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

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... Full description

Journal Title: American journal of human genetics 2014-02-06, Vol.94 (2), p.233-245
Main Author: Schmidt, Ellen M
Other Authors: Bizon, Chris , Jun, Goo , Auer, Paul , Li, Kuo-ping , Locke, Adam , Schreiner, Pamela J , Zhang, Qunyuan , Crosby, Jacy , Assimes, Themistocles L , Rosenthal, Elisabeth A , Tsai, Michael , Rotter, Jerome I , Taylor, Herman A , Borecki, Ingrid B , O’Donnell, Christopher J , Reiner, Alexander P , Jarvik, Gail P , Cupples, L. Adrienne , Nickerson, Deborah A , Tracy, Russell P , Daly, Mark J , Farlow, Deborah N , Kang, Hyun Min , Lettre, Guillaume , Rivas, Manuel A , Stitziel, Nathaniel O , Stoletzki, Nina , Ballantyne, Christie M , Barr, R. Graham , Carr, Jeff , Chen, Ida Y , Dupuis, Josée , Ellis, Jaclyn , Fornage, Myriam , Goff, David , Grody, Wayne , Lange, Ethan M , Lange, Leslie A , Levy, Daniel , Li, Dalin , Loria, Cay , Mackey, Aaron J , Mychaleckyj, Josyf C , Nettleton, Jennifer A , Quinlan, Aaron R , Rice, Kenneth , Watson, Karol , Wiggins, Kerri L , Wilson, Gregory , Zakai, Neil A , Nalls, Michael , Accurso, Frank , Beaty, Terri , Caplan, Daniel , Chidekel, Aaron , De Paula, Alicia , Emond, Mary J , Gutierrez, Hector , Hassoun, Paul M , Hiatt, Peter , Hokanson, John E , Kim, Yoonhee , Lin, Xihong , Martin, Thomas R , Mathias, Rasika A , McNamara, John , McNamara, Sharon , Nielson, Dennis , Orenstein, David , O’Sullivan, Brian , Passero, Mary Ann , Perkett, Elizabeth , Rafaels, Nicholas M , Spencer, Terry , Tabor, Holly K , Wigley, Fred , Wurfel, Mark M , Nickerson, Deborah A , Fu, Wenqing , Jarvik, Gail P , Kenny, Eimear E , O’Connor, Timothy D , Staples, Jeffrey C , Tennessen, Jacob A , Peters, Ulrike , Auer, Paul L , Brzyski, Robert , Carty, Cara L , Curb, J. David , Heiss, Gerardo , Lasser, Norman , Lin, Dan-Yu , Martin, Lisa , Phillips, Lawrence S , Simon, Michael S , Stein, Evan , Taylor, Kira C , Applebaum-Bowden, Deborah , Sturcke, Anne
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
Zum Text:
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recordid: cdi_swepub_primary_oai_lup_lub_lu_se_d54d1c01_1819_4796_b980_e2d848aed7ae
title: Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol
format: Article
creator:
  • Schmidt, Ellen M
  • Bizon, Chris
  • Jun, Goo
  • Auer, Paul
  • Li, Kuo-ping
  • Locke, Adam
  • Schreiner, Pamela J
  • Zhang, Qunyuan
  • Crosby, Jacy
  • Assimes, Themistocles L
  • Rosenthal, Elisabeth A
  • Tsai, Michael
  • Rotter, Jerome I
  • Taylor, Herman A
  • Borecki, Ingrid B
  • O’Donnell, Christopher J
  • Reiner, Alexander P
  • Jarvik, Gail P
  • Cupples, L. Adrienne
  • Nickerson, Deborah A
  • Tracy, Russell P
  • Daly, Mark J
  • Farlow, Deborah N
  • Kang, Hyun Min
  • Lettre, Guillaume
  • Rivas, Manuel A
  • Stitziel, Nathaniel O
  • Stoletzki, Nina
  • Ballantyne, Christie M
  • Barr, R. Graham
  • Carr, Jeff
  • Chen, Ida Y
  • Dupuis, Josée
  • Ellis, Jaclyn
  • Fornage, Myriam
  • Goff, David
  • Grody, Wayne
  • Lange, Ethan M
  • Lange, Leslie A
  • Levy, Daniel
  • Li, Dalin
  • Loria, Cay
  • Mackey, Aaron J
  • Mychaleckyj, Josyf C
  • Nettleton, Jennifer A
  • Quinlan, Aaron R
  • Rice, Kenneth
  • Watson, Karol
  • Wiggins, Kerri L
  • Wilson, Gregory
  • Zakai, Neil A
  • Nalls, Michael
  • Accurso, Frank
  • Beaty, Terri
  • Caplan, Daniel
  • Chidekel, Aaron
  • De Paula, Alicia
  • Emond, Mary J
  • Gutierrez, Hector
  • Hassoun, Paul M
  • Hiatt, Peter
  • Hokanson, John E
  • Kim, Yoonhee
  • Lin, Xihong
  • Martin, Thomas R
  • Mathias, Rasika A
  • McNamara, John
  • McNamara, Sharon
  • Nielson, Dennis
  • Orenstein, David
  • O’Sullivan, Brian
  • Passero, Mary Ann
  • Perkett, Elizabeth
  • Rafaels, Nicholas M
  • Spencer, Terry
  • Tabor, Holly K
  • Wigley, Fred
  • Wurfel, Mark M
  • Nickerson, Deborah A
  • Fu, Wenqing
  • Jarvik, Gail P
  • Kenny, Eimear E
  • O’Connor, Timothy D
  • Staples, Jeffrey C
  • Tennessen, Jacob A
  • Peters, Ulrike
  • Auer, Paul L
  • Brzyski, Robert
  • Carty, Cara L
  • Curb, J. David
  • Heiss, Gerardo
  • Lasser, Norman
  • Lin, Dan-Yu
  • Martin, Lisa
  • Phillips, Lawrence S
  • Simon, Michael S
  • Stein, Evan
  • Taylor, Kira C
  • Applebaum-Bowden, Deborah
  • Sturcke, Anne
subjects:
  • Adult
  • Aged
  • Apolipoproteins E - blood
  • Apolipoproteins E - genetics
  • Article
  • Basic Medicine
  • Cholesterol
  • Cholesterol, LDL
  • Cholesterol, LDL - genetics
  • Cohort Studies
  • DNA sequencing
  • Dyslipidemias - blood
  • Dyslipidemias - genetics
  • Exome
  • Female
  • Follow-Up Studies
  • Gene Frequency
  • Genes
  • Genetic aspects
  • Genetic Code
  • Genetic research
  • Genetic variation
  • Genetics
  • Genetics(clinical)
  • Genome-Wide Association Study
  • Genotype
  • Genotype & phenotype
  • Humans
  • Lipase - genetics
  • lipids (amino acids
  • Low density lipoprotein
  • Male
  • Medical and Health Sciences
  • Medical Genetics
  • Medicin och hälsovetenskap
  • Medicinsk genetik
  • Medicinska och farmaceutiska grundvetenskaper
  • Middle Aged
  • Nucleotide sequencing
  • peptides
  • Phenotype
  • Physiological aspects
  • Polymorphism, Single Nucleotide
  • Proprotein Convertase 9
  • Proprotein Convertases - genetics
  • proteins
  • Receptors, LDL - genetics
  • Research
  • Risk factors
  • Sequence Analysis, DNA
  • Serine Endopeptidases - genetics
ispartof: American journal of human genetics, 2014-02-06, Vol.94 (2), p.233-245
description: 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
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleWhole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol
sourceAlma/SFX Local Collection
creatorSchmidt, Ellen M ; Bizon, Chris ; Jun, Goo ; Auer, Paul ; Li, Kuo-ping ; Locke, Adam ; Schreiner, Pamela J ; Zhang, Qunyuan ; Crosby, Jacy ; Assimes, Themistocles L ; Rosenthal, Elisabeth A ; Tsai, Michael ; Rotter, Jerome I ; Taylor, Herman A ; Borecki, Ingrid B ; O’Donnell, Christopher J ; Reiner, Alexander P ; Jarvik, Gail P ; Cupples, L. Adrienne ; Nickerson, Deborah A ; Tracy, Russell P ; Daly, Mark J ; Farlow, Deborah N ; Kang, Hyun Min ; Lettre, Guillaume ; Rivas, Manuel A ; Stitziel, Nathaniel O ; Stoletzki, Nina ; Ballantyne, Christie M ; Barr, R. Graham ; Carr, Jeff ; Chen, Ida Y ; Dupuis, Josée ; Ellis, Jaclyn ; Fornage, Myriam ; Goff, David ; Grody, Wayne ; Lange, Ethan M ; Lange, Leslie A ; Levy, Daniel ; Li, Dalin ; Loria, Cay ; Mackey, Aaron J ; Mychaleckyj, Josyf C ; Nettleton, Jennifer A ; Quinlan, Aaron R ; Rice, Kenneth ; Watson, Karol ; Wiggins, Kerri L ; Wilson, Gregory ; Zakai, Neil A ; Nalls, Michael ; Accurso, Frank ; Beaty, Terri ; Caplan, Daniel ; Chidekel, Aaron ; De Paula, Alicia ; Emond, Mary J ; Gutierrez, Hector ; Hassoun, Paul M ; Hiatt, Peter ; Hokanson, John E ; Kim, Yoonhee ; Lin, Xihong ; Martin, Thomas R ; Mathias, Rasika A ; McNamara, John ; McNamara, Sharon ; Nielson, Dennis ; Orenstein, David ; O’Sullivan, Brian ; Passero, Mary Ann ; Perkett, Elizabeth ; Rafaels, Nicholas M ; Spencer, Terry ; Tabor, Holly K ; Wigley, Fred ; Wurfel, Mark M ; Nickerson, Deborah A ; Fu, Wenqing ; Jarvik, Gail P ; Kenny, Eimear E ; O’Connor, Timothy D ; Staples, Jeffrey C ; Tennessen, Jacob A ; Peters, Ulrike ; Auer, Paul L ; Brzyski, Robert ; Carty, Cara L ; Curb, J. David ; Heiss, Gerardo ; Lasser, Norman ; Lin, Dan-Yu ; Martin, Lisa ; Phillips, Lawrence S ; Simon, Michael S ; Stein, Evan ; Taylor, Kira C ; Applebaum-Bowden, Deborah ; Sturcke, Anne
creatorcontribSchmidt, Ellen M ; Bizon, Chris ; Jun, Goo ; Auer, Paul ; Li, Kuo-ping ; Locke, Adam ; Schreiner, Pamela J ; Zhang, Qunyuan ; Crosby, Jacy ; Assimes, Themistocles L ; Rosenthal, Elisabeth A ; Tsai, Michael ; Rotter, Jerome I ; Taylor, Herman A ; Borecki, Ingrid B ; O’Donnell, Christopher J ; Reiner, Alexander P ; Jarvik, Gail P ; Cupples, L. Adrienne ; Nickerson, Deborah A ; Tracy, Russell P ; Daly, Mark J ; Farlow, Deborah N ; Kang, Hyun Min ; Lettre, Guillaume ; Rivas, Manuel A ; Stitziel, Nathaniel O ; Stoletzki, Nina ; Ballantyne, Christie M ; Barr, R. Graham ; Carr, Jeff ; Chen, Ida Y ; Dupuis, Josée ; Ellis, Jaclyn ; Fornage, Myriam ; Goff, David ; Grody, Wayne ; Lange, Ethan M ; Lange, Leslie A ; Levy, Daniel ; Li, Dalin ; Loria, Cay ; Mackey, Aaron J ; Mychaleckyj, Josyf C ; Nettleton, Jennifer A ; Quinlan, Aaron R ; Rice, Kenneth ; Watson, Karol ; Wiggins, Kerri L ; Wilson, Gregory ; Zakai, Neil A ; Nalls, Michael ; Accurso, Frank ; Beaty, Terri ; Caplan, Daniel ; Chidekel, Aaron ; De Paula, Alicia ; Emond, Mary J ; Gutierrez, Hector ; Hassoun, Paul M ; Hiatt, Peter ; Hokanson, John E ; Kim, Yoonhee ; Lin, Xihong ; Martin, Thomas R ; Mathias, Rasika A ; McNamara, John ; McNamara, Sharon ; Nielson, Dennis ; Orenstein, David ; O’Sullivan, Brian ; Passero, Mary Ann ; Perkett, Elizabeth ; Rafaels, Nicholas M ; Spencer, Terry ; Tabor, Holly K ; Wigley, Fred ; Wurfel, Mark M ; Nickerson, Deborah A ; Fu, Wenqing ; Jarvik, Gail P ; Kenny, Eimear E ; O’Connor, Timothy D ; Staples, Jeffrey C ; Tennessen, Jacob A ; Peters, Ulrike ; Auer, Paul L ; Brzyski, Robert ; Carty, Cara L ; Curb, J. David ; Heiss, Gerardo ; Lasser, Norman ; Lin, Dan-Yu ; Martin, Lisa ; Phillips, Lawrence S ; Simon, Michael S ; Stein, Evan ; Taylor, Kira C ; Applebaum-Bowden, Deborah ; Sturcke, Anne ; the NHLBI Grand Opportunity Exome Sequencing Project ; NHLBI Grand Opportunity Exome Sequencing Project
descriptionElevated 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.
identifier
0ISSN: 0002-9297
1EISSN: 1537-6605
2DOI: 10.1016/j.ajhg.2014.01.010
3PMID: 24507775
languageeng
publisherUnited States: Elsevier Inc
subjectAdult ; Aged ; Apolipoproteins E - blood ; Apolipoproteins E - genetics ; Article ; Basic Medicine ; Cholesterol ; Cholesterol, LDL ; Cholesterol, LDL - genetics ; Cohort Studies ; DNA sequencing ; Dyslipidemias - blood ; Dyslipidemias - genetics ; Exome ; Female ; Follow-Up Studies ; Gene Frequency ; Genes ; Genetic aspects ; Genetic Code ; Genetic research ; Genetic variation ; Genetics ; Genetics(clinical) ; Genome-Wide Association Study ; Genotype ; Genotype & phenotype ; Humans ; Lipase - genetics ; lipids (amino acids ; Low density lipoprotein ; Male ; Medical and Health Sciences ; Medical Genetics ; Medicin och hälsovetenskap ; Medicinsk genetik ; Medicinska och farmaceutiska grundvetenskaper ; Middle Aged ; Nucleotide sequencing ; peptides ; Phenotype ; Physiological aspects ; Polymorphism, Single Nucleotide ; Proprotein Convertase 9 ; Proprotein Convertases - genetics ; proteins ; Receptors, LDL - genetics ; Research ; Risk factors ; Sequence Analysis, DNA ; Serine Endopeptidases - genetics
ispartofAmerican journal of human genetics, 2014-02-06, Vol.94 (2), p.233-245
rights
02014 The American Society of Human Genetics
1info:eu-repo/semantics/openAccess
2Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
3COPYRIGHT 2014 Elsevier B.V.
4Copyright Cell Press Feb 6, 2014
52014 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2014 The American Society of Human Genetics
lds50peer_reviewed
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creatorcontrib
0Schmidt, Ellen M
1Bizon, Chris
2Jun, Goo
3Auer, Paul
4Li, Kuo-ping
5Locke, Adam
6Schreiner, Pamela J
7Zhang, Qunyuan
8Crosby, Jacy
9Assimes, Themistocles L
10Rosenthal, Elisabeth A
11Tsai, Michael
12Rotter, Jerome I
13Taylor, Herman A
14Borecki, Ingrid B
15O’Donnell, Christopher J
16Reiner, Alexander P
17Jarvik, Gail P
18Cupples, L. Adrienne
19Nickerson, Deborah A
20Tracy, Russell P
21Daly, Mark J
22Farlow, Deborah N
23Kang, Hyun Min
24Lettre, Guillaume
25Rivas, Manuel A
26Stitziel, Nathaniel O
27Stoletzki, Nina
28Ballantyne, Christie M
29Barr, R. Graham
30Carr, Jeff
31Chen, Ida Y
32Dupuis, Josée
33Ellis, Jaclyn
34Fornage, Myriam
35Goff, David
36Grody, Wayne
37Lange, Ethan M
38Lange, Leslie A
39Levy, Daniel
40Li, Dalin
41Loria, Cay
42Mackey, Aaron J
43Mychaleckyj, Josyf C
44Nettleton, Jennifer A
45Quinlan, Aaron R
46Rice, Kenneth
47Watson, Karol
48Wiggins, Kerri L
49Wilson, Gregory
50Zakai, Neil A
51Nalls, Michael
52Accurso, Frank
53Beaty, Terri
54Caplan, Daniel
55Chidekel, Aaron
56De Paula, Alicia
57Emond, Mary J
58Gutierrez, Hector
59Hassoun, Paul M
60Hiatt, Peter
61Hokanson, John E
62Kim, Yoonhee
63Lin, Xihong
64Martin, Thomas R
65Mathias, Rasika A
66McNamara, John
67McNamara, Sharon
68Nielson, Dennis
69Orenstein, David
70O’Sullivan, Brian
71Passero, Mary Ann
72Perkett, Elizabeth
73Rafaels, Nicholas M
74Spencer, Terry
75Tabor, Holly K
76Wigley, Fred
77Wurfel, Mark M
78Nickerson, Deborah A
79Fu, Wenqing
80Jarvik, Gail P
81Kenny, Eimear E
82O’Connor, Timothy D
83Staples, Jeffrey C
84Tennessen, Jacob A
85Peters, Ulrike
86Auer, Paul L
87Brzyski, Robert
88Carty, Cara L
89Curb, J. David
90Heiss, Gerardo
91Lasser, Norman
92Lin, Dan-Yu
93Martin, Lisa
94Phillips, Lawrence S
95Simon, Michael S
96Stein, Evan
97Taylor, Kira C
98Applebaum-Bowden, Deborah
99Sturcke, Anne
100the NHLBI Grand Opportunity Exome Sequencing Project
101NHLBI Grand Opportunity Exome Sequencing Project
title
0Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol
1American journal of human genetics
addtitleAm J Hum Genet
descriptionElevated 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.
subject
0Adult
1Aged
2Apolipoproteins E - blood
3Apolipoproteins E - genetics
4Article
5Basic Medicine
6Cholesterol
7Cholesterol, LDL
8Cholesterol, LDL - genetics
9Cohort Studies
10DNA sequencing
11Dyslipidemias - blood
12Dyslipidemias - genetics
13Exome
14Female
15Follow-Up Studies
16Gene Frequency
17Genes
18Genetic aspects
19Genetic Code
20Genetic research
21Genetic variation
22Genetics
23Genetics(clinical)
24Genome-Wide Association Study
25Genotype
26Genotype & phenotype
27Humans
28Lipase - genetics
29lipids (amino acids
30Low density lipoprotein
31Male
32Medical and Health Sciences
33Medical Genetics
34Medicin och hälsovetenskap
35Medicinsk genetik
36Medicinska och farmaceutiska grundvetenskaper
37Middle Aged
38Nucleotide sequencing
39peptides
40Phenotype
41Physiological aspects
42Polymorphism, Single Nucleotide
43Proprotein Convertase 9
44Proprotein Convertases - genetics
45proteins
46Receptors, LDL - genetics
47Research
48Risk factors
49Sequence Analysis, DNA
50Serine Endopeptidases - genetics
issn
00002-9297
11537-6605
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creator
0Schmidt, Ellen M
1Bizon, Chris
2Jun, Goo
3Auer, Paul
4Li, Kuo-ping
5Locke, Adam
6Schreiner, Pamela J
7Zhang, Qunyuan
8Crosby, Jacy
9Assimes, Themistocles L
10Rosenthal, Elisabeth A
11Tsai, Michael
12Rotter, Jerome I
13Taylor, Herman A
14Borecki, Ingrid B
15O’Donnell, Christopher J
16Reiner, Alexander P
17Jarvik, Gail P
18Cupples, L. Adrienne
19Nickerson, Deborah A
20Tracy, Russell P
21Daly, Mark J
22Farlow, Deborah N
23Kang, Hyun Min
24Lettre, Guillaume
25Rivas, Manuel A
26Stitziel, Nathaniel O
27Stoletzki, Nina
28Ballantyne, Christie M
29Barr, R. Graham
30Carr, Jeff
31Chen, Ida Y
32Dupuis, Josée
33Ellis, Jaclyn
34Fornage, Myriam
35Goff, David
36Grody, Wayne
37Lange, Ethan M
38Lange, Leslie A
39Levy, Daniel
40Li, Dalin
41Loria, Cay
42Mackey, Aaron J
43Mychaleckyj, Josyf C
44Nettleton, Jennifer A
45Quinlan, Aaron R
46Rice, Kenneth
47Watson, Karol
48Wiggins, Kerri L
49Wilson, Gregory
50Zakai, Neil A
51Nalls, Michael
52Accurso, Frank
53Beaty, Terri
54Caplan, Daniel
55Chidekel, Aaron
56De Paula, Alicia
57Emond, Mary J
58Gutierrez, Hector
59Hassoun, Paul M
60Hiatt, Peter
61Hokanson, John E
62Kim, Yoonhee
63Lin, Xihong
64Martin, Thomas R
65Mathias, Rasika A
66McNamara, John
67McNamara, Sharon
68Nielson, Dennis
69Orenstein, David
70O’Sullivan, Brian
71Passero, Mary Ann
72Perkett, Elizabeth
73Rafaels, Nicholas M
74Spencer, Terry
75Tabor, Holly K
76Wigley, Fred
77Wurfel, Mark M
78Nickerson, Deborah A
79Fu, Wenqing
80Jarvik, Gail P
81Kenny, Eimear E
82O’Connor, Timothy D
83Staples, Jeffrey C
84Tennessen, Jacob A
85Peters, Ulrike
86Auer, Paul L
87Brzyski, Robert
88Carty, Cara L
89Curb, J. David
90Heiss, Gerardo
91Lasser, Norman
92Lin, Dan-Yu
93Martin, Lisa
94Phillips, Lawrence S
95Simon, Michael S
96Stein, Evan
97Taylor, Kira C
98Applebaum-Bowden, Deborah
99Sturcke, Anne
general
0Elsevier Inc
1Elsevier B.V
2Cell Press
3Elsevier
scope
06I.
1AAFTH
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35DJ
4AGBBJ
5QVL
6CGR
7CUY
8CVF
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13CITATION
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187U7
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21FR3
22K9.
23NAPCQ
24P64
25RC3
26BOBZL
27CLFQK
285PM
29ADTPV
30AOWAS
31D95
sort
creationdate20140206
titleWhole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol
authorSchmidt, Ellen M ; Bizon, Chris ; Jun, Goo ; Auer, Paul ; Li, Kuo-ping ; Locke, Adam ; Schreiner, Pamela J ; Zhang, Qunyuan ; Crosby, Jacy ; Assimes, Themistocles L ; Rosenthal, Elisabeth A ; Tsai, Michael ; Rotter, Jerome I ; Taylor, Herman A ; Borecki, Ingrid B ; O’Donnell, Christopher J ; Reiner, Alexander P ; Jarvik, Gail P ; Cupples, L. Adrienne ; Nickerson, Deborah A ; Tracy, Russell P ; Daly, Mark J ; Farlow, Deborah N ; Kang, Hyun Min ; Lettre, Guillaume ; Rivas, Manuel A ; Stitziel, Nathaniel O ; Stoletzki, Nina ; Ballantyne, Christie M ; Barr, R. Graham ; Carr, Jeff ; Chen, Ida Y ; Dupuis, Josée ; Ellis, Jaclyn ; Fornage, Myriam ; Goff, David ; Grody, Wayne ; Lange, Ethan M ; Lange, Leslie A ; Levy, Daniel ; Li, Dalin ; Loria, Cay ; Mackey, Aaron J ; Mychaleckyj, Josyf C ; Nettleton, Jennifer A ; Quinlan, Aaron R ; Rice, Kenneth ; Watson, Karol ; Wiggins, Kerri L ; Wilson, Gregory ; Zakai, Neil A ; Nalls, Michael ; Accurso, Frank ; Beaty, Terri ; Caplan, Daniel ; Chidekel, Aaron ; De Paula, Alicia ; Emond, Mary J ; Gutierrez, Hector ; Hassoun, Paul M ; Hiatt, Peter ; Hokanson, John E ; Kim, Yoonhee ; Lin, Xihong ; Martin, Thomas R ; Mathias, Rasika A ; McNamara, John ; McNamara, Sharon ; Nielson, Dennis ; Orenstein, David ; O’Sullivan, Brian ; Passero, Mary Ann ; Perkett, Elizabeth ; Rafaels, Nicholas M ; Spencer, Terry ; Tabor, Holly K ; Wigley, Fred ; Wurfel, Mark M ; Nickerson, Deborah A ; Fu, Wenqing ; Jarvik, Gail P ; Kenny, Eimear E ; O’Connor, Timothy D ; Staples, Jeffrey C ; Tennessen, Jacob A ; Peters, Ulrike ; Auer, Paul L ; Brzyski, Robert ; Carty, Cara L ; Curb, J. David ; Heiss, Gerardo ; Lasser, Norman ; Lin, Dan-Yu ; Martin, Lisa ; Phillips, Lawrence S ; Simon, Michael S ; Stein, Evan ; Taylor, Kira C ; Applebaum-Bowden, Deborah ; Sturcke, Anne
facets
frbrtype5
frbrgroupidcdi_FETCH-LOGICAL-1740t-2469c56ef363b5581cc7562951d37e8587d4aaa85f42cb102fc26d82d973ae393
rsrctypearticles
prefilterarticles
languageeng
creationdate2014
topic
0Adult
1Aged
2Apolipoproteins E - blood
3Apolipoproteins E - genetics
4Article
5Basic Medicine
6Cholesterol
7Cholesterol, LDL
8Cholesterol, LDL - genetics
9Cohort Studies
10DNA sequencing
11Dyslipidemias - blood
12Dyslipidemias - genetics
13Exome
14Female
15Follow-Up Studies
16Gene Frequency
17Genes
18Genetic aspects
19Genetic Code
20Genetic research
21Genetic variation
22Genetics
23Genetics(clinical)
24Genome-Wide Association Study
25Genotype
26Genotype & phenotype
27Humans
28Lipase - genetics
29lipids (amino acids
30Low density lipoprotein
31Male
32Medical and Health Sciences
33Medical Genetics
34Medicin och hälsovetenskap
35Medicinsk genetik
36Medicinska och farmaceutiska grundvetenskaper
37Middle Aged
38Nucleotide sequencing
39peptides
40Phenotype
41Physiological aspects
42Polymorphism, Single Nucleotide
43Proprotein Convertase 9
44Proprotein Convertases - genetics
45proteins
46Receptors, LDL - genetics
47Research
48Risk factors
49Sequence Analysis, DNA
50Serine Endopeptidases - genetics
toplevel
0peer_reviewed
1online_resources
creatorcontrib
0Schmidt, Ellen M
1Bizon, Chris
2Jun, Goo
3Auer, Paul
4Li, Kuo-ping
5Locke, Adam
6Schreiner, Pamela J
7Zhang, Qunyuan
8Crosby, Jacy
9Assimes, Themistocles L
10Rosenthal, Elisabeth A
11Tsai, Michael
12Rotter, Jerome I
13Taylor, Herman A
14Borecki, Ingrid B
15O’Donnell, Christopher J
16Reiner, Alexander P
17Jarvik, Gail P
18Cupples, L. Adrienne
19Nickerson, Deborah A
20Tracy, Russell P
21Daly, Mark J
22Farlow, Deborah N
23Kang, Hyun Min
24Lettre, Guillaume
25Rivas, Manuel A
26Stitziel, Nathaniel O
27Stoletzki, Nina
28Ballantyne, Christie M
29Barr, R. Graham
30Carr, Jeff
31Chen, Ida Y
32Dupuis, Josée
33Ellis, Jaclyn
34Fornage, Myriam
35Goff, David
36Grody, Wayne
37Lange, Ethan M
38Lange, Leslie A
39Levy, Daniel
40Li, Dalin
41Loria, Cay
42Mackey, Aaron J
43Mychaleckyj, Josyf C
44Nettleton, Jennifer A
45Quinlan, Aaron R
46Rice, Kenneth
47Watson, Karol
48Wiggins, Kerri L
49Wilson, Gregory
50Zakai, Neil A
51Nalls, Michael
52Accurso, Frank
53Beaty, Terri
54Caplan, Daniel
55Chidekel, Aaron
56De Paula, Alicia
57Emond, Mary J
58Gutierrez, Hector
59Hassoun, Paul M
60Hiatt, Peter
61Hokanson, John E
62Kim, Yoonhee
63Lin, Xihong
64Martin, Thomas R
65Mathias, Rasika A
66McNamara, John
67McNamara, Sharon
68Nielson, Dennis
69Orenstein, David
70O’Sullivan, Brian
71Passero, Mary Ann
72Perkett, Elizabeth
73Rafaels, Nicholas M
74Spencer, Terry
75Tabor, Holly K
76Wigley, Fred
77Wurfel, Mark M
78Nickerson, Deborah A
79Fu, Wenqing
80Jarvik, Gail P
81Kenny, Eimear E
82O’Connor, Timothy D
83Staples, Jeffrey C
84Tennessen, Jacob A
85Peters, Ulrike
86Auer, Paul L
87Brzyski, Robert
88Carty, Cara L
89Curb, J. David
90Heiss, Gerardo
91Lasser, Norman
92Lin, Dan-Yu
93Martin, Lisa
94Phillips, Lawrence S
95Simon, Michael S
96Stein, Evan
97Taylor, Kira C
98Applebaum-Bowden, Deborah
99Sturcke, Anne
100the NHLBI Grand Opportunity Exome Sequencing Project
101NHLBI Grand Opportunity Exome Sequencing Project
collection
0ScienceDirect Open Access Titles
1Elsevier:ScienceDirect:Open Access
2NARCIS
3NARCIS: Datasets
4Narcis: Open Access
5NARCIS:Publications
6Medline
7MEDLINE
8MEDLINE (Ovid)
9MEDLINE
10MEDLINE
11PubMed
12CrossRef
13Academic OneFile (A&I only)
14Calcium & Calcified Tissue Abstracts
15Neurosciences Abstracts
16Nucleic Acids Abstracts
17Toxicology Abstracts
18Technology Research Database
19Environmental Sciences and Pollution Management
20Engineering Research Database
21ProQuest Health & Medical Complete (Alumni)
22Nursing & Allied Health Premium
23Biotechnology and BioEngineering Abstracts
24Genetics Abstracts
25OpenAIRE (Open Access)
26OpenAIRE
27PubMed Central (Full Participant titles)
28SwePub
29SwePub Articles
30SWEPUB Lunds universitet
jtitleAmerican journal of human genetics
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Schmidt, Ellen M
1Bizon, Chris
2Jun, Goo
3Auer, Paul
4Li, Kuo-ping
5Locke, Adam
6Schreiner, Pamela J
7Zhang, Qunyuan
8Crosby, Jacy
9Assimes, Themistocles L
10Rosenthal, Elisabeth A
11Tsai, Michael
12Rotter, Jerome I
13Taylor, Herman A
14Borecki, Ingrid B
15O’Donnell, Christopher J
16Reiner, Alexander P
17Jarvik, Gail P
18Cupples, L. Adrienne
19Nickerson, Deborah A
20Tracy, Russell P
21Daly, Mark J
22Farlow, Deborah N
23Kang, Hyun Min
24Lettre, Guillaume
25Rivas, Manuel A
26Stitziel, Nathaniel O
27Stoletzki, Nina
28Ballantyne, Christie M
29Barr, R. Graham
30Carr, Jeff
31Chen, Ida Y
32Dupuis, Josée
33Ellis, Jaclyn
34Fornage, Myriam
35Goff, David
36Grody, Wayne
37Lange, Ethan M
38Lange, Leslie A
39Levy, Daniel
40Li, Dalin
41Loria, Cay
42Mackey, Aaron J
43Mychaleckyj, Josyf C
44Nettleton, Jennifer A
45Quinlan, Aaron R
46Rice, Kenneth
47Watson, Karol
48Wiggins, Kerri L
49Wilson, Gregory
50Zakai, Neil A
51Nalls, Michael
52Accurso, Frank
53Beaty, Terri
54Caplan, Daniel
55Chidekel, Aaron
56De Paula, Alicia
57Emond, Mary J
58Gutierrez, Hector
59Hassoun, Paul M
60Hiatt, Peter
61Hokanson, John E
62Kim, Yoonhee
63Lin, Xihong
64Martin, Thomas R
65Mathias, Rasika A
66McNamara, John
67McNamara, Sharon
68Nielson, Dennis
69Orenstein, David
70O’Sullivan, Brian
71Passero, Mary Ann
72Perkett, Elizabeth
73Rafaels, Nicholas M
74Spencer, Terry
75Tabor, Holly K
76Wigley, Fred
77Wurfel, Mark M
78Nickerson, Deborah A
79Fu, Wenqing
80Jarvik, Gail P
81Kenny, Eimear E
82O’Connor, Timothy D
83Staples, Jeffrey C
84Tennessen, Jacob A
85Peters, Ulrike
86Auer, Paul L
87Brzyski, Robert
88Carty, Cara L
89Curb, J. David
90Heiss, Gerardo
91Lasser, Norman
92Lin, Dan-Yu
93Martin, Lisa
94Phillips, Lawrence S
95Simon, Michael S
96Stein, Evan
97Taylor, Kira C
98Applebaum-Bowden, Deborah
99Sturcke, Anne
aucorp
0the NHLBI Grand Opportunity Exome Sequencing Project
1NHLBI Grand Opportunity Exome Sequencing Project
formatjournal
genrearticle
ristypeJOUR
atitleWhole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol
jtitleAmerican journal of human genetics
addtitleAm J Hum Genet
date2014-02-06
risdate2014
volume94
issue2
spage233
epage245
pages233-245
issn0002-9297
eissn1537-6605
notesThese authors contributed equally to this work
abstractElevated 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.
copUnited States
pubElsevier Inc
pmid24507775
doi10.1016/j.ajhg.2014.01.010
oafree_for_read