Abstract
It has been hypothesised that low frequency (1-5% 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 (6 had MAF < 5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1-5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5-2.5 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.
| Original language | English |
|---|---|
| Pages (from-to) | 4094-4106 |
| Number of pages | 13 |
| Journal | Human Molecular Genetics |
| Volume | 25 |
| Issue number | 18 |
| Early online date | 27 Jul 2016 |
| DOIs | |
| Publication status | Published - 27 Jul 2016 |
Keywords
- ldl cholesterol lipoproteins
- high density lipoprotein cholesterol
- genome
- single nucleotide polymorphism
- genetics
- lipids
- exome
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In: Human Molecular Genetics, Vol. 25, No. 18, 27.07.2016, p. 4094-4106.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Analysis with the exome array identifies multiple new independent variants in lipid loci
AU - Kanoni, Stavroula
AU - Masca, Nicholas G. D.
AU - Stirrups, Kathleen E.
AU - Varga, Tibor V.
AU - Warren, Helen R.
AU - Scott, Robert A.
AU - Southam, Lorraine
AU - Zhang, Weihua
AU - Yaghootkar, Hanieh
AU - Müller-Nurasyid, Martina
AU - Couto Alves, Alexessander
AU - Strawbridge, Rona J.
AU - Lataniotis, Lazaros
AU - Hashim, Nikman An
AU - Besse, Céline
AU - Boland, Anne
AU - Braund, Peter S.
AU - Connell, John M.
AU - Dominiczak, Anna
AU - Farmaki, Aliki-Eleni
AU - Franks, Stephen
AU - Grallert, Harald
AU - Jansson, Jan-Håkan
AU - Karaleftheri, Maria
AU - Keinänen-Kiukaanniemi, Sirkka
AU - Matchan, Angela
AU - Pasko, Dorota
AU - Peters, Annette
AU - Poulter, Neil
AU - Rayner, Nigel W.
AU - Renström, Frida
AU - Rolandsson, Olov
AU - Sabater-Lleal, Maria
AU - Sennblad, Bengt
AU - Sever, Peter
AU - Shields, Denis
AU - Silveira, Angela
AU - Stanton, Alice V.
AU - Strauch, Konstantin
AU - Tomaszewski, Maciej
AU - Tsafantakis, Emmanouil
AU - Waldenberger, Melanie
AU - Blakemore, Alexandra I. F.
AU - Dedoussis, George
AU - Escher, Stefan A.
AU - Kooner, Jaspal S.
AU - McCarthy, Mark I.
AU - Palmer, Colin N. A.
AU - Wellcome Trust Case Control Consortium
AU - Hamsten, Anders
AU - Caulfield, Mark J.
N1 - 1958BC was funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. This work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research. PD is supported by British Heart Foundation grant RG/14/5/30893. ASCOT was supported by Pfizer, New York, NY, USA, Servier Research Group, Paris, France and by Leo Laboratories, Copenhagen, Denmark. BRIGHT was supported by the Medical Research Council of Great Britain (grant number G9521010D), the British Heart Foundation (grant number PG/02/128) and the Wellcome Trust Strategic Awards 083948A and 085475. AFD was supported by the British Heart Foundation (grant numbers RG/07/005/23633, SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). DIABNORD was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation, and the Skåne Regional Health Authority (all to PWF). The EFSOCH study was supported by South West NHS Research and Development, Exeter NHS Research and Development, the Darlington Trust, and the Peninsula NIHR Clinical Research Facility at the University of Exeter. Timothy Frayling is supported by the European Research Council grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. EPIC and EPIC-Norfolk is supported by the Medical Research Council programme grants (G0401527, G1000143) and Cancer Research UK programme grant (C864/A8257). The Fenland Study is funded by the Medical Research Council (MC_U106179471). FIA3 was supported in part by a grant from the Swedish Heart-Lung Foundation (grant no. 2020389 to PW Franks). GLACIER was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation, and the Skåne Regional Health Authority (all to PWF). GoDARTS was supported by the Wellcome Trust (Wellcome Trust UK Type 2 Diabetes Case Control Collection) and the Scottish Health Informatics Programme. The Chief Scientist Office supported informatics. Project funded by the UK Medical Research Council (G0601261). GRAPHIC exome array genotyping was funded by the NIHR and the Wellcome Trust. NJS holds a Chair funded by the British Heart Foundation and is a NIHR Senior Investigator. NM is funded by the NIHR Leicester Cardiovascular Biomedical Research Unit. The GRAPHIC Study is part of the portfolio of studies supported by the NIHR Leicester Cardiovascular BRU. HELICMANOLIS and HELICPomak were funded by the Wellcome Trust (098051) and the European Research Council (ERC-2011-StG 280559-SEPI). KORA was funded by the German Federal Ministry of Education and Research and by the State of Bavaria, DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research). LOLIPOP is supported by the National Institute for Health Research (NIHR), the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966,G0700931), the Wellcome Trust (084723/Z/08/Z) the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). NFBC1986: was supported by the Academy of Finland (project grants 104781, 120315, 129269, 1114194, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), the Medical Research Council, UK (G0500539, G0600705, PrevMetSyn/SALVE) and the Wellcome Trust (project grant GR069224), UK, ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the EU Framework Programme 7 small-scale focused research collaborative project EurHEALTHAgeing 277849. SCARF was funded by the Foundation for Strategic Research, the Swedish Heart-Lung Foundation, the Swedish Research Council (8691, 12660, 20653), the European Commission (LSHM-CT-2007-037273), the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and the Stockholm County Council, and the Stockholm County Council (560183). BS acknowledge funding from the Magnus Bergvall Foundation and the Foundation for Old Servants. MF acknowledge funding from the Swedish e-Science Research Center (SeRC).
PY - 2016/7/27
Y1 - 2016/7/27
N2 - It has been hypothesised that low frequency (1-5% 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 (6 had MAF < 5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1-5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5-2.5 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.
AB - It has been hypothesised that low frequency (1-5% 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 (6 had MAF < 5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1-5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5-2.5 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.
KW - ldl cholesterol lipoproteins
KW - high density lipoprotein cholesterol
KW - genome
KW - single nucleotide polymorphism
KW - genetics
KW - lipids
KW - exome
U2 - 10.1093/hmg/ddw227
DO - 10.1093/hmg/ddw227
M3 - Article
C2 - 27466198
SN - 0964-6906
VL - 25
SP - 4094
EP - 4106
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 18
ER -