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

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Analysis with the exome array identifies multiple new independent variants in lipid loci. / Wellcome Trust Case-Control Consortium.

In: Human Molecular Genetics, Vol. 25, No. 18, 15.09.2016, p. 4094-4106.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Wellcome Trust Case-Control Consortium 2016, 'Analysis with the exome array identifies multiple new independent variants in lipid loci', Human Molecular Genetics, vol. 25, no. 18, pp. 4094-4106. https://doi.org/10.1093/hmg/ddw227

APA

Wellcome Trust Case-Control Consortium (2016). Analysis with the exome array identifies multiple new independent variants in lipid loci. Human Molecular Genetics, 25(18), 4094-4106. https://doi.org/10.1093/hmg/ddw227

Vancouver

Wellcome Trust Case-Control Consortium. Analysis with the exome array identifies multiple new independent variants in lipid loci. Human Molecular Genetics. 2016 Sep 15;25(18):4094-4106. https://doi.org/10.1093/hmg/ddw227

Author

Wellcome Trust Case-Control Consortium. / Analysis with the exome array identifies multiple new independent variants in lipid loci. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 18. pp. 4094-4106.

Bibtex

@article{63b751b2e8a44187aa2fcb66136acd22,
title = "Analysis with the exome array identifies multiple new independent variants in lipid loci",
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.",
keywords = "Adolescent, Adult, Aged, Child, Cholesterol, HDL/blood, Cholesterol, LDL/blood, European Continental Ancestry Group, Exome/genetics, Gene Frequency, Genome-Wide Association Study, Humans, Lipid Metabolism/genetics, Lipids/blood, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides/blood",
author = "Stavroula Kanoni and Masca, {Nicholas G D} and Stirrups, {Kathleen E} and Varga, {Tibor V} and Warren, {Helen R} and Scott, {Robert A} and Lorraine Southam and Weihua Zhang and Hanieh Yaghootkar and Martina M{\"u}ller-Nurasyid and {Couto Alves}, Alexessander and Strawbridge, {Rona J} and Lazaros Lataniotis and {An Hashim}, Nikman and C{\'e}line Besse and Anne Boland and Braund, {Peter S} and Connell, {John M} and Anna Dominiczak and Aliki-Eleni Farmaki and Stephen Franks and Harald Grallert and Jan-H{\aa}kan Jansson and Maria Karaleftheri and Sirkka Kein{\"a}nen-Kiukaanniemi and Angela Matchan and Dorota Pasko and Annette Peters and Neil Poulter and Rayner, {Nigel W} and Frida Renstr{\"o}m and Olov Rolandsson and Maria Sabater-Lleal and Bengt Sennblad and Peter Sever and Denis Shields and Angela Silveira and Stanton, {Alice V} and Konstantin Strauch and Maciej Tomaszewski and Emmanouil Tsafantakis and Melanie Waldenberger and Blakemore, {Alexandra I F} and George Dedoussis and Escher, {Stefan A} and Kooner, {Jaspal S} and McCarthy, {Mark I} and Palmer, {Colin N A} and Anders Hamsten and Caulfield, {Mark J} and {Wellcome Trust Case-Control Consortium}",
note = "{\textcopyright} The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
year = "2016",
month = sep,
day = "15",
doi = "10.1093/hmg/ddw227",
language = "English",
volume = "25",
pages = "4094--4106",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "18",

}

RIS

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 - An Hashim, Nikman

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 - Hamsten, Anders

AU - Caulfield, Mark J

AU - Wellcome Trust Case-Control Consortium

N1 - © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2016/9/15

Y1 - 2016/9/15

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Child

KW - Cholesterol, HDL/blood

KW - Cholesterol, LDL/blood

KW - European Continental Ancestry Group

KW - Exome/genetics

KW - Gene Frequency

KW - Genome-Wide Association Study

KW - Humans

KW - Lipid Metabolism/genetics

KW - Lipids/blood

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Triglycerides/blood

U2 - 10.1093/hmg/ddw227

DO - 10.1093/hmg/ddw227

M3 - Journal article

C2 - 27466198

VL - 25

SP - 4094

EP - 4106

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 18

ER -

ID: 242837559