Wen W, Kraft P, Lindström S, Peters U, Schildkraut J, Schumacher F, Bofetta P, Risch A, Bickeböller H, Amos CI, Easton D, Eeles RA, Gruber SB, Haiman CA, Hunter DJ, Chanock SJ, Pierce BL, Zheng W, Colorectal Transdisciplinary Study (CORECT), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Transdisciplinary Research in Cancer of the Lung (TRICL)
(2016) PLoS Med 13: e1002118
MeSH Terms: Adult, Aged, Aged, 80 and over, Body Height, Colorectal Neoplasms, Female, Genetic Variation, Genome-Wide Association Study, Humans, Lung Neoplasms, Male, Mendelian Randomization Analysis, Middle Aged, Odds Ratio, Prospective Studies, Prostatic Neoplasms, Risk Factors, Young Adult
Show Abstract · Added April 10, 2018
BACKGROUND - Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers.
METHODS AND FINDINGS - A systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate.
CONCLUSIONS - Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers.
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MeSH Terms
Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.
Guo Y, Warren Andersen S, Shu XO, Michailidou K, Bolla MK, Wang Q, Garcia-Closas M, Milne RL, Schmidt MK, Chang-Claude J, Dunning A, Bojesen SE, Ahsan H, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bogdanova NV, Bonanni B, Børresen-Dale AL, Brand J, Brauch H, Brenner H, Brüning T, Burwinkel B, Casey G, Chenevix-Trench G, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Dörk T, Dumont M, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fostira F, Gammon M, Giles GG, Guénel P, Haiman CA, Hamann U, Hooning MJ, Hopper JL, Jakubowska A, Jasmine F, Jenkins M, John EM, Johnson N, Jones ME, Kabisch M, Kibriya M, Knight JA, Koppert LB, Kosma VM, Kristensen V, Le Marchand L, Lee E, Li J, Lindblom A, Luben R, Lubinski J, Malone KE, Mannermaa A, Margolin S, Marme F, McLean C, Meijers-Heijboer H, Meindl A, Neuhausen SL, Nevanlinna H, Neven P, Olson JE, Perez JI, Perkins B, Peterlongo P, Phillips KA, Pylkäs K, Rudolph A, Santella R, Sawyer EJ, Schmutzler RK, Seynaeve C, Shah M, Shrubsole MJ, Southey MC, Swerdlow AJ, Toland AE, Tomlinson I, Torres D, Truong T, Ursin G, Van Der Luijt RB, Verhoef S, Whittemore AS, Winqvist R, Zhao H, Zhao S, Hall P, Simard J, Kraft P, Pharoah P, Hunter D, Easton DF, Zheng W
(2016) PLoS Med 13: e1002105
MeSH Terms: Body Mass Index, Breast Neoplasms, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Humans, Mendelian Randomization Analysis, Menopause, Middle Aged, Models, Statistical, Polymorphism, Single Nucleotide, Risk Factors
Show Abstract · Added April 18, 2017
BACKGROUND - Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.
METHODS - We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.
RESULTS - In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.
CONCLUSIONS - BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
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12 MeSH Terms
Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization.
Zhang B, Shu XO, Delahanty RJ, Zeng C, Michailidou K, Bolla MK, Wang Q, Dennis J, Wen W, Long J, Li C, Dunning AM, Chang-Claude J, Shah M, Perkins BJ, Czene K, Darabi H, Eriksson M, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Lambrechts D, Neven P, Wildiers H, Floris G, Schmidt MK, Rookus MA, van den Hurk K, de Kort WL, Couch FJ, Olson JE, Hallberg E, Vachon C, Rudolph A, Seibold P, Flesch-Janys D, Peto J, Dos-Santos-Silva I, Fletcher O, Johnson N, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Li J, Humphreys K, Brand J, Guénel P, Truong T, Cordina-Duverger E, Menegaux F, Burwinkel B, Marme F, Yang R, Surowy H, Benitez J, Zamora MP, Perez JI, Cox A, Cross SS, Reed MW, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Chenevix-Trench G, kConFab Investigators, Australian Ovarian Study Group, Haiman CA, Henderson BE, Schumacher F, Marchand LL, Lindblom A, Margolin S, Hooning MJ, Martens JW, Tilanus-Linthorst MM, Collée JM, Hopper JL, Southey MC, Tsimiklis H, Apicella C, Slager S, Toland AE, Ambrosone CB, Yannoukakos D, Giles GG, Milne RL, McLean C, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Swerdlow AJ, Ashworth A, Orr N, Jones M, Figueroa J, Garcia-Closas M, Brinton L, Lissowska J, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Brauch H, Brüning T, Ko YD, Peterlongo P, Manoukian S, Bonanni B, Radice P, Bogdanova N, Antonenkova N, Dörk T, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Devilee P, Seynaeve C, Van Asperen CJ, Jakubowska A, Lubiński J, Jaworska-Bieniek K, Durda K, Hamann U, Torres D, Schmutzler RK, Neuhausen SL, Anton-Culver H, Kristensen VN, Grenaker Alnæs GI, DRIVE Project, Pierce BL, Kraft P, Peters U, Lindstrom S, Seminara D, Burgess S, Ahsan H, Whittemore AS, John EM, Gammon MD, Malone KE, Tessier DC, Vincent D, Bacot F, Luccarini C, Baynes C, Ahmed S, Maranian M, Healey CS, González-Neira A, Pita G, Alonso MR, Álvarez N, Herrero D, Pharoah PD, Simard J, Hall P, Hunter DJ, Easton DF, Zheng W
(2015) J Natl Cancer Inst 107:
MeSH Terms: Body Height, Breast Neoplasms, Evidence-Based Medicine, Female, Humans, Mendelian Randomization Analysis, Odds Ratio, Prospective Studies, Risk Factors
Show Abstract · Added February 22, 2016
BACKGROUND - Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.
METHODS - We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients.
RESULTS - The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8).
CONCLUSIONS - Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.
Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Hiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, Wood AR, Michaëlsson K, Vandenput L, Zgaga L, Yerges-Armstrong LM, McCarthy MI, Dupuis J, Kaakinen M, Kleber ME, Jameson K, Arden N, Raitakari O, Viikari J, Lohman KK, Ferrucci L, Melhus H, Ingelsson E, Byberg L, Lind L, Lorentzon M, Salomaa V, Campbell H, Dunlop M, Mitchell BD, Herzig KH, Pouta A, Hartikainen AL, Genetic Investigation of Anthropometric Traits-GIANT Consortium, Streeten EA, Theodoratou E, Jula A, Wareham NJ, Ohlsson C, Frayling TM, Kritchevsky SB, Spector TD, Richards JB, Lehtimäki T, Ouwehand WH, Kraft P, Cooper C, März W, Power C, Loos RJ, Wang TJ, Järvelin MR, Whittaker JC, Hingorani AD, Hyppönen E
(2013) PLoS Med 10: e1001383
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Body Mass Index, Europe, European Continental Ancestry Group, Evidence-Based Medicine, Female, Genetic Predisposition to Disease, Humans, Linear Models, Male, Mendelian Randomization Analysis, Middle Aged, Multivariate Analysis, North America, Obesity, Phenotype, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Vitamin D, Vitamin D Deficiency
Show Abstract · Added April 15, 2014
BACKGROUND - Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.
METHODS AND FINDINGS - We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).
CONCLUSIONS - On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
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24 MeSH Terms