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Analysis with the exome array identifies multiple new independent variants in lipid loci

Author:
  • Stavroula Kanoni
  • Nicholas G D Masca
  • Kathleen E. Stirrups
  • Tibor V. Varga
  • Helen R Warren
  • Robert A. Scott
  • Lorraine Southam
  • Weihua Zhang
  • Hanieh Yaghootkar
  • Martina Müller-Nurasyid
  • Alexessander Couto Alves
  • Rona J. Strawbridge
  • Lazaros Lataniotis
  • Nikman An Hashim
  • Céline Besse
  • Anne Boland
  • Peter S. Braund
  • John M. Connell
  • Anna Dominiczak
  • Aliki-Eleni Farmaki
  • Stephen Franks
  • Harald Grallert
  • Jan-Håkan Jansson
  • Maria Karaleftheri
  • Sirkka Keinänen-Kiukaanniemi
  • Angela Matchan
  • Dorota Pasko
  • Annette Peters
  • Neil Poulter
  • Nigel W. Rayner
  • Frida Renström
  • Olov Rolandsson
  • Maria Sabater-Lleal
  • Bengt Sennblad
  • Peter Sever
  • Denis C Shields
  • Angela Silveira
  • Alice V Stanton
  • Konstantin Strauch
  • Maciej Tomaszewski
  • Emmanouil Tsafantakis
  • Melanie Waldenberger
  • Alexandra I. F. Blakemore
  • George Dedoussis
  • Stefan A Escher
  • Jaspal S Kooner
  • Mark I. McCarthy
  • Colin N. A. Palmer
  • Anders Hamsten
  • Mark J. Caulfield
  • Timothy M. Frayling
  • Martin D Tobin
  • Marjo Riitta Jarvelin
  • Eleftheria Zeggini
  • Christian Gieger
  • John C Chambers
  • Nick J. Wareham
  • Patricia B. Munroe
  • Paul W. Franks
  • Nilesh J. Samani
  • Panos Deloukas
Publishing year: 2016
Language: English
Pages: 4094-4106
Publication/Series: Human Molecular Genetics
Volume: 25
Issue: 18
Document type: Journal article
Publisher: Oxford University Press

Abstract english

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were > 1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF < 5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

Keywords

  • Medical Genetics

Other

Published
  • Genetic and Molecular Epidemiology
  • ISSN: 0964-6906
Paul Franks
E-mail: paul.franks [at] med.lu.se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49

60-12-021

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00