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

LA Lange; YN Hu; H Zhang; CY Xue; EM Schmidt; ZZ Tang; C Bizon; EM Lange; JD Smith; EH Turner; G Jun; HM Kang; G Peloso; P Auer; KP Li; J Flannick; J Zhang; C Fuchsberger; K Gaulton; C Lindgren; A Locke; A Manning; XL Sim; MA Rivas; OL Holmen; O Gottesman; YC Lu; D Ruderfer; EA Stah; Q Duan; Y Li; P Durda; S Jiao; Aaron Isaacs; Bert Hofman; JC Bis; A Correa; ME Griswold; J Jakobsdottir; AV Smith; PJ Schreiner; ME Feitosa; QY Zhang; JE Huffman; J Crosby; CL Wasse; R Do; N Franceschini; LW Martin; JG Robinson; TL Assimes; DR Crosslin; EA Rosenthal; M Tsai; MJ Rieder; DN Farlow; AR Folsom; T Lumley; ER Fox; CS Carlson; U Peters; RD Jackson; Cornelia Duijn; André Uitterlinden; D Levy; JI Rotter; HA Taylor; V Gudnason; DS Siscovick; M Fornage; IB Borecki; C Hayward; I Rudan; YE Chen; EP Bottinger; RJF Loos; P Strom; K Hveem; M Boehnke; L Groop; M McCarthy; T Meitinger; CM Ballantyne; SB Gabriel; CJ O'Donne; WS Post; KE North; AP Reiner; E Boerwinkle; BM Psaty; D Altshuler; S Kathiresan; DY Lin; GP Jarvik; LA Cupples; C Kooperberg; JG Wilson; DA Nickerson; GR Abecasis; SS Rich; RP Tracy; CJ Willer

doi:10.1016/j.ajhg.2014.01.010

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

LA Lange, YN Hu, H Zhang, CY Xue, EM Schmidt, ZZ Tang, C Bizon, EM Lange, JD Smith, EH Turner, G Jun, HM Kang, G Peloso, P Auer, KP Li, J Flannick, J Zhang, C Fuchsberger, K Gaulton, C LindgrenA Locke, A Manning, XL Sim, MA Rivas, OL Holmen, O Gottesman, YC Lu, D Ruderfer, EA Stah, Q Duan, Y Li, P Durda, S Jiao, Aaron Isaacs, Bert Hofman, JC Bis, A Correa, ME Griswold, J Jakobsdottir, AV Smith, PJ Schreiner, ME Feitosa, QY Zhang, JE Huffman, J Crosby, CL Wasse, R Do, N Franceschini, LW Martin, JG Robinson, TL Assimes, DR Crosslin, EA Rosenthal, M Tsai, MJ Rieder, DN Farlow, AR Folsom, T Lumley, ER Fox, CS Carlson, U Peters, RD Jackson, Cornelia Duijn, André Uitterlinden, D Levy, JI Rotter, HA Taylor, V Gudnason, DS Siscovick, M Fornage, IB Borecki, C Hayward, I Rudan, YE Chen, EP Bottinger, RJF Loos, P Strom, K Hveem, M Boehnke, L Groop, M McCarthy, T Meitinger, CM Ballantyne, SB Gabriel, CJ O'Donne, WS Post, KE North, AP Reiner, E Boerwinkle, BM Psaty, D Altshuler, S Kathiresan, DY Lin, GP Jarvik, LA Cupples, C Kooperberg, JG Wilson, DA Nickerson, GR Abecasis, SS Rich, RP Tracy, CJ Willer

Research output: Contribution to journal › Article › Academic › peer-review

184 Citations (Scopus)

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 (>98th or <2nd 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	Undefined/Unknown
Pages (from-to)	233-245
Number of pages	13
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

Research programs

EMC MM-01-39-09-A
EMC NIHES-01-64-02

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ajhg.2014.01.010

http://hdl.handle.net/1765/54062

Cite this

Lange, LA., Hu, YN., Zhang, H., Xue, CY., Schmidt, EM., Tang, ZZ., Bizon, C., Lange, EM., Smith, JD., Turner, EH., Jun, G., Kang, HM., Peloso, G., Auer, P., Li, KP., Flannick, J., Zhang, J., Fuchsberger, C., Gaulton, K., ... Willer, CJ. (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

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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 (>98th or <2nd 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 = "LA Lange and YN Hu and H Zhang and CY Xue and EM Schmidt and ZZ Tang and C Bizon and EM Lange and JD Smith and EH Turner and G Jun and HM Kang and G Peloso and P Auer and KP Li and J Flannick and J Zhang and C Fuchsberger and K Gaulton and C Lindgren and A Locke and A Manning and XL Sim and MA Rivas and OL Holmen and O Gottesman and YC Lu and D Ruderfer and EA Stah and Q Duan and Y Li and P Durda and S Jiao and Aaron Isaacs and Bert Hofman and JC Bis and A Correa and ME Griswold and J Jakobsdottir and AV Smith and PJ Schreiner and ME Feitosa and QY Zhang and JE Huffman and J Crosby and CL Wasse and R Do and N Franceschini and LW Martin and JG Robinson and TL Assimes and DR Crosslin and EA Rosenthal and M Tsai and MJ Rieder and DN Farlow and AR Folsom and T Lumley and ER Fox and CS Carlson and U Peters and RD Jackson and Cornelia Duijn and Andr{\'e} Uitterlinden and D Levy and JI Rotter and HA Taylor and V Gudnason and DS Siscovick and M Fornage and IB Borecki and C Hayward and I Rudan and YE Chen and EP Bottinger and RJF Loos and P Strom and K Hveem and M Boehnke and L Groop and M McCarthy and T Meitinger and CM Ballantyne and SB Gabriel and CJ O'Donne and WS Post and KE North and AP Reiner and E Boerwinkle and BM Psaty and D Altshuler and S Kathiresan and DY Lin and GP Jarvik and LA Cupples and C Kooperberg and JG Wilson and DA Nickerson and GR Abecasis and SS Rich and RP Tracy and CJ Willer",

year = "2014",

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

language = "Undefined/Unknown",

volume = "94",

pages = "233--245",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

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Lange, LA, Hu, YN, Zhang, H, Xue, CY, Schmidt, EM, Tang, ZZ, Bizon, C, Lange, EM, Smith, JD, Turner, EH, Jun, G, Kang, HM, Peloso, G, Auer, P, Li, KP, Flannick, J, Zhang, J, Fuchsberger, C, Gaulton, K, Lindgren, C, Locke, A, Manning, A, Sim, XL, Rivas, MA, Holmen, OL, Gottesman, O, Lu, YC, Ruderfer, D, Stah, EA, Duan, Q, Li, Y, Durda, P, Jiao, S, Isaacs, A, Hofman, B, Bis, JC, Correa, A, Griswold, ME, Jakobsdottir, J, Smith, AV, Schreiner, PJ, Feitosa, ME, Zhang, QY, Huffman, JE, Crosby, J, Wasse, 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, Duijn, C, Uitterlinden, A, Levy, D, Rotter, JI, Taylor, HA, Gudnason, V, Siscovick, DS, Fornage, M, Borecki, IB, Hayward, C, Rudan, I, Chen, YE, Bottinger, EP, Loos, RJF, Strom, P, Hveem, K, Boehnke, M, Groop, L, McCarthy, M, Meitinger, T, Ballantyne, CM, Gabriel, SB, O'Donne, CJ, Post, WS, North, KE, Reiner, AP, Boerwinkle, E, Psaty, BM, Altshuler, D, Kathiresan, S, Lin, DY, 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, LA

AU - Hu, YN

AU - Zhang, H

AU - Xue, CY

AU - Schmidt, EM

AU - Tang, ZZ

AU - Bizon, C

AU - Lange, EM

AU - Smith, JD

AU - Turner, EH

AU - Jun, G

AU - Kang, HM

AU - Peloso, G

AU - Auer, P

AU - Li, KP

AU - Flannick, J

AU - Zhang, J

AU - Fuchsberger, C

AU - Gaulton, K

AU - Lindgren, C

AU - Locke, A

AU - Manning, A

AU - Sim, XL

AU - Rivas, MA

AU - Holmen, OL

AU - Gottesman, O

AU - Lu, YC

AU - Ruderfer, D

AU - Stah, EA

AU - Duan, Q

AU - Li, Y

AU - Durda, P

AU - Jiao, S

AU - Isaacs, Aaron

AU - Hofman, Bert

AU - Bis, JC

AU - Correa, A

AU - Griswold, ME

AU - Jakobsdottir, J

AU - Smith, AV

AU - Schreiner, PJ

AU - Feitosa, ME

AU - Zhang, QY

AU - Huffman, JE

AU - Crosby, J

AU - Wasse, CL

AU - Do, R

AU - Franceschini, N

AU - Martin, LW

AU - Robinson, JG

AU - Assimes, TL

AU - Crosslin, DR

AU - Rosenthal, EA

AU - Tsai, M

AU - Rieder, MJ

AU - Farlow, DN

AU - Folsom, AR

AU - Lumley, T

AU - Fox, ER

AU - Carlson, CS

AU - Peters, U

AU - Jackson, RD

AU - Duijn, Cornelia

AU - Uitterlinden, André

AU - Levy, D

AU - Rotter, JI

AU - Taylor, HA

AU - Gudnason, V

AU - Siscovick, DS

AU - Fornage, M

AU - Borecki, IB

AU - Hayward, C

AU - Rudan, I

AU - Chen, YE

AU - Bottinger, EP

AU - Loos, RJF

AU - Strom, P

AU - Hveem, K

AU - Boehnke, M

AU - Groop, L

AU - McCarthy, M

AU - Meitinger, T

AU - Ballantyne, CM

AU - Gabriel, SB

AU - O'Donne, CJ

AU - Post, WS

AU - North, KE

AU - Reiner, AP

AU - Boerwinkle, E

AU - Psaty, BM

AU - Altshuler, D

AU - Kathiresan, S

AU - Lin, DY

AU - Jarvik, GP

AU - Cupples, LA

AU - Kooperberg, C

AU - Wilson, JG

AU - Nickerson, DA

AU - Abecasis, GR

AU - Rich, SS

AU - Tracy, RP

AU - Willer, CJ

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 (>98th or <2nd 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 (>98th or <2nd 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

SN - 0002-9297

VL - 94

SP - 233

EP - 245

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -