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Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseas... Full description

Journal Title: American Journal of Human Genetics 2014-11-06, Vol.95 (5), p.535-552
Main Author: Trynka, Gosia
Other Authors: Stahl, Eli , Collier, David A , Pers, Tune H , Albus, Margot , Cahn, Wiepke , Cai, Guiqing , Cantor, Rita M , Chan, Raymond C.K , Cheng, Wei , Cheung, Eric F.C , Cohen, David , Cormican, Paul , Craddock, Nick , Demontis, Ditte , Djurovic, Srdjan , Donohoe, Gary , Dudbridge, Frank , Durmishi, Naser , Eriksson, Johan , Freimer, Nelson B , Fromer, Menachem , Godard, Stephanie , Grove, Jakob , Henskens, Frans A , Herms, Stefan , Hoffmann, Per , Ikeda, Masashi , Julià, Antonio , Kahn, René S , Kelly, Brian J , Knowles, James A , Kucinskas, Vaidutis , Kuzelova-Ptackova, Hana , Kähler, Anna K , Laurent, Claudine , Lee, S. Hong , Limborska, Svetlana , Lnnqvist, Jouko , Marsal, Sara , Meijer, Carin J , Melegh, Bela , Melle, Ingrid , Mors, Ole , Myin-Germeys, Inez , Nikitina-Zake, Liene , O’Callaghan, Eadbhard , O’Dushlaine, Colm , O’Neill, F. Anthony , Oh, Sang-Yun , Pantelis, Christos , Parkhomenko, Elena , Pocklington, Andrew J , Powell, John , Pulver, Ann E , Purcell, Shaun M , Quested, Digby , Richards, Alexander L , Ruderfer, Douglas M , Salomaa, Veikko , Schwab, Sibylle G , Shi, Jianxin , Sigurdsson, Engilbert , Sim, Kang , Spencer, Chris C.A , Stahl, Eli A , Stogmann, Elisabeth , Strengman, Eric , Suvisaari, Jaana , Szatkiewicz, Jin P , Thirumalai, Srinivas , Veijola, Juha , Walsh, Dermot , Weiser, Mark , Wildenauer, Dieter B , Witt, Stephanie H , Wolen, Aaron R , Wu, Jing Qin , Stefansson, Kari , Andreassen, Ole A , Ehrenreich, Hannelore , Gurling, Hugh , Hultman, Christina M , Jablensky, Assen V , Li, Qingqin S , McQuillin, Andrew , Mowry, Bryan J , Nthen, Markus M , Palotie, Aarno , Rietschel, Marcella , Daly, Mark J , Kähler, Anna K , Bergen, Sarah , Hultman, Christina M , Kähler, Anna K , Hultman, Christina M , McCarroll, Steven A , Pasaniuc, Bogdan , Raychaudhuri, Soumya , Price, Alkes L
Format: Electronic Article Electronic Article
Language: English
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Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
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title: Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
format: Article
creator:
  • Trynka, Gosia
  • Stahl, Eli
  • Collier, David A
  • Pers, Tune H
  • Albus, Margot
  • Cahn, Wiepke
  • Cai, Guiqing
  • Cantor, Rita M
  • Chan, Raymond C.K
  • Cheng, Wei
  • Cheung, Eric F.C
  • Cohen, David
  • Cormican, Paul
  • Craddock, Nick
  • Demontis, Ditte
  • Djurovic, Srdjan
  • Donohoe, Gary
  • Dudbridge, Frank
  • Durmishi, Naser
  • Eriksson, Johan
  • Freimer, Nelson B
  • Fromer, Menachem
  • Godard, Stephanie
  • Grove, Jakob
  • Henskens, Frans A
  • Herms, Stefan
  • Hoffmann, Per
  • Ikeda, Masashi
  • Julià, Antonio
  • Kahn, René S
  • Kelly, Brian J
  • Knowles, James A
  • Kucinskas, Vaidutis
  • Kuzelova-Ptackova, Hana
  • Kähler, Anna K
  • Laurent, Claudine
  • Lee, S. Hong
  • Limborska, Svetlana
  • Lnnqvist, Jouko
  • Marsal, Sara
  • Meijer, Carin J
  • Melegh, Bela
  • Melle, Ingrid
  • Mors, Ole
  • Myin-Germeys, Inez
  • Nikitina-Zake, Liene
  • O’Callaghan, Eadbhard
  • O’Dushlaine, Colm
  • O’Neill, F. Anthony
  • Oh, Sang-Yun
  • Pantelis, Christos
  • Parkhomenko, Elena
  • Pocklington, Andrew J
  • Powell, John
  • Pulver, Ann E
  • Purcell, Shaun M
  • Quested, Digby
  • Richards, Alexander L
  • Ruderfer, Douglas M
  • Salomaa, Veikko
  • Schwab, Sibylle G
  • Shi, Jianxin
  • Sigurdsson, Engilbert
  • Sim, Kang
  • Spencer, Chris C.A
  • Stahl, Eli A
  • Stogmann, Elisabeth
  • Strengman, Eric
  • Suvisaari, Jaana
  • Szatkiewicz, Jin P
  • Thirumalai, Srinivas
  • Veijola, Juha
  • Walsh, Dermot
  • Weiser, Mark
  • Wildenauer, Dieter B
  • Witt, Stephanie H
  • Wolen, Aaron R
  • Wu, Jing Qin
  • Stefansson, Kari
  • Andreassen, Ole A
  • Ehrenreich, Hannelore
  • Gurling, Hugh
  • Hultman, Christina M
  • Jablensky, Assen V
  • Li, Qingqin S
  • McQuillin, Andrew
  • Mowry, Bryan J
  • Nthen, Markus M
  • Palotie, Aarno
  • Rietschel, Marcella
  • Daly, Mark J
  • Kähler, Anna K
  • Bergen, Sarah
  • Hultman, Christina M
  • Kähler, Anna K
  • Hultman, Christina M
  • McCarroll, Steven A
  • Pasaniuc, Bogdan
  • Raychaudhuri, Soumya
  • Price, Alkes L
subjects:
  • Article
  • Biological variation
  • Cells
  • coding variants
  • Computer Simulation
  • Disease
  • disease architecture
  • Epigenetic inheritance
  • exome chips
  • Genetic Diseases, Inborn - genetics
  • Genetic regulation
  • Genetic research
  • Genetic Variation - genetics
  • Genetics
  • Genetics & Heredity
  • Genetics(clinical)
  • genome
  • Genome-Wide Association Study - methods
  • Genomics
  • Genotype & phenotype
  • genotype imputation
  • Humans
  • Inheritance Patterns - genetics
  • Medicin och hälsovetenskap
  • Models, Genetic
  • Open Reading Frames - genetics
  • Regulatory Elements, Transcriptional - genetics
  • Research
  • Simulation
  • trait heritability
  • wide association study
ispartof: American Journal of Human Genetics, 2014-11-06, Vol.95 (5), p.535-552
description: Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg2) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg2 from imputed SNPs (5.1× enrichment; p = 3.7 × 10−17) and 38% (SE = 4%) of hg2 from genotyped SNPs (1.6× enrichment, p = 1.0 × 10−4). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
  • 1537-6605
url: Link


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titlePartitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
sourceAlma/SFX Local Collection
creatorTrynka, Gosia ; Stahl, Eli ; Collier, David A ; Pers, Tune H ; Albus, Margot ; Cahn, Wiepke ; Cai, Guiqing ; Cantor, Rita M ; Chan, Raymond C.K ; Cheng, Wei ; Cheung, Eric F.C ; Cohen, David ; Cormican, Paul ; Craddock, Nick ; Demontis, Ditte ; Djurovic, Srdjan ; Donohoe, Gary ; Dudbridge, Frank ; Durmishi, Naser ; Eriksson, Johan ; Freimer, Nelson B ; Fromer, Menachem ; Godard, Stephanie ; Grove, Jakob ; Henskens, Frans A ; Herms, Stefan ; Hoffmann, Per ; Ikeda, Masashi ; Julià, Antonio ; Kahn, René S ; Kelly, Brian J ; Knowles, James A ; Kucinskas, Vaidutis ; Kuzelova-Ptackova, Hana ; Kähler, Anna K ; Laurent, Claudine ; Lee, S. Hong ; Limborska, Svetlana ; Lnnqvist, Jouko ; Marsal, Sara ; Meijer, Carin J ; Melegh, Bela ; Melle, Ingrid ; Mors, Ole ; Myin-Germeys, Inez ; Nikitina-Zake, Liene ; O’Callaghan, Eadbhard ; O’Dushlaine, Colm ; O’Neill, F. Anthony ; Oh, Sang-Yun ; Pantelis, Christos ; Parkhomenko, Elena ; Pocklington, Andrew J ; Powell, John ; Pulver, Ann E ; Purcell, Shaun M ; Quested, Digby ; Richards, Alexander L ; Ruderfer, Douglas M ; Salomaa, Veikko ; Schwab, Sibylle G ; Shi, Jianxin ; Sigurdsson, Engilbert ; Sim, Kang ; Spencer, Chris C.A ; Stahl, Eli A ; Stogmann, Elisabeth ; Strengman, Eric ; Suvisaari, Jaana ; Szatkiewicz, Jin P ; Thirumalai, Srinivas ; Veijola, Juha ; Walsh, Dermot ; Weiser, Mark ; Wildenauer, Dieter B ; Witt, Stephanie H ; Wolen, Aaron R ; Wu, Jing Qin ; Stefansson, Kari ; Andreassen, Ole A ; Ehrenreich, Hannelore ; Gurling, Hugh ; Hultman, Christina M ; Jablensky, Assen V ; Li, Qingqin S ; McQuillin, Andrew ; Mowry, Bryan J ; Nthen, Markus M ; Palotie, Aarno ; Rietschel, Marcella ; Daly, Mark J ; Kähler, Anna K ; Bergen, Sarah ; Hultman, Christina M ; Kähler, Anna K ; Hultman, Christina M ; McCarroll, Steven A ; Pasaniuc, Bogdan ; Raychaudhuri, Soumya ; Price, Alkes L
creatorcontribTrynka, Gosia ; Stahl, Eli ; Collier, David A ; Pers, Tune H ; Albus, Margot ; Cahn, Wiepke ; Cai, Guiqing ; Cantor, Rita M ; Chan, Raymond C.K ; Cheng, Wei ; Cheung, Eric F.C ; Cohen, David ; Cormican, Paul ; Craddock, Nick ; Demontis, Ditte ; Djurovic, Srdjan ; Donohoe, Gary ; Dudbridge, Frank ; Durmishi, Naser ; Eriksson, Johan ; Freimer, Nelson B ; Fromer, Menachem ; Godard, Stephanie ; Grove, Jakob ; Henskens, Frans A ; Herms, Stefan ; Hoffmann, Per ; Ikeda, Masashi ; Julià, Antonio ; Kahn, René S ; Kelly, Brian J ; Knowles, James A ; Kucinskas, Vaidutis ; Kuzelova-Ptackova, Hana ; Kähler, Anna K ; Laurent, Claudine ; Lee, S. Hong ; Limborska, Svetlana ; Lnnqvist, Jouko ; Marsal, Sara ; Meijer, Carin J ; Melegh, Bela ; Melle, Ingrid ; Mors, Ole ; Myin-Germeys, Inez ; Nikitina-Zake, Liene ; O’Callaghan, Eadbhard ; O’Dushlaine, Colm ; O’Neill, F. Anthony ; Oh, Sang-Yun ; Pantelis, Christos ; Parkhomenko, Elena ; Pocklington, Andrew J ; Powell, John ; Pulver, Ann E ; Purcell, Shaun M ; Quested, Digby ; Richards, Alexander L ; Ruderfer, Douglas M ; Salomaa, Veikko ; Schwab, Sibylle G ; Shi, Jianxin ; Sigurdsson, Engilbert ; Sim, Kang ; Spencer, Chris C.A ; Stahl, Eli A ; Stogmann, Elisabeth ; Strengman, Eric ; Suvisaari, Jaana ; Szatkiewicz, Jin P ; Thirumalai, Srinivas ; Veijola, Juha ; Walsh, Dermot ; Weiser, Mark ; Wildenauer, Dieter B ; Witt, Stephanie H ; Wolen, Aaron R ; Wu, Jing Qin ; Stefansson, Kari ; Andreassen, Ole A ; Ehrenreich, Hannelore ; Gurling, Hugh ; Hultman, Christina M ; Jablensky, Assen V ; Li, Qingqin S ; McQuillin, Andrew ; Mowry, Bryan J ; Nthen, Markus M ; Palotie, Aarno ; Rietschel, Marcella ; Daly, Mark J ; Kähler, Anna K ; Bergen, Sarah ; Hultman, Christina M ; Kähler, Anna K ; Hultman, Christina M ; McCarroll, Steven A ; Pasaniuc, Bogdan ; Raychaudhuri, Soumya ; Price, Alkes L ; Psychosis Endophenotypes International Consortium ; Wellcome Trust Case Control Consortium ; Schizophrenia Working Group of the Psychiatric Genomics Consortium ; SWE-SCZ Consortium
descriptionRegulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg2) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg2 from imputed SNPs (5.1× enrichment; p = 3.7 × 10−17) and 38% (SE = 4%) of hg2 from genotyped SNPs (1.6× enrichment, p = 1.0 × 10−4). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg2 despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.
identifier
0ISSN: 0002-9297
1ISSN: 1537-6605
2EISSN: 1537-6605
3DOI: 10.1016/j.ajhg.2014.10.004
4PMID: 25439723
languageeng
publisherUnited States: Elsevier Inc
subjectArticle ; Biological variation ; Cells ; coding variants ; Computer Simulation ; Disease ; disease architecture ; Epigenetic inheritance ; exome chips ; Genetic Diseases, Inborn - genetics ; Genetic regulation ; Genetic research ; Genetic Variation - genetics ; Genetics ; Genetics & Heredity ; Genetics(clinical) ; genome ; Genome-Wide Association Study - methods ; Genomics ; Genotype & phenotype ; genotype imputation ; Humans ; Inheritance Patterns - genetics ; Medicin och hälsovetenskap ; Models, Genetic ; Open Reading Frames - genetics ; Regulatory Elements, Transcriptional - genetics ; Research ; Simulation ; trait heritability ; wide association study
ispartofAmerican Journal of Human Genetics, 2014-11-06, Vol.95 (5), p.535-552
rights
02014 The American Society of Human Genetics
1info:eu-repo/semantics/restrictedAccess
2Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
3COPYRIGHT 2014 Elsevier B.V.
4Copyright Cell Press Nov 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
0Trynka, Gosia
1Stahl, Eli
2Collier, David A
3Pers, Tune H
4Albus, Margot
5Cahn, Wiepke
6Cai, Guiqing
7Cantor, Rita M
8Chan, Raymond C.K
9Cheng, Wei
10Cheung, Eric F.C
11Cohen, David
12Cormican, Paul
13Craddock, Nick
14Demontis, Ditte
15Djurovic, Srdjan
16Donohoe, Gary
17Dudbridge, Frank
18Durmishi, Naser
19Eriksson, Johan
20Freimer, Nelson B
21Fromer, Menachem
22Godard, Stephanie
23Grove, Jakob
24Henskens, Frans A
25Herms, Stefan
26Hoffmann, Per
27Ikeda, Masashi
28Julià, Antonio
29Kahn, René S
30Kelly, Brian J
31Knowles, James A
32Kucinskas, Vaidutis
33Kuzelova-Ptackova, Hana
34Kähler, Anna K
35Laurent, Claudine
36Lee, S. Hong
37Limborska, Svetlana
38Lnnqvist, Jouko
39Marsal, Sara
40Meijer, Carin J
41Melegh, Bela
42Melle, Ingrid
43Mors, Ole
44Myin-Germeys, Inez
45Nikitina-Zake, Liene
46O’Callaghan, Eadbhard
47O’Dushlaine, Colm
48O’Neill, F. Anthony
49Oh, Sang-Yun
50Pantelis, Christos
51Parkhomenko, Elena
52Pocklington, Andrew J
53Powell, John
54Pulver, Ann E
55Purcell, Shaun M
56Quested, Digby
57Richards, Alexander L
58Ruderfer, Douglas M
59Salomaa, Veikko
60Schwab, Sibylle G
61Shi, Jianxin
62Sigurdsson, Engilbert
63Sim, Kang
64Spencer, Chris C.A
65Stahl, Eli A
66Stogmann, Elisabeth
67Strengman, Eric
68Suvisaari, Jaana
69Szatkiewicz, Jin P
70Thirumalai, Srinivas
71Veijola, Juha
72Walsh, Dermot
73Weiser, Mark
74Wildenauer, Dieter B
75Witt, Stephanie H
76Wolen, Aaron R
77Wu, Jing Qin
78Stefansson, Kari
79Andreassen, Ole A
80Ehrenreich, Hannelore
81Gurling, Hugh
82Hultman, Christina M
83Jablensky, Assen V
84Li, Qingqin S
85McQuillin, Andrew
86Mowry, Bryan J
87Nthen, Markus M
88Palotie, Aarno
89Rietschel, Marcella
90Daly, Mark J
91Kähler, Anna K
92Bergen, Sarah
93Hultman, Christina M
94Kähler, Anna K
95Hultman, Christina M
96McCarroll, Steven A
97Pasaniuc, Bogdan
98Raychaudhuri, Soumya
99Price, Alkes L
100Psychosis Endophenotypes International Consortium
101Wellcome Trust Case Control Consortium
102Schizophrenia Working Group of the Psychiatric Genomics Consortium
103SWE-SCZ Consortium
title
0Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
1American Journal of Human Genetics
addtitleAm J Hum Genet
descriptionRegulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg2) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg2 from imputed SNPs (5.1× enrichment; p = 3.7 × 10−17) and 38% (SE = 4%) of hg2 from genotyped SNPs (1.6× enrichment, p = 1.0 × 10−4). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg2 despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.
subject
0Article
1Biological variation
2Cells
3coding variants
4Computer Simulation
5Disease
6disease architecture
7Epigenetic inheritance
8exome chips
9Genetic Diseases, Inborn - genetics
10Genetic regulation
11Genetic research
12Genetic Variation - genetics
13Genetics
14Genetics & Heredity
15Genetics(clinical)
16genome
17Genome-Wide Association Study - methods
18Genomics
19Genotype & phenotype
20genotype imputation
21Humans
22Inheritance Patterns - genetics
23Medicin och hälsovetenskap
24Models, Genetic
25Open Reading Frames - genetics
26Regulatory Elements, Transcriptional - genetics
27Research
28Simulation
29trait heritability
30wide association study
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0Trynka, Gosia
1Stahl, Eli
2Collier, David A
3Pers, Tune H
4Albus, Margot
5Cahn, Wiepke
6Cai, Guiqing
7Cantor, Rita M
8Chan, Raymond C.K
9Cheng, Wei
10Cheung, Eric F.C
11Cohen, David
12Cormican, Paul
13Craddock, Nick
14Demontis, Ditte
15Djurovic, Srdjan
16Donohoe, Gary
17Dudbridge, Frank
18Durmishi, Naser
19Eriksson, Johan
20Freimer, Nelson B
21Fromer, Menachem
22Godard, Stephanie
23Grove, Jakob
24Henskens, Frans A
25Herms, Stefan
26Hoffmann, Per
27Ikeda, Masashi
28Julià, Antonio
29Kahn, René S
30Kelly, Brian J
31Knowles, James A
32Kucinskas, Vaidutis
33Kuzelova-Ptackova, Hana
34Kähler, Anna K
35Laurent, Claudine
36Lee, S. Hong
37Limborska, Svetlana
38Lnnqvist, Jouko
39Marsal, Sara
40Meijer, Carin J
41Melegh, Bela
42Melle, Ingrid
43Mors, Ole
44Myin-Germeys, Inez
45Nikitina-Zake, Liene
46O’Callaghan, Eadbhard
47O’Dushlaine, Colm
48O’Neill, F. Anthony
49Oh, Sang-Yun
50Pantelis, Christos
51Parkhomenko, Elena
52Pocklington, Andrew J
53Powell, John
54Pulver, Ann E
55Purcell, Shaun M
56Quested, Digby
57Richards, Alexander L
58Ruderfer, Douglas M
59Salomaa, Veikko
60Schwab, Sibylle G
61Shi, Jianxin
62Sigurdsson, Engilbert
63Sim, Kang
64Spencer, Chris C.A
65Stahl, Eli A
66Stogmann, Elisabeth
67Strengman, Eric
68Suvisaari, Jaana
69Szatkiewicz, Jin P
70Thirumalai, Srinivas
71Veijola, Juha
72Walsh, Dermot
73Weiser, Mark
74Wildenauer, Dieter B
75Witt, Stephanie H
76Wolen, Aaron R
77Wu, Jing Qin
78Stefansson, Kari
79Andreassen, Ole A
80Ehrenreich, Hannelore
81Gurling, Hugh
82Hultman, Christina M
83Jablensky, Assen V
84Li, Qingqin S
85McQuillin, Andrew
86Mowry, Bryan J
87Nthen, Markus M
88Palotie, Aarno
89Rietschel, Marcella
90Daly, Mark J
91Kähler, Anna K
92Bergen, Sarah
93Hultman, Christina M
94Kähler, Anna K
95Hultman, Christina M
96McCarroll, Steven A
97Pasaniuc, Bogdan
98Raychaudhuri, Soumya
99Price, Alkes L
general
0Elsevier Inc
1Elsevier B.V
2Cell Press
3Elsevier
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creationdate20141106
titlePartitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
authorTrynka, Gosia ; Stahl, Eli ; Collier, David A ; Pers, Tune H ; Albus, Margot ; Cahn, Wiepke ; Cai, Guiqing ; Cantor, Rita M ; Chan, Raymond C.K ; Cheng, Wei ; Cheung, Eric F.C ; Cohen, David ; Cormican, Paul ; Craddock, Nick ; Demontis, Ditte ; Djurovic, Srdjan ; Donohoe, Gary ; Dudbridge, Frank ; Durmishi, Naser ; Eriksson, Johan ; Freimer, Nelson B ; Fromer, Menachem ; Godard, Stephanie ; Grove, Jakob ; Henskens, Frans A ; Herms, Stefan ; Hoffmann, Per ; Ikeda, Masashi ; Julià, Antonio ; Kahn, René S ; Kelly, Brian J ; Knowles, James A ; Kucinskas, Vaidutis ; Kuzelova-Ptackova, Hana ; Kähler, Anna K ; Laurent, Claudine ; Lee, S. Hong ; Limborska, Svetlana ; Lnnqvist, Jouko ; Marsal, Sara ; Meijer, Carin J ; Melegh, Bela ; Melle, Ingrid ; Mors, Ole ; Myin-Germeys, Inez ; Nikitina-Zake, Liene ; O’Callaghan, Eadbhard ; O’Dushlaine, Colm ; O’Neill, F. Anthony ; Oh, Sang-Yun ; Pantelis, Christos ; Parkhomenko, Elena ; Pocklington, Andrew J ; Powell, John ; Pulver, Ann E ; Purcell, Shaun M ; Quested, Digby ; Richards, Alexander L ; Ruderfer, Douglas M ; Salomaa, Veikko ; Schwab, Sibylle G ; Shi, Jianxin ; Sigurdsson, Engilbert ; Sim, Kang ; Spencer, Chris C.A ; Stahl, Eli A ; Stogmann, Elisabeth ; Strengman, Eric ; Suvisaari, Jaana ; Szatkiewicz, Jin P ; Thirumalai, Srinivas ; Veijola, Juha ; Walsh, Dermot ; Weiser, Mark ; Wildenauer, Dieter B ; Witt, Stephanie H ; Wolen, Aaron R ; Wu, Jing Qin ; Stefansson, Kari ; Andreassen, Ole A ; Ehrenreich, Hannelore ; Gurling, Hugh ; Hultman, Christina M ; Jablensky, Assen V ; Li, Qingqin S ; McQuillin, Andrew ; Mowry, Bryan J ; Nthen, Markus M ; Palotie, Aarno ; Rietschel, Marcella ; Daly, Mark J ; Kähler, Anna K ; Bergen, Sarah ; Hultman, Christina M ; Kähler, Anna K ; Hultman, Christina M ; McCarroll, Steven A ; Pasaniuc, Bogdan ; Raychaudhuri, Soumya ; Price, Alkes L
facets
frbrtype5
frbrgroupidcdi_FETCH-LOGICAL-1734t-ad6afbbc2c5678f65f02bf2bc51b356a968fea4d986cbbfda6350df3bc20c01b3
rsrctypearticles
prefilterarticles
languageeng
creationdate2014
topic
0Article
1Biological variation
2Cells
3coding variants
4Computer Simulation
5Disease
6disease architecture
7Epigenetic inheritance
8exome chips
9Genetic Diseases, Inborn - genetics
10Genetic regulation
11Genetic research
12Genetic Variation - genetics
13Genetics
14Genetics & Heredity
15Genetics(clinical)
16genome
17Genome-Wide Association Study - methods
18Genomics
19Genotype & phenotype
20genotype imputation
21Humans
22Inheritance Patterns - genetics
23Medicin och hälsovetenskap
24Models, Genetic
25Open Reading Frames - genetics
26Regulatory Elements, Transcriptional - genetics
27Research
28Simulation
29trait heritability
30wide association study
toplevel
0peer_reviewed
1online_resources
creatorcontrib
0Trynka, Gosia
1Stahl, Eli
2Collier, David A
3Pers, Tune H
4Albus, Margot
5Cahn, Wiepke
6Cai, Guiqing
7Cantor, Rita M
8Chan, Raymond C.K
9Cheng, Wei
10Cheung, Eric F.C
11Cohen, David
12Cormican, Paul
13Craddock, Nick
14Demontis, Ditte
15Djurovic, Srdjan
16Donohoe, Gary
17Dudbridge, Frank
18Durmishi, Naser
19Eriksson, Johan
20Freimer, Nelson B
21Fromer, Menachem
22Godard, Stephanie
23Grove, Jakob
24Henskens, Frans A
25Herms, Stefan
26Hoffmann, Per
27Ikeda, Masashi
28Julià, Antonio
29Kahn, René S
30Kelly, Brian J
31Knowles, James A
32Kucinskas, Vaidutis
33Kuzelova-Ptackova, Hana
34Kähler, Anna K
35Laurent, Claudine
36Lee, S. Hong
37Limborska, Svetlana
38Lnnqvist, Jouko
39Marsal, Sara
40Meijer, Carin J
41Melegh, Bela
42Melle, Ingrid
43Mors, Ole
44Myin-Germeys, Inez
45Nikitina-Zake, Liene
46O’Callaghan, Eadbhard
47O’Dushlaine, Colm
48O’Neill, F. Anthony
49Oh, Sang-Yun
50Pantelis, Christos
51Parkhomenko, Elena
52Pocklington, Andrew J
53Powell, John
54Pulver, Ann E
55Purcell, Shaun M
56Quested, Digby
57Richards, Alexander L
58Ruderfer, Douglas M
59Salomaa, Veikko
60Schwab, Sibylle G
61Shi, Jianxin
62Sigurdsson, Engilbert
63Sim, Kang
64Spencer, Chris C.A
65Stahl, Eli A
66Stogmann, Elisabeth
67Strengman, Eric
68Suvisaari, Jaana
69Szatkiewicz, Jin P
70Thirumalai, Srinivas
71Veijola, Juha
72Walsh, Dermot
73Weiser, Mark
74Wildenauer, Dieter B
75Witt, Stephanie H
76Wolen, Aaron R
77Wu, Jing Qin
78Stefansson, Kari
79Andreassen, Ole A
80Ehrenreich, Hannelore
81Gurling, Hugh
82Hultman, Christina M
83Jablensky, Assen V
84Li, Qingqin S
85McQuillin, Andrew
86Mowry, Bryan J
87Nthen, Markus M
88Palotie, Aarno
89Rietschel, Marcella
90Daly, Mark J
91Kähler, Anna K
92Bergen, Sarah
93Hultman, Christina M
94Kähler, Anna K
95Hultman, Christina M
96McCarroll, Steven A
97Pasaniuc, Bogdan
98Raychaudhuri, Soumya
99Price, Alkes L
100Psychosis Endophenotypes International Consortium
101Wellcome Trust Case Control Consortium
102Schizophrenia Working Group of the Psychiatric Genomics Consortium
103SWE-SCZ Consortium
collection
0ScienceDirect Open Access Titles
1Elsevier:ScienceDirect:Open Access
2NARCIS
3NARCIS: Datasets
4NARCIS:Publications
5Medline
6MEDLINE
7MEDLINE (Ovid)
8MEDLINE
9MEDLINE
10PubMed
11CrossRef
12Academic OneFile (A&I only)
13Calcium & Calcified Tissue Abstracts
14Neurosciences Abstracts
15Nucleic Acids Abstracts
16Toxicology Abstracts
17Technology Research Database
18Environmental Sciences and Pollution Management
19Engineering Research Database
20ProQuest Health & Medical Complete (Alumni)
21Nursing & Allied Health Premium
22Biotechnology and BioEngineering Abstracts
23Genetics Abstracts
24MEDLINE - Academic
25OpenAIRE (Open Access)
26OpenAIRE
27PubMed Central (Full Participant titles)
28SwePub
29SwePub Articles
30SWEPUB Freely available online
jtitleAmerican Journal of Human Genetics
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Trynka, Gosia
1Stahl, Eli
2Collier, David A
3Pers, Tune H
4Albus, Margot
5Cahn, Wiepke
6Cai, Guiqing
7Cantor, Rita M
8Chan, Raymond C.K
9Cheng, Wei
10Cheung, Eric F.C
11Cohen, David
12Cormican, Paul
13Craddock, Nick
14Demontis, Ditte
15Djurovic, Srdjan
16Donohoe, Gary
17Dudbridge, Frank
18Durmishi, Naser
19Eriksson, Johan
20Freimer, Nelson B
21Fromer, Menachem
22Godard, Stephanie
23Grove, Jakob
24Henskens, Frans A
25Herms, Stefan
26Hoffmann, Per
27Ikeda, Masashi
28Julià, Antonio
29Kahn, René S
30Kelly, Brian J
31Knowles, James A
32Kucinskas, Vaidutis
33Kuzelova-Ptackova, Hana
34Kähler, Anna K
35Laurent, Claudine
36Lee, S. Hong
37Limborska, Svetlana
38Lnnqvist, Jouko
39Marsal, Sara
40Meijer, Carin J
41Melegh, Bela
42Melle, Ingrid
43Mors, Ole
44Myin-Germeys, Inez
45Nikitina-Zake, Liene
46O’Callaghan, Eadbhard
47O’Dushlaine, Colm
48O’Neill, F. Anthony
49Oh, Sang-Yun
50Pantelis, Christos
51Parkhomenko, Elena
52Pocklington, Andrew J
53Powell, John
54Pulver, Ann E
55Purcell, Shaun M
56Quested, Digby
57Richards, Alexander L
58Ruderfer, Douglas M
59Salomaa, Veikko
60Schwab, Sibylle G
61Shi, Jianxin
62Sigurdsson, Engilbert
63Sim, Kang
64Spencer, Chris C.A
65Stahl, Eli A
66Stogmann, Elisabeth
67Strengman, Eric
68Suvisaari, Jaana
69Szatkiewicz, Jin P
70Thirumalai, Srinivas
71Veijola, Juha
72Walsh, Dermot
73Weiser, Mark
74Wildenauer, Dieter B
75Witt, Stephanie H
76Wolen, Aaron R
77Wu, Jing Qin
78Stefansson, Kari
79Andreassen, Ole A
80Ehrenreich, Hannelore
81Gurling, Hugh
82Hultman, Christina M
83Jablensky, Assen V
84Li, Qingqin S
85McQuillin, Andrew
86Mowry, Bryan J
87Nthen, Markus M
88Palotie, Aarno
89Rietschel, Marcella
90Daly, Mark J
91Kähler, Anna K
92Bergen, Sarah
93Hultman, Christina M
94Kähler, Anna K
95Hultman, Christina M
96McCarroll, Steven A
97Pasaniuc, Bogdan
98Raychaudhuri, Soumya
99Price, Alkes L
aucorp
0Psychosis Endophenotypes International Consortium
1Wellcome Trust Case Control Consortium
2Schizophrenia Working Group of the Psychiatric Genomics Consortium
3SWE-SCZ Consortium
formatjournal
genrearticle
ristypeJOUR
atitlePartitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
jtitleAmerican Journal of Human Genetics
addtitleAm J Hum Genet
date2014-11-06
risdate2014
volume95
issue5
spage535
epage552
pages535-552
issn
00002-9297
11537-6605
eissn1537-6605
notesPresent address: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK
abstractRegulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg2) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg2 from imputed SNPs (5.1× enrichment; p = 3.7 × 10−17) and 38% (SE = 4%) of hg2 from genotyped SNPs (1.6× enrichment, p = 1.0 × 10−4). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg2 despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.
copUnited States
pubElsevier Inc
pmid25439723
doi10.1016/j.ajhg.2014.10.004
oafree_for_read