Mendelian randomization: genetic anchors for causal inference in epidemiological studies
George Davey Smith,Gibran Hemani +1 more
Reads0
Chats0
TLDR
Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review.Abstract:
Observational epidemiological studies are prone to confounding, reverse causation and various biases and have generated findings that have proved to be unreliable indicators of the causal effects of modifiable exposures on disease outcomes. Mendelian randomization (MR) is a method that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence regarding which interventions should produce health benefits. The approach is being widely applied, and various ways to strengthen inference given the known potential limitations of MR are now available. Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review. The integration of genetic information into population-based epidemiological studies presents translational opportunities, which capitalize on the investment in genomic discovery research.read more
Citations
More filters
Journal ArticleDOI
Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression
TL;DR: An adaption of Egger regression can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations, and provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation.
Journal ArticleDOI
An atlas of genetic correlations across human diseases and traits.
Brendan Bulik-Sullivan,Brendan Bulik-Sullivan,Hilary K. Finucane,Verneri Anttila,Verneri Anttila,Alexander Gusev,Felix R. Day,Po-Ru Loh,Po-Ru Loh,Laramie E. Duncan,Laramie E. Duncan,John R. B. Perry,Nick Patterson,Elise B. Robinson,Elise B. Robinson,Mark J. Daly,Mark J. Daly,Alkes L. Price,Alkes L. Price,Benjamin M. Neale,Benjamin M. Neale +20 more
TL;DR: This work introduces a technique—cross-trait LD Score regression—for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap, and uses this method to estimate 276 genetic correlations among 24 traits.
Journal ArticleDOI
Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator.
TL;DR: A novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate is presented, which is consistent even when up to 50% of the information comes from invalid instrumental variables.
Journal ArticleDOI
The MR-Base platform supports systematic causal inference across the human phenome
Gibran Hemani,Jie Zheng,Benjamin Elsworth,Kaitlin H Wade,Valeriia Haberland,Denis Baird,Charles Laurin,Stephen Burgess,Jack Bowden,Ryan Langdon,Vanessa Y Tan,James Yarmolinsky,Hashem A Shihab,Nicholas J. Timpson,David M. Evans,David M. Evans,Caroline L Relton,Richard M. Martin,George Davey Smith,Tom R. Gaunt,Philip C Haycock +20 more
TL;DR: MR-Base is a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR, and includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions.
Journal ArticleDOI
An Expanded View of Complex Traits: From Polygenic to Omnigenic
TL;DR: It is proposed that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways.
References
More filters
Journal ArticleDOI
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
Shaun Purcell,Shaun Purcell,Naomi R. Wray,Jennifer Stone,Jennifer Stone,Peter M. Visscher,Michael Conlon O'Donovan,Patrick F. Sullivan,Pamela Sklar,Pamela Sklar,Douglas M. Ruderfer,Andrew McQuillin,Derek W. Morris,Colm O'Dushlaine,Aiden Corvin,Peter Holmans,Stuart MacGregor,Hugh Gurling,Douglas Blackwood,Nicholas John Craddock,Michael Gill,Christina M. Hultman,Christina M. Hultman,George Kirov,Paul Lichtenstein,Walter J. Muir,Michael John Owen,Carlos N. Pato,Edward M. Scolnick,Edward M. Scolnick,David St Clair,Nigel Williams,Lyudmila Georgieva,Ivan Nikolov,Nadine Norton,Hywel Williams,Draga Toncheva,Vihra Milanova,Emma Flordal Thelander,Patrick Sullivan,Elaine Kenny,Emma M. Quinn,Khalid Choudhury,Susmita Datta,Jonathan Pimm,Srinivasa Thirumalai,Vinay Puri,Robert Krasucki,Jacob Lawrence,Digby Quested,Nicholas Bass,Caroline Crombie,Gillian Fraser,Soh Leh Kuan,Nicholas Walker,Kevin A. McGhee,Ben S. Pickard,P. Malloy,Alan W Maclean,Margaret Van Beck,Michele T. Pato,Helena Medeiros,Frank A. Middleton,Célia Barreto Carvalho,Christopher P. Morley,Ayman H. Fanous,David V. Conti,James A. Knowles,Carlos Ferreira,António Macedo,M. Helena Azevedo,Andrew Kirby,Andrew Kirby,Manuel A. R. Ferreira,Manuel A. R. Ferreira,Mark J. Daly,Mark J. Daly,Kimberly Chambert,Finny G Kuruvilla,Stacey Gabriel,Kristin G. Ardlie,Jennifer L. Moran +81 more
TL;DR: The extent to which common genetic variation underlies the risk of schizophrenia is shown, using two analytic approaches, and the major histocompatibility complex is implicate, which is shown to involve thousands of common alleles of very small effect.
Journal ArticleDOI
A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity
Timothy M. Frayling,Nicholas J. Timpson,Michael N. Weedon,Eleftheria Zeggini,Eleftheria Zeggini,Eleftheria Zeggini,Rachel M. Freathy,Cecilia M. Lindgren,John R. B. Perry,Katherine S. Elliott,Katherine S. Elliott,Hana Lango,Nigel W. Rayner,Nigel W. Rayner,Nigel W. Rayner,Beverley M. Shields,Lorna W. Harries,Jeffrey C. Barrett,Jeffrey C. Barrett,Sian Ellard,Christopher J. Groves,Christopher J. Groves,Bridget A. Knight,Ann-Marie Patch,Andy R Ness,Shah Ebrahim,Debbie A Lawlor,Susan M. Ring,Yoav Ben-Shlomo,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Ulla Sovio,Ulla Sovio,Amanda J. Bennett,Amanda J. Bennett,David Melzer,Luigi Ferrucci,Ruth J. F. Loos,Inês Barroso,Nicholas J. Wareham,Fredrik Karpe,Fredrik Karpe,Katharine R. Owen,Katharine R. Owen,Lon R. Cardon,Mark Walker,Graham A. Hitman,Graham A. Hitman,Colin N. A. Palmer,Colin N. A. Palmer,Alex S. F. Doney,Alex S. F. Doney,Andrew D. Morris,George Davey Smith,Andrew T. Hattersley,Mark I. McCarthy +55 more
TL;DR: A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI).
Journal ArticleDOI
‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?
George Davey Smith,Shah Ebrahim +1 more
TL;DR: Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
Journal ArticleDOI
Effects of Torcetrapib in Patients at High Risk for Coronary Events
Philip J. Barter,Mark J. Caulfield,Mats Eriksson,Scott M. Grundy,John J.P. Kastelein,Michel Komajda,Jose Lopez-Sendon,Lori Mosca,Jean-Claude Tardif,David D. Waters,Charles L. Shear,James H. Revkin,Kevin A. Buhr,Marian R. Fisher,Alan R. Tall,Bryan Brewer +15 more
TL;DR: Although there was evidence of an off-target effect of torcetrapib, it cannot rule out adverse effects related to CETP inhibition, and the trial was terminated prematurely because of an increased risk of death and cardiac events.
Journal ArticleDOI
Discovery and refinement of loci associated with lipid levels
Cristen J. Willer,Ellen M. Schmidt,Sebanti Sengupta,Gina M. Peloso,Gina M. Peloso,Gina M. Peloso,Stefan Gustafsson,Stavroula Kanoni,Andrea Ganna,Andrea Ganna,Jin Chen,Martin L. Buchkovich,Samia Mora,Jacques S. Beckmann,Jennifer L. Bragg-Gresham,Hsing-Yi Chang,Ayse Demirkan,Heleen M. den Hertog,Ron Do,Louise A. Donnelly,Georg Ehret,Georg Ehret,Tõnu Esko,Tõnu Esko,Mary F. Feitosa,Teresa Ferreira,Krista Fischer,Pierre Fontanillas,Ross M. Fraser,Daniel F. Freitag,Deepti Gurdasani,Deepti Gurdasani,Kauko Heikkilä,Elina Hyppönen,Aaron Isaacs,Anne U. Jackson,Åsa Johansson,Toby Johnson,Marika Kaakinen,Johannes Kettunen,Johannes Kettunen,Marcus E. Kleber,Marcus E. Kleber,Xiaohui Li,Jian'an Luan,Leo-Pekka Lyytikäinen,Patrik K. E. Magnusson,Massimo Mangino,Evelin Mihailov,May E. Montasser,Martina Müller-Nurasyid,Ilja M. Nolte,Jeffrey R. O'Connell,Cameron D. Palmer,Cameron D. Palmer,Markus Perola,Markus Perola,Markus Perola,Ann-Kristin Petersen,Serena Sanna,Richa Saxena,Sonia Shah,Dmitry Shungin,Dmitry Shungin,Carlo Sidore,Carlo Sidore,Ci Song,Ci Song,Rona J. Strawbridge,Ida Surakka,Ida Surakka,Toshiko Tanaka,Tanya M. Teslovich,Gudmar Thorleifsson,Evita G. Van Den Herik,Benjamin F. Voight,Kelly A. Volcik,Lindsay L. Waite,Andrew Wong,Ying Wu,Weihua Zhang,Weihua Zhang,Devin Absher,Gershim Asiki,Inês Barroso,Inês Barroso,Inês Barroso,Latonya F. Been,Jennifer L. Bolton,Lori L. Bonnycastle,Paolo Brambilla,Mary Susan Burnett,Giancarlo Cesana,Maria Dimitriou,Alex S. F. Doney,Angela Döring,Paul Elliott,Paul Elliott,Stephen E. Epstein,Gudmundur I. Eyjolfsson,Bruna Gigante,Mark O. Goodarzi,Harald Grallert,Martha L. Gravito,Christopher J. Groves,Göran Hallmans,Anna-Liisa Hartikainen,Caroline Hayward,Dena G. Hernandez,Andrew A. Hicks,Hilma Holm,Yi Jen Hung,Thomas Illig,Matthew Jones,Pontiano Kaleebu,John J.P. Kastelein,Kay-Tee Khaw,Eric Kim,Norman Klopp,Pirjo Komulainen,Meena Kumari,Claudia Langenberg,Terho Lehtimäki,Shih-Yi Lin,Jaana Lindström,Ruth J. F. Loos,Ruth J. F. Loos,François Mach,Wendy L. McArdle,Christa Meisinger,Braxton D. Mitchell,Gabrielle Müller,Ramaiah Nagaraja,Narisu Narisu,Tuomo Nieminen,Rebecca N. Nsubuga,Isleifur Olafsson,Ken K. Ong,Ken K. Ong,Aarno Palotie,Aarno Palotie,Theodore Papamarkou,Theodore Papamarkou,Theodore Papamarkou,Cristina Pomilla,Cristina Pomilla,Anneli Pouta,Anneli Pouta,Daniel J. Rader,Muredach P. Reilly,Paul M. Ridker,Fernando Rivadeneira,Igor Rudan,Aimo Ruokonen,Nilesh J. Samani,Nilesh J. Samani,Hubert Scharnagl,Janet Seeley,Janet Seeley,Kaisa Silander,Kaisa Silander,Alena Stančáková,Kathleen Stirrups,Amy J. Swift,Laurence Tiret,André G. Uitterlinden,L. Joost van Pelt,Sailaja Vedantam,Sailaja Vedantam,Nicholas W.J. Wainwright,Nicholas W.J. Wainwright,Cisca Wijmenga,Sarah H. Wild,Gonneke Willemsen,Tom Wilsgaard,James F. Wilson,Elizabeth H. Young,Elizabeth H. Young,Jing Hua Zhao,Linda S. Adair,Dominique Arveiler,Themistocles L. Assimes,Stefania Bandinelli,Franklyn I. Bennett,Murielle Bochud,Bernhard O. Boehm,Bernhard O. Boehm,Dorret I. Boomsma,Ingrid B. Borecki,Stefan R. Bornstein,Pascal Bovet,Michel Burnier,Harry Campbell,Aravinda Chakravarti,John C. Chambers,John C. Chambers,John C. Chambers,Yii-Der Ida Chen,Yii-Der Ida Chen,Francis S. Collins,Richard S. Cooper,John Danesh,George Dedoussis,Ulf de Faire,Alan B. Feranil,Jean Ferrières,Luigi Ferrucci,Nelson B. Freimer,Christian Gieger,Leif Groop,Leif Groop,Vilmundur Gudnason,Ulf Gyllensten,Anders Hamsten,Tamara B. Harris,Aroon D. Hingorani,Joel N. Hirschhorn,Joel N. Hirschhorn,Albert Hofman,G. Kees Hovingh,Chao A. Hsiung,Steve E. Humphries,Steven C. Hunt,Kristian Hveem,Carlos Iribarren,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Antti Jula,Mika Kähönen,Jaakko Kaprio,Jaakko Kaprio,Antero Kesäniemi,Mika Kivimäki,Jaspal S. Kooner,Jaspal S. Kooner,Jaspal S. Kooner,Peter J. Koudstaal,Ronald M. Krauss,Diana Kuh,Johanna Kuusisto,Kirsten Ohm Kyvik,Markku Laakso,Timo A. Lakka,Timo A. Lakka,Lars Lind,Cecilia M. Lindgren,Nicholas G. Martin,Winfried März,Winfried März,Winfried März,Mark I. McCarthy,Colin A. McKenzie,Pierre Meneton,Andres Metspalu,Leena Moilanen,Andrew D. Morris,Patricia B. Munroe,Inger Njølstad,Nancy L. Pedersen,Chris Power,Peter P. Pramstaller,Peter P. Pramstaller,Jackie F. Price,Bruce M. Psaty,Bruce M. Psaty,Thomas Quertermous,Rainer Rauramaa,Rainer Rauramaa,Danish Saleheen,Danish Saleheen,Veikko Salomaa,Dharambir K. Sanghera,Jouko Saramies,Peter Schwarz,Wayne Huey-Herng Sheu,Alan R. Shuldiner,Alan R. Shuldiner,Agneta Siegbahn,Tim D. Spector,Kari Stefansson,Kari Stefansson,David P. Strachan,Bamidele O. Tayo,Elena Tremoli,Jaakko Tuomilehto,Matti Uusitupa,Cornelia M. van Duijn,Peter Vollenweider,Lars Wallentin,Nicholas J. Wareham,John Whitfield,Bruce H. R. Wolffenbuttel,Jose M. Ordovas,Jose M. Ordovas,Eric Boerwinkle,Colin N. A. Palmer,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Daniel I. Chasman,Jerome I. Rotter,Paul W. Franks,Paul W. Franks,Paul W. Franks,Samuli Ripatti,Samuli Ripatti,Samuli Ripatti,L. Adrienne Cupples,L. Adrienne Cupples,Manjinder S. Sandhu,Manjinder S. Sandhu,Stephen S. Rich,Michael Boehnke,Panos Deloukas,Sekar Kathiresan,Sekar Kathiresan,Karen L. Mohlke,Erik Ingelsson,Erik Ingelsson,Gonçalo R. Abecasis +319 more
TL;DR: It is found that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index.
Related Papers (5)
‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?
George Davey Smith,Shah Ebrahim +1 more
The MR-Base platform supports systematic causal inference across the human phenome
Gibran Hemani,Jie Zheng,Benjamin Elsworth,Kaitlin H Wade,Valeriia Haberland,Denis Baird,Charles Laurin,Stephen Burgess,Jack Bowden,Ryan Langdon,Vanessa Y Tan,James Yarmolinsky,Hashem A Shihab,Nicholas J. Timpson,David M. Evans,David M. Evans,Caroline L Relton,Richard M. Martin,George Davey Smith,Tom R. Gaunt,Philip C Haycock +20 more