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

Kanoni, Stavroula; Masca, Nicholas G D; Stirrups, Kathleen E.; Varga, Tibor V. LU ; Warren, Helen R; Scott, Robert A.; Southam, Lorraine; Zhang, Weihua; Yaghootkar, Hanieh and Müller-Nurasyid, Martina, et al. (2016) In Human Molecular Genetics 25(18). p.4094-4106
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,... (More)

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.

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Human Molecular Genetics
volume
25
issue
18
pages
13 pages
publisher
Oxford University Press
external identifiers
  • scopus:85014345453
  • wos:000395806000016
ISSN
0964-6906
DOI
10.1093/hmg/ddw227
language
English
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yes
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442dca1f-de73-40cd-a9ac-2c9d40e3dcfd
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2017-03-16 11:59:31
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2017-11-14 09:53:01
@article{442dca1f-de73-40cd-a9ac-2c9d40e3dcfd,
  abstract     = {<p>It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (&lt;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 &gt; 1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF &lt; 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.</p>},
  author       = {Kanoni, Stavroula and Masca, Nicholas G D and Stirrups, Kathleen E. and Varga, Tibor V. and Warren, Helen R and Scott, Robert A. and Southam, Lorraine and Zhang, Weihua and Yaghootkar, Hanieh and Müller-Nurasyid, Martina and Alves, Alexessander Couto and Strawbridge, Rona J. and Lataniotis, Lazaros and Hashim, Nikman An and Besse, Céline and Boland, Anne and Braund, Peter S. and Connell, John M. and Dominiczak, Anna and Farmaki, Aliki-Eleni and Franks, Stephen and Grallert, Harald and Jansson, Jan-Håkan and Karaleftheri, Maria and Keinänen-Kiukaanniemi, Sirkka and Matchan, Angela and Pasko, Dorota and Peters, Annette and Poulter, Neil and Rayner, Nigel W. and Renström, Frida and Rolandsson, Olov and Sabater-Lleal, Maria and Sennblad, Bengt and Sever, Peter and Shields, Denis C and Silveira, Angela and Stanton, Alice V and Strauch, Konstantin and Tomaszewski, Maciej and Tsafantakis, Emmanouil and Waldenberger, Melanie and Blakemore, Alexandra I. F. and Dedoussis, George and Escher, Stefan A and Kooner, Jaspal S and McCarthy, Mark I. and Palmer, Colin N. A. and Hamsten, Anders and Caulfield, Mark J. and Frayling, Timothy M. and Tobin, Martin D and Jarvelin, Marjo Riitta and Zeggini, Eleftheria and Gieger, Christian and Chambers, John C and Wareham, Nick J. and Munroe, Patricia B. and Franks, Paul W. and Samani, Nilesh J. and Deloukas, Panos},
  issn         = {0964-6906},
  language     = {eng},
  number       = {18},
  pages        = {4094--4106},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Analysis with the exome array identifies multiple new independent variants in lipid loci},
  url          = {http://dx.doi.org/10.1093/hmg/ddw227},
  volume       = {25},
  year         = {2016},
}