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Olle Melander

Principal investigator

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Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

Author

  • Folkert W. Asselbergs
  • Yiran Guo
  • Erik P. A. van Iperen
  • Suthesh Sivapalaratnam
  • Vinicius Tragante
  • Matthew B. Lanktree
  • Leslie A. Lange
  • Berta Almoguera
  • Yolande E. Appelman
  • John Barnard
  • Jens Baumert
  • Amber L. Beitelshees
  • Tushar R. Bhangale
  • Yii-Der Ida Chen
  • Tom R. Gaunt
  • Yan Gong
  • Jemma C. Hopewell
  • Toby Johnson
  • Marcus E. Kleber
  • Taimour Y. Langaee
  • Mingyao Li
  • Yun R. Li
  • Kiang Liu
  • Caitrin W. McDonough
  • Matthijs El. Meijs
  • Rita P. S. Middelberg
  • Kiran Musunuru
  • Christopher P. Nelson
  • Jeffery R. O'Connell
  • Sandosh Padmanabhan
  • James S. Pankow
  • Nathan Pankratz
  • Suzanne Rafelt
  • Ramakrishnan Rajagopalan
  • Simon P. R. Romaine
  • Nicholas J. Schork
  • Jonathan Shaffer
  • Haiqing Shen
  • Erin N. Smith
  • Sam E. Tischfield
  • Peter J. van der Most
  • Jana V. van Vliet-Ostaptchouk
  • Niek Verweij
  • Kelly A. Volcik
  • Li Zhang
  • Kent R. Bailey
  • Kristian M. Bailey
  • Florianne Bauer
  • Jolanda M. A. Boer
  • Peter S. Braund
  • Amber Burt
  • Paul R. Burton
  • Sarah G. Buxbaum
  • Wei Chen
  • Rhonda M. Cooper-DeHoff
  • L. Adrienne Cupples
  • Jonas S. deJong
  • Christian Delles
  • David Duggan
  • Myriam Fornage
  • Clement E. Furlong
  • Nicole Glazer
  • John G. Gums
  • Claire Hastie
  • Michael V. Holmes
  • Thomas Illig
  • Susan A. Kirkland
  • Mika Kivimaki
  • Ronald Klein
  • Barbara E. Klein
  • Charles Kooperberg
  • Kandice Kottke-Marchant
  • Meena Kumari
  • Andrea Z. LaCroix
  • Laya Mallela
  • Gurunathan Murugesan
  • Jose Ordovas
  • Willem H. Ouwehand
  • Wendy S. Post
  • Richa Saxena
  • Hubert Scharnagl
  • Pamela J. Schreiner
  • Tina Shah
  • Denis C. Shields
  • Daichi Shimbo
  • Sathanur R. Srinivasan
  • Ronald P. Stolk
  • Daniel I. Swerdlow
  • Herman A. Taylor Jr
  • Eric J. Topo
  • Elina Toskala
  • Joost L. van Pelt
  • Jessica van Setten
  • Salim Yusuf
  • John C. Whittaker
  • A. H. Zwinderman
  • Sonia S. Anand
  • Anthony J. Balmforth
  • Gerald S. Berenson
  • Connie R. Bezzina
  • Bernhard O. Boehm
  • Eric Boerwinkle
  • Juan P. Casas
  • Mark J. Caulfield
  • Robert Clarke
  • John M. Connell
  • Karen J. Cruickshanks
  • Karina W. Davidson
  • Ian N. M. Day
  • Paul I. W. de Bakker
  • Pieter A. Doevendans
  • Anna E. Dominiczak
  • Alistair S. Hall
  • Catharina A. Hartman
  • Christian Hengstenberg
  • Hans L. Hillege
  • Marten H. Hofker
  • Steve E. Humphries
  • Gail P. Jarvik
  • Julie A. Johnson
  • Bernhard M. Kaess
  • Sekar Kathiresan
  • Wolfgang Koenig
  • Debbie A. Lawlor
  • Winfried Maerz
  • Olle Melander
  • Braxton D. Mitchell
  • Grant W. Montgomery
  • Patricia B. Munroe
  • Sarah S. Murray
  • Stephen J. Newhouse
  • N. Charlotte Onland-Moret
  • Neil Poulter
  • Bruce Psaty
  • Susan Redline
  • Stephen S. Rich
  • Jerome I. Rotter
  • Heribert Schunkert
  • Peter Sever
  • Alan R. Shuldiner
  • Roy L. Silverstein
  • Alice Stanton
  • Barbara Thorand
  • Mieke D. Trip
  • Michael Y. Tsai
  • Pim van der Harst
  • Ellen van der Schoot
  • Yvonne T. van der Schouw
  • W. M. Monique Verschuren
  • Hugh Watkins
  • Arthur A. M. Wilde
  • Bruce H. R. Wolffenbuttel
  • John B. Whitfield
  • G. Kees Hovingh
  • Christie M. Ballantyne
  • Cisca Wijmenga
  • Muredach P. Reilly
  • Nicholas G. Martin
  • James G. Wilson
  • Daniel J. Rader
  • Nilesh J. Samani
  • Alex P. Reiner
  • Robert A. Hegele
  • John J. P. Kastelein
  • Aroon D. Hingorani
  • Philippa J. Talmud
  • Hakon Hakonarson
  • Clara C. Elbers
  • Brendan J. Keating
  • Fotios Drenos

Summary, in English

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

Department/s

  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2012

Language

English

Pages

823-838

Publication/Series

American Journal of Human Genetics

Volume

91

Issue

5

Document type

Journal article

Publisher

Cell Press

Topic

  • Medical Genetics

Status

Published

Research group

  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 0002-9297