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

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

16 Citations (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.

Original language	English
Journal	Human Molecular Genetics
Volume	25
Issue number	18
Pages (from-to)	4094-4106
Number of pages	13
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddw227
Publication status	Published - 15 Sept 2016
Externally published	Yes

Bibliographical note

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

Access to Document

10.1093/hmg/ddw227

Cite this

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, vol. 25, no. 18, pp. 4094-4106. https://doi.org/10.1093/hmg/ddw227

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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.",

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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 -