Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.

Leslie A Lange; Youna Hu; He Zhang; Chenyi Xue; Ellen M Schmidt; Zheng-Zheng Tang; Chris Bizon; Ethan M Lange; Joshua D Smith; Emily H Turner; Goo Jun; Hyun Min Kang; Gina Peloso; Paul Auer; Kuo-Ping Li; Jason Flannick; Ji Zhang; Christian Fuchsberger; Kyle Gaulton; Cecilia Lindgren; Adam Locke; Alisa Manning; Xueling Sim; Manuel A Rivas; Oddgeir L Holmen; Omri Gottesman; Yingchang Lu; Douglas Ruderfer; Eli A Stahl; Qing Duan; Yun Li; Peter Durda; Shuo Jiao; Aaron Isaacs; Albert Hofman; Joshua C Bis; Adolfo Correa; Michael E Griswold; Johanna Jakobsdottir; Albert V Smith; Pamela J Schreiner; Mary F Feitosa; Qunyuan Zhang; Jennifer E Huffman; Jacy Crosby; Christina L Wassel; Ron Do; Nora Franceschini; Lisa W Martin; Jennifer G Robinson; Themistocles L Assimes; David R Crosslin; Elisabeth A Rosenthal; Michael Tsai; Mark J Rieder; Deborah N Farlow; Aaron R Folsom; Thomas Lumley; Ervin R Fox; Christopher S Carlson; Ulrike Peters; Rebecca D Jackson; Cornelia M van Duijn; André G Uitterlinden; Daniel Levy; Jerome I Rotter; Herman A Taylor; Vilmundur Gudnason; David S Siscovick; Myriam Fornage; Ingrid B Borecki; Caroline Hayward; Igor Rudan; Y Eugene Chen; Erwin P Bottinger; Ruth J F Loos; Pål Sætrom; Kristian Hveem; Michael Boehnke; Leif Groop; Mark McCarthy; Thomas Meitinger; Christie M Ballantyne; Stacey B Gabriel; Christopher J O'Donnell; Wendy S Post; Kari E North; Alexander P Reiner; Eric Boerwinkle; Bruce M Psaty; David Altshuler; Sekar Kathiresan; Dan-Yu Lin; Gail P Jarvik; L Adrienne Cupples; Charles Kooperberg; James G Wilson; Deborah A Nickerson; Goncalo R Abecasis; Stephen S Rich; Russell P Tracy; Cristen J Willer

doi:10.1016/j.ajhg.2014.01.010

Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.

Leslie A Lange, Youna Hu, He Zhang, Chenyi Xue, Ellen M Schmidt, Zheng-Zheng Tang, Chris Bizon, Ethan M Lange, Joshua D Smith, Emily H Turner, Goo Jun, Hyun Min Kang, Gina Peloso, Paul Auer, Kuo-Ping Li, Jason Flannick, Ji Zhang, Christian Fuchsberger, Kyle Gaulton, Cecilia LindgrenAdam Locke, Alisa Manning, Xueling Sim, Manuel A Rivas, Oddgeir L Holmen, Omri Gottesman, Yingchang Lu, Douglas Ruderfer, Eli A Stahl, Qing Duan, Yun Li, Peter Durda, Shuo Jiao, Aaron Isaacs, Albert Hofman, Joshua C Bis, Adolfo Correa, Michael E Griswold, Johanna Jakobsdottir, Albert V Smith, Pamela J Schreiner, Mary F Feitosa, Qunyuan Zhang, Jennifer E Huffman, Jacy Crosby, Christina L Wassel, Ron Do, Nora Franceschini, Lisa W Martin, Jennifer G Robinson, Themistocles L Assimes, David R Crosslin, Elisabeth A Rosenthal, Michael Tsai, Mark J Rieder, Deborah N Farlow, Aaron R Folsom, Thomas Lumley, Ervin R Fox, Christopher S Carlson, Ulrike Peters, Rebecca D Jackson, Cornelia M van Duijn, André G Uitterlinden, Daniel Levy, Jerome I Rotter, Herman A Taylor, Vilmundur Gudnason, David S Siscovick, Myriam Fornage, Ingrid B Borecki, Caroline Hayward, Igor Rudan, Y Eugene Chen, Erwin P Bottinger, Ruth J F Loos, Pål Sætrom, Kristian Hveem, Michael Boehnke, Leif Groop, Mark McCarthy, Thomas Meitinger, Christie M Ballantyne, Stacey B Gabriel, Christopher J O'Donnell, Wendy S Post, Kari E North, Alexander P Reiner, Eric Boerwinkle, Bruce M Psaty, David Altshuler, Sekar Kathiresan, Dan-Yu Lin, Gail P Jarvik, L Adrienne Cupples, Charles Kooperberg, James G Wilson, Deborah A Nickerson, Goncalo R Abecasis, Stephen S Rich, Russell P Tracy, Cristen J Willer

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Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

Original language	English
Pages (from-to)	233-245
Journal	American Journal of Human Genetics
Volume	94
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2014.01.010
Publication status	Published - 2014

Subject classification (UKÄ)

Medical Genetics

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10.1016/j.ajhg.2014.01.010

http://www.ncbi.nlm.nih.gov/pubmed/24507775?dopt=Abstract

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Lange, L. A., Hu, Y., Zhang, H., Xue, C., Schmidt, E. M., Tang, Z-Z., Bizon, C., Lange, E. M., Smith, J. D., Turner, E. H., Jun, G., Kang, H. M., Peloso, G., Auer, P., Li, K-P., Flannick, J., Zhang, J., Fuchsberger, C., Gaulton, K., ... Willer, C. J. (2014). Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol. American Journal of Human Genetics, 94(2), 233-245. https://doi.org/10.1016/j.ajhg.2014.01.010

@article{d54d1c0118194796b980e2d848aed7ae,

title = "Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.",

abstract = "Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.",

author = "Lange, {Leslie A} and Youna Hu and He Zhang and Chenyi Xue and Schmidt, {Ellen M} and Zheng-Zheng Tang and Chris Bizon and Lange, {Ethan M} and Smith, {Joshua D} and Turner, {Emily H} and Goo Jun and Kang, {Hyun Min} and Gina Peloso and Paul Auer and Kuo-Ping Li and Jason Flannick and Ji Zhang and Christian Fuchsberger and Kyle Gaulton and Cecilia Lindgren and Adam Locke and Alisa Manning and Xueling Sim and Rivas, {Manuel A} and Holmen, {Oddgeir L} and Omri Gottesman and Yingchang Lu and Douglas Ruderfer and Stahl, {Eli A} and Qing Duan and Yun Li and Peter Durda and Shuo Jiao and Aaron Isaacs and Albert Hofman and Bis, {Joshua C} and Adolfo Correa and Griswold, {Michael E} and Johanna Jakobsdottir and Smith, {Albert V} and Schreiner, {Pamela J} and Feitosa, {Mary F} and Qunyuan Zhang and Huffman, {Jennifer E} and Jacy Crosby and Wassel, {Christina L} and Ron Do and Nora Franceschini and Martin, {Lisa W} and Robinson, {Jennifer G} and Assimes, {Themistocles L} and Crosslin, {David R} and Rosenthal, {Elisabeth A} and Michael Tsai and Rieder, {Mark J} and Farlow, {Deborah N} and Folsom, {Aaron R} and Thomas Lumley and Fox, {Ervin R} and Carlson, {Christopher S} and Ulrike Peters and Jackson, {Rebecca D} and {van Duijn}, {Cornelia M} and Uitterlinden, {Andr{\'e} G} and Daniel Levy and Rotter, {Jerome I} and Taylor, {Herman A} and Vilmundur Gudnason and Siscovick, {David S} and Myriam Fornage and Borecki, {Ingrid B} and Caroline Hayward and Igor Rudan and Chen, {Y Eugene} and Bottinger, {Erwin P} and Loos, {Ruth J F} and P{\aa}l S{\ae}trom and Kristian Hveem and Michael Boehnke and Leif Groop and Mark McCarthy and Thomas Meitinger and Ballantyne, {Christie M} and Gabriel, {Stacey B} and O'Donnell, {Christopher J} and Post, {Wendy S} and North, {Kari E} and Reiner, {Alexander P} and Eric Boerwinkle and Psaty, {Bruce M} and David Altshuler and Sekar Kathiresan and Dan-Yu Lin and Jarvik, {Gail P} and Cupples, {L Adrienne} and Charles Kooperberg and Wilson, {James G} and Nickerson, {Deborah A} and Abecasis, {Goncalo R} and Rich, {Stephen S} and Tracy, {Russell P} and Willer, {Cristen J}",

year = "2014",

doi = "10.1016/j.ajhg.2014.01.010",

language = "English",

volume = "94",

pages = "233--245",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Lange, LA, Hu, Y, Zhang, H, Xue, C, Schmidt, EM, Tang, Z-Z, Bizon, C, Lange, EM, Smith, JD, Turner, EH, Jun, G, Kang, HM, Peloso, G, Auer, P, Li, K-P, Flannick, J, Zhang, J, Fuchsberger, C, Gaulton, K, Lindgren, C, Locke, A, Manning, A, Sim, X, Rivas, MA, Holmen, OL, Gottesman, O, Lu, Y, Ruderfer, D, Stahl, EA, Duan, Q, Li, Y, Durda, P, Jiao, S, Isaacs, A, Hofman, A, Bis, JC, Correa, A, Griswold, ME, Jakobsdottir, J, Smith, AV, Schreiner, PJ, Feitosa, MF, Zhang, Q, Huffman, JE, Crosby, J, Wassel, CL, Do, R, Franceschini, N, Martin, LW, Robinson, JG, Assimes, TL, Crosslin, DR, Rosenthal, EA, Tsai, M, Rieder, MJ, Farlow, DN, Folsom, AR, Lumley, T, Fox, ER, Carlson, CS, Peters, U, Jackson, RD, van Duijn, CM, Uitterlinden, AG, Levy, D, Rotter, JI, Taylor, HA, Gudnason, V, Siscovick, DS, Fornage, M, Borecki, IB, Hayward, C, Rudan, I, Chen, YE, Bottinger, EP, Loos, RJF, Sætrom, P, Hveem, K, Boehnke, M, Groop, L, McCarthy, M, Meitinger, T, Ballantyne, CM, Gabriel, SB, O'Donnell, CJ, Post, WS, North, KE, Reiner, AP, Boerwinkle, E, Psaty, BM, Altshuler, D, Kathiresan, S, Lin, D-Y, Jarvik, GP, Cupples, LA, Kooperberg, C, Wilson, JG, Nickerson, DA, Abecasis, GR, Rich, SS, Tracy, RP & Willer, CJ 2014, 'Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.', American Journal of Human Genetics, vol. 94, no. 2, pp. 233-245. https://doi.org/10.1016/j.ajhg.2014.01.010

TY - JOUR

T1 - Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.

AU - Lange, Leslie A

AU - Hu, Youna

AU - Zhang, He

AU - Xue, Chenyi

AU - Schmidt, Ellen M

AU - Tang, Zheng-Zheng

AU - Bizon, Chris

AU - Lange, Ethan M

AU - Smith, Joshua D

AU - Turner, Emily H

AU - Jun, Goo

AU - Kang, Hyun Min

AU - Peloso, Gina

AU - Auer, Paul

AU - Li, Kuo-Ping

AU - Flannick, Jason

AU - Zhang, Ji

AU - Fuchsberger, Christian

AU - Gaulton, Kyle

AU - Lindgren, Cecilia

AU - Locke, Adam

AU - Manning, Alisa

AU - Sim, Xueling

AU - Rivas, Manuel A

AU - Holmen, Oddgeir L

AU - Gottesman, Omri

AU - Lu, Yingchang

AU - Ruderfer, Douglas

AU - Stahl, Eli A

AU - Duan, Qing

AU - Li, Yun

AU - Durda, Peter

AU - Jiao, Shuo

AU - Isaacs, Aaron

AU - Hofman, Albert

AU - Bis, Joshua C

AU - Correa, Adolfo

AU - Griswold, Michael E

AU - Jakobsdottir, Johanna

AU - Smith, Albert V

AU - Schreiner, Pamela J

AU - Feitosa, Mary F

AU - Zhang, Qunyuan

AU - Huffman, Jennifer E

AU - Crosby, Jacy

AU - Wassel, Christina L

AU - Do, Ron

AU - Franceschini, Nora

AU - Martin, Lisa W

AU - Robinson, Jennifer G

AU - Assimes, Themistocles L

AU - Crosslin, David R

AU - Rosenthal, Elisabeth A

AU - Tsai, Michael

AU - Rieder, Mark J

AU - Farlow, Deborah N

AU - Folsom, Aaron R

AU - Lumley, Thomas

AU - Fox, Ervin R

AU - Carlson, Christopher S

AU - Peters, Ulrike

AU - Jackson, Rebecca D

AU - van Duijn, Cornelia M

AU - Uitterlinden, André G

AU - Levy, Daniel

AU - Rotter, Jerome I

AU - Taylor, Herman A

AU - Gudnason, Vilmundur

AU - Siscovick, David S

AU - Fornage, Myriam

AU - Borecki, Ingrid B

AU - Hayward, Caroline

AU - Rudan, Igor

AU - Chen, Y Eugene

AU - Bottinger, Erwin P

AU - Loos, Ruth J F

AU - Sætrom, Pål

AU - Hveem, Kristian

AU - Boehnke, Michael

AU - Groop, Leif

AU - McCarthy, Mark

AU - Meitinger, Thomas

AU - Ballantyne, Christie M

AU - Gabriel, Stacey B

AU - O'Donnell, Christopher J

AU - Post, Wendy S

AU - North, Kari E

AU - Reiner, Alexander P

AU - Boerwinkle, Eric

AU - Psaty, Bruce M

AU - Altshuler, David

AU - Kathiresan, Sekar

AU - Lin, Dan-Yu

AU - Jarvik, Gail P

AU - Cupples, L Adrienne

AU - Kooperberg, Charles

AU - Wilson, James G

AU - Nickerson, Deborah A

AU - Abecasis, Goncalo R

AU - Rich, Stephen S

AU - Tracy, Russell P

AU - Willer, Cristen J

PY - 2014

Y1 - 2014

N2 - Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

AB - Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

U2 - 10.1016/j.ajhg.2014.01.010

DO - 10.1016/j.ajhg.2014.01.010

M3 - Article

C2 - 24507775

VL - 94

SP - 233

EP - 245

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -

Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.

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