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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

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.

Detaljer

Författare
  • Stavroula Kanoni
  • Nicholas G D Masca
  • Kathleen E. Stirrups
  • 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
  • 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
  • Nilesh J. Samani
  • Panos Deloukas
Enheter & grupper
Externa organisationer
  • Queen Mary University
  • University of Leicester
  • Broad Institute
  • Massachusetts General Hospital
  • Addenbrooke's Hospital
  • Wellcome Trust Sanger Institute
  • Imperial College London
  • University of Exeter
  • Karolinska Institute
  • Centre National de Génotypage
  • University of Dundee
  • University of Glasgow
  • National and Kapodistrian University of Athens
  • Umeå University
  • Echinos Medical Centre
  • University College Dublin
  • Royal College of Surgeons in Ireland
  • Anogia Medical Centre
  • Harvard University
  • Lund University
  • Helmholtz Zentrum München
  • German Center for Diabetes Research
  • University of Oulu
  • Ealing Hospital
  • University of Oxford
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Originalspråkengelska
Sidor (från-till)4094-4106
Antal sidor13
TidskriftHuman Molecular Genetics
Volym25
Utgivningsnummer18
StatusPublished - 2016
PublikationskategoriForskning
Peer review utfördJa