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

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 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

doi:10.1093/hmg/ddw227

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

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 FarmakiStephen 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 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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

16 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Human Molecular Genetics
Vol/bind	25
Udgave nummer	18
Sider (fra-til)	4094-4106
Antal sider	13
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/ddw227
Status	Udgivet - 15 sep. 2016
Udgivet eksternt	Ja

Bibliografisk note

Adgang til dokumentet

10.1093/hmg/ddw227

Citationsformater

Kanoni, S., Masca, N. G. D., Stirrups, K. E., Varga, T. V., Warren, H. R., Scott, R. A., Southam, L., Zhang, W., Yaghootkar, H., Müller-Nurasyid, M., Couto Alves, A., Strawbridge, R. J., Lataniotis, L., An Hashim, N., Besse, C., Boland, A., Braund, P. S., Connell, J. M., Dominiczak, A., ... Caulfield, M. J. (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

Kanoni, S, Masca, NGD, Stirrups, KE, Varga, TV, Warren, HR, Scott, RA, Southam, L, Zhang, W, Yaghootkar, H, Müller-Nurasyid, M, Couto Alves, A, Strawbridge, RJ, Lataniotis, L, An Hashim, N, Besse, C, Boland, A, Braund, PS, Connell, JM, Dominiczak, A, Farmaki, A-E, Franks, S, Grallert, H, Jansson, J-H, Karaleftheri, M, Keinänen-Kiukaanniemi, S, Matchan, A, Pasko, D, Peters, A, Poulter, N, Rayner, NW, Renström, F, Rolandsson, O, Sabater-Lleal, M, Sennblad, B, Sever, P, Shields, D, Silveira, A, Stanton, AV, Strauch, K, Tomaszewski, M, Tsafantakis, E, Waldenberger, M, Blakemore, AIF, Dedoussis, G, Escher, SA, Kooner, JS, McCarthy, MI, Palmer, CNA, Hamsten, A & Caulfield, MJ 2016, 'Analysis with the exome array identifies multiple new independent variants in lipid loci', Human Molecular Genetics, bind 25, nr. 18, s. 4094-4106. https://doi.org/10.1093/hmg/ddw227

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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.",

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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.}",

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doi = "10.1093/hmg/ddw227",

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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.

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

SN - 0964-6906

VL - 25

SP - 4094

EP - 4106

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 18

ER -