Discovery and Refinement of Loci Associated with Lipid Levels

  title={Discovery and Refinement of Loci Associated with Lipid Levels},
  author={Cristen J. Willer and Ellen M. Schmidt and Sebanti Sengupta and Gina M. Peloso and Stefan Gustafsson and Stavroula Kanoni and Andrea Ganna and Jin Chen and Martin L Buchkovich and Samia Mora and Jacques S. Beckmann and Jennifer L. Bragg-Gresham and Hsing-Yi Chang and Ayşe Demirkan and Heleen M. den Hertog and Ron Do and Louise Donnelly and Georg B. Ehret and T{\~o}nu Esko and Mary F. Feitosa and Teresa Ferreira and Krista Fischer and Pierre Fontanillas and Ross M Fraser and Daniel F. Freitag and Deepti Gurdasani and Kauko Heikkil{\"a} and Elina Hypp{\"o}nen and Aaron Isaacs and Anne U. Jackson and {\AA}sa Johansson and Toby Johnson and Marika A Kaakinen and Johannes Kettunen and Marcus Edi Kleber and Xiaohui Li and Jian’an Luan and Leo-Pekka Lyytik{\"a}inen and Patrik K. E. Magnusson and Massimo Mangino and Evelin Mihailov and May E. Montasser and Martina M{\"u}ller-Nurasyid and Ilja Maria Nolte and Jeffrey R. O’Connell and Cameron Palmer and Markus Perola and Ann-Kristin Petersen and Serena Sanna and Richa Saxena and Susan K. Service and Sonia Shah and Dmitry Shungin and Carlo Sidore and Ci Song and Rona J. Strawbridge and Ida Surakka and Toshiko Tanaka and Tanya M. Teslovich and Gudmar Thorleifsson and Evita G. van den Herik and Benjamin F. Voight and Kelly A. Volcik and Lindsay L. Waite and Andrew Wong and Ying Wu and Weihua Zhang and Devin M Absher and Gershim Asiki and In{\^e}s Barroso and Latonya Been and Jennifer L. Bolton and Lori L Bonnycastle and Paolo Brambilla and Mary Susan Burnett and Giancarlo Cesana and Maria Dimitriou and Alex S. F. Doney and Angela D{\"o}ring and Paul Elliott and Stephen E. Epstein and Gudmundur Ingi Eyjolfsson and Bruna Gigante and Mark O. Goodarzi and Harald Grallert and Martha L. Gravito and Christopher J. Groves and Göran Hallmans and A-L. Hartikainen and Caroline Hayward and Dena G Hernandez and Andrew A. Hicks and Hilma H{\'o}lm and Yi-Jen Hung and Thomas Illig and Michelle R Jones and Pontiano Kaleebu and John J Kastelein and Kay-Tee Khaw and Eric S. Kim and Norman Klopp and Pirjo Komulainen and Meena Kumari and Claudia Langenberg and Terho Lehtim{\"a}ki and Shih-Yi Lin and Jaana Lindstr{\"o}m and Ruth J. F. Loos and François Mach and Wendy L McArdle and Christa Meisinger and Braxton D. Mitchell and Gabrielle M{\"u}ller and Ramaiah Nagaraja and Narisu Narisu and Tuomo V M Nieminen and Rebecca N. Nsubuga and Isleifur Olafsson and Ken K. Ong and Aarno Palotie and Theodore Papamarkou and Cristina Pomilla and Anneli Pouta and Daniel J. Rader and Muredach P. Reilly and Paul M. Ridker and Fernando Rivadeneira and Igor Rudan and Aimo O Ruokonen and Nilesh J. Samani and Hubert Scharnagl and Janet Seeley and Kaisa Silander and Alena Stan{\vc}{\'a}kov{\'a} and Kathleen E. Stirrups and Amy J. Swift and Laurence Tiret and Andr{\'e} G. Uitterlinden and Lucas Joost Van Pelt and Sailaja Vedantam and Nicholas W. J. Wainwright and Cisca Wijmenga and Sarah H. Wild and Gonneke Willemsen and Tom Wilsgaard and James F. Wilson and Elizabeth H. Young and Jing Hua Zhao and Linda S Adair and Dominique Arveiler and Themistocles L. Assimes and Stefania Bandinelli and Franklyn I. Bennett and Murielle Bochud and Bernhard Otto Boehm and Dorret I. Boomsma and Ingrid B. Borecki and Stefan R. Bornstein and Pascal Bovet and Michel Burnier and Harry Campbell and Aravinda Chakravarti and John C Chambers and Yii-der Ida Chen and Francis S. Collins and Richard S. Cooper and John Danesh and George V. Dedoussis and Ulf de Faire and Alan B. Feranil and Jean Ferri{\`e}res and Luigi Ferrucci and Nelson B. Freimer and Christian Gieger and Leif C. Groop and Vilmundur G. Gudnason and Ulf Gyllensten and Anders Hamsten and Tamara B. Harris and Aroon D. Hingorani and Joel N. Hirschhorn and Albert Hofman and G Kees Hovingh and Chao A. Hsiung and Steve E. Humphries and Steven C. Hunt and Kristian Hveem and Carlos Iribarren and Marjo-Riitta J{\"a}rvelin and Antti M. Jula and Mika K{\"a}h{\"o}nen and Jaakko A Kaprio and Antero Y. Kes{\"a}niemi and Mika Kivimaki and Jaspal S Kooner and Peter J. Koudstaal and Ronald M. Krauss and Diana Kuh and Johanna Kuusisto and Kirsten Ohm Kyvik and Markku Laakso and Timo A. Lakka and Lars Lind and Cecilia M. Lindgren and Nicholas G. Martin and Winfried M{\"a}rz and Mark I. McCarthy and Colin A Mckenzie and Pierre Meneton and Andres Metspalu and Leena Moilanen and Andrew D. Morris and Patricia B. Munroe and Inger Nj{\o}lstad and Nancy L. Pedersen and Christine Power and Peter Paul Pramstaller and Jackie F. Price and Bruce M. Psaty and Thomas Quertermous and Rainer Rauramaa and Danish Saleheen and Veikko V Salomaa and Dharambir K. Sanghera and Jouko Saramies and Peter E H Schwarz and Wayne Huey-Herng Sheu and Alan R. Shuldiner and Agneta Siegbahn and Tim D. Spector and K{\'a}ri Stef{\'a}nsson and David P. Strachan and Bamidele O. Tayo and Elena Tremoli and Jaakko Tuomilehto and Matti Uusitupa and Cornelia M. van Duijn and Peter Vollenweider and Lars Wallentin and Nicholas J. Wareham and John B. Whitfield and Bruce H. R. Wolffenbuttel and Jos{\'e} M. Ordov{\'a}s and Eric Boerwinkle and Colin N. A. Palmer and Unnur Thorsteinsd{\'o}ttir and Daniel I. Chasman and Jerome I. Rotter and Paul W. Franks and Samuli Ripatti and L. Adrienne Cupples and Manjinder S. Sandhu and Stephen S. Rich and Michael Boehnke and Panos Deloukas and Sekar Kathiresan and Karen L. Mohlke and Erik Ingelsson and Gonçalo R. Abecasis},
  journal={Nature genetics},
  pages={1274 - 1283}
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10−8, including 62 loci not previously associated with lipid levels in… 

Genetics of Circulating Blood Lipids

New biology behind lipid levels is demonstrated, in addition to how large scale studies with dense SNP panels enabled by genotype imputation, can be a key in revealing biological determinants behind complex diseases and traits.

The power of genetic diversity in genome-wide association studies of lipids.

A multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries, finds that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction.

Bivariate GWAS scan identifies six novel loci associated with lipid levels and coronary artery disease

Six novel variants individually associated with both lipids and coronary artery disease are discovered, indicating that these loci may be affecting disease risk through regulatory activity.

Bivariate Genome-Wide Association Scan Identifies 6 Novel Loci Associated With Lipid Levels and Coronary Artery Disease

At several of the loci, the GWAS signals jointly localize with genetic variants associated with expression level changes for more than one neighboring genes, indicating that these loci may be affecting disease risk through regulatory activity.

Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease

Apolipoprotein B is of fundamental causal relevance in the aetiology of CHD, and underlies the relationship of LDL cholesterol and triglycerides with CHD.

Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial

A genome-wide association study of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial finds many statistically significant CV findings replicate findings in large meta-analyses in non-diabetic subjects.

Replication and fine-mapping of genetic predictors of lipid traits in African-Americans

The genetic architecture of lipid traits in AAs differs substantially from that in Caucasians and it remains poorly characterized.

Mining genomic variants and causal pathways linking HDL and triglycerides to coronary disease

The findings suggest that HDL functionality in driving cholesterol removal through SR-BI (the reverse cholesterol transport hypothesis) is protective from CHD in humans, and provides a sampling of approaches for leveraging the spectrum of genomic methods to identify clinically relevant variants impacting HDL, TG and CHD risk.

Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis

Genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation suggest that apolipoprotein B is a leading candidate for a causal role in the aetiology of CHD, but these effect estimates attenuated substantially to the null on accounting for apoliprotein B.



Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids

The results identify several novel loci associated with plasma lipids that are also associated with CAD and provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Common variants associated with plasma triglycerides and risk for coronary artery disease

It is suggested that triglyceride-rich lipoproteins causally influence risk for CAD, and the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk.

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising

The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits

The Metabochip and its component SNP sets are described and evaluated, its performance in capturing variation across the allele-frequency spectrum is evaluated, solutions to methodological challenges commonly encountered in its analysis are described, and its performance as a platform for genotype imputation is evaluated.

Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project

It is suggested that no major loci uniquely explain the high prevalence of CHD in African Americans, and resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia are developed.

Effects of polymorphisms in apolipoproteins E, A-IV, and H on quantitative traits related to risk for cardiovascular disease.

It is indicated that variation in many genes may influence variation in a particular trait and that a particular gene may have pleiotropic effects on several traits.

Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis

While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle

Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability

The results suggest that targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci, and that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritable explained by a set of loci.