Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.

Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized...
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Autor*in:	Serena Sanna [verfasserIn] Bingshan Li [verfasserIn] Antonella Mulas [verfasserIn] Carlo Sidore [verfasserIn] Hyun M Kang [verfasserIn] Anne U Jackson [verfasserIn] Maria Grazia Piras [verfasserIn] Gianluca Usala [verfasserIn] Giuseppe Maninchedda [verfasserIn] Alessandro Sassu [verfasserIn] Fabrizio Serra [verfasserIn] Maria Antonietta Palmas [verfasserIn] William H Wood [verfasserIn] Inger Njølstad [verfasserIn] Markku Laakso [verfasserIn] Kristian Hveem [verfasserIn] Jaakko Tuomilehto [verfasserIn] Timo A Lakka [verfasserIn] Rainer Rauramaa [verfasserIn] Michael Boehnke [verfasserIn] Francesco Cucca [verfasserIn] Manuela Uda [verfasserIn] David Schlessinger [verfasserIn] Ramaiah Nagaraja [verfasserIn] Gonçalo R Abecasis [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2011

Übergeordnetes Werk:	In: PLoS Genetics - Public Library of Science (PLoS), 2005, 7(2011), 7, p e1002198
Übergeordnetes Werk:	volume:7 ; year:2011 ; number:7, p e1002198

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1371/journal.pgen.1002198

Katalog-ID:	DOAJ037150588

Internformat


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520			\|a Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.
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allfields	10.1371/journal.pgen.1002198 doi (DE-627)DOAJ037150588 (DE-599)DOAJb7f4549516ff4fdfb01e7c55dac19995 DE-627 ger DE-627 rakwb eng QH426-470 Serena Sanna verfasserin aut Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. Genetics Bingshan Li verfasserin aut Antonella Mulas verfasserin aut Carlo Sidore verfasserin aut Hyun M Kang verfasserin aut Anne U Jackson verfasserin aut Maria Grazia Piras verfasserin aut Gianluca Usala verfasserin aut Giuseppe Maninchedda verfasserin aut Alessandro Sassu verfasserin aut Fabrizio Serra verfasserin aut Maria Antonietta Palmas verfasserin aut William H Wood verfasserin aut Inger Njølstad verfasserin aut Markku Laakso verfasserin aut Kristian Hveem verfasserin aut Jaakko Tuomilehto verfasserin aut Timo A Lakka verfasserin aut Rainer Rauramaa verfasserin aut Michael Boehnke verfasserin aut Francesco Cucca verfasserin aut Manuela Uda verfasserin aut David Schlessinger verfasserin aut Ramaiah Nagaraja verfasserin aut Gonçalo R Abecasis verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 7(2011), 7, p e1002198 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:7 year:2011 number:7, p e1002198 https://doi.org/10.1371/journal.pgen.1002198 kostenfrei https://doaj.org/article/b7f4549516ff4fdfb01e7c55dac19995 kostenfrei http://europepmc.org/articles/PMC3145627?pdf=render kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2011 7, p e1002198
spelling	10.1371/journal.pgen.1002198 doi (DE-627)DOAJ037150588 (DE-599)DOAJb7f4549516ff4fdfb01e7c55dac19995 DE-627 ger DE-627 rakwb eng QH426-470 Serena Sanna verfasserin aut Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. Genetics Bingshan Li verfasserin aut Antonella Mulas verfasserin aut Carlo Sidore verfasserin aut Hyun M Kang verfasserin aut Anne U Jackson verfasserin aut Maria Grazia Piras verfasserin aut Gianluca Usala verfasserin aut Giuseppe Maninchedda verfasserin aut Alessandro Sassu verfasserin aut Fabrizio Serra verfasserin aut Maria Antonietta Palmas verfasserin aut William H Wood verfasserin aut Inger Njølstad verfasserin aut Markku Laakso verfasserin aut Kristian Hveem verfasserin aut Jaakko Tuomilehto verfasserin aut Timo A Lakka verfasserin aut Rainer Rauramaa verfasserin aut Michael Boehnke verfasserin aut Francesco Cucca verfasserin aut Manuela Uda verfasserin aut David Schlessinger verfasserin aut Ramaiah Nagaraja verfasserin aut Gonçalo R Abecasis verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 7(2011), 7, p e1002198 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:7 year:2011 number:7, p e1002198 https://doi.org/10.1371/journal.pgen.1002198 kostenfrei https://doaj.org/article/b7f4549516ff4fdfb01e7c55dac19995 kostenfrei http://europepmc.org/articles/PMC3145627?pdf=render kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2011 7, p e1002198
allfields_unstemmed	10.1371/journal.pgen.1002198 doi (DE-627)DOAJ037150588 (DE-599)DOAJb7f4549516ff4fdfb01e7c55dac19995 DE-627 ger DE-627 rakwb eng QH426-470 Serena Sanna verfasserin aut Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. Genetics Bingshan Li verfasserin aut Antonella Mulas verfasserin aut Carlo Sidore verfasserin aut Hyun M Kang verfasserin aut Anne U Jackson verfasserin aut Maria Grazia Piras verfasserin aut Gianluca Usala verfasserin aut Giuseppe Maninchedda verfasserin aut Alessandro Sassu verfasserin aut Fabrizio Serra verfasserin aut Maria Antonietta Palmas verfasserin aut William H Wood verfasserin aut Inger Njølstad verfasserin aut Markku Laakso verfasserin aut Kristian Hveem verfasserin aut Jaakko Tuomilehto verfasserin aut Timo A Lakka verfasserin aut Rainer Rauramaa verfasserin aut Michael Boehnke verfasserin aut Francesco Cucca verfasserin aut Manuela Uda verfasserin aut David Schlessinger verfasserin aut Ramaiah Nagaraja verfasserin aut Gonçalo R Abecasis verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 7(2011), 7, p e1002198 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:7 year:2011 number:7, p e1002198 https://doi.org/10.1371/journal.pgen.1002198 kostenfrei https://doaj.org/article/b7f4549516ff4fdfb01e7c55dac19995 kostenfrei http://europepmc.org/articles/PMC3145627?pdf=render kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2011 7, p e1002198
allfieldsGer	10.1371/journal.pgen.1002198 doi (DE-627)DOAJ037150588 (DE-599)DOAJb7f4549516ff4fdfb01e7c55dac19995 DE-627 ger DE-627 rakwb eng QH426-470 Serena Sanna verfasserin aut Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. Genetics Bingshan Li verfasserin aut Antonella Mulas verfasserin aut Carlo Sidore verfasserin aut Hyun M Kang verfasserin aut Anne U Jackson verfasserin aut Maria Grazia Piras verfasserin aut Gianluca Usala verfasserin aut Giuseppe Maninchedda verfasserin aut Alessandro Sassu verfasserin aut Fabrizio Serra verfasserin aut Maria Antonietta Palmas verfasserin aut William H Wood verfasserin aut Inger Njølstad verfasserin aut Markku Laakso verfasserin aut Kristian Hveem verfasserin aut Jaakko Tuomilehto verfasserin aut Timo A Lakka verfasserin aut Rainer Rauramaa verfasserin aut Michael Boehnke verfasserin aut Francesco Cucca verfasserin aut Manuela Uda verfasserin aut David Schlessinger verfasserin aut Ramaiah Nagaraja verfasserin aut Gonçalo R Abecasis verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 7(2011), 7, p e1002198 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:7 year:2011 number:7, p e1002198 https://doi.org/10.1371/journal.pgen.1002198 kostenfrei https://doaj.org/article/b7f4549516ff4fdfb01e7c55dac19995 kostenfrei http://europepmc.org/articles/PMC3145627?pdf=render kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2011 7, p e1002198
allfieldsSound	10.1371/journal.pgen.1002198 doi (DE-627)DOAJ037150588 (DE-599)DOAJb7f4549516ff4fdfb01e7c55dac19995 DE-627 ger DE-627 rakwb eng QH426-470 Serena Sanna verfasserin aut Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. Genetics Bingshan Li verfasserin aut Antonella Mulas verfasserin aut Carlo Sidore verfasserin aut Hyun M Kang verfasserin aut Anne U Jackson verfasserin aut Maria Grazia Piras verfasserin aut Gianluca Usala verfasserin aut Giuseppe Maninchedda verfasserin aut Alessandro Sassu verfasserin aut Fabrizio Serra verfasserin aut Maria Antonietta Palmas verfasserin aut William H Wood verfasserin aut Inger Njølstad verfasserin aut Markku Laakso verfasserin aut Kristian Hveem verfasserin aut Jaakko Tuomilehto verfasserin aut Timo A Lakka verfasserin aut Rainer Rauramaa verfasserin aut Michael Boehnke verfasserin aut Francesco Cucca verfasserin aut Manuela Uda verfasserin aut David Schlessinger verfasserin aut Ramaiah Nagaraja verfasserin aut Gonçalo R Abecasis verfasserin aut In PLoS Genetics Public Library of Science (PLoS), 2005 7(2011), 7, p e1002198 (DE-627)485248026 (DE-600)2186725-2 15537404 nnns volume:7 year:2011 number:7, p e1002198 https://doi.org/10.1371/journal.pgen.1002198 kostenfrei https://doaj.org/article/b7f4549516ff4fdfb01e7c55dac19995 kostenfrei http://europepmc.org/articles/PMC3145627?pdf=render kostenfrei https://doaj.org/toc/1553-7390 Journal toc kostenfrei https://doaj.org/toc/1553-7404 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2011 7, p e1002198
language	English
source	In PLoS Genetics 7(2011), 7, p e1002198 volume:7 year:2011 number:7, p e1002198
sourceStr	In PLoS Genetics 7(2011), 7, p e1002198 volume:7 year:2011 number:7, p e1002198
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Genetics
isfreeaccess_bool	true
container_title	PLoS Genetics
authorswithroles_txt_mv	Serena Sanna @@aut@@ Bingshan Li @@aut@@ Antonella Mulas @@aut@@ Carlo Sidore @@aut@@ Hyun M Kang @@aut@@ Anne U Jackson @@aut@@ Maria Grazia Piras @@aut@@ Gianluca Usala @@aut@@ Giuseppe Maninchedda @@aut@@ Alessandro Sassu @@aut@@ Fabrizio Serra @@aut@@ Maria Antonietta Palmas @@aut@@ William H Wood @@aut@@ Inger Njølstad @@aut@@ Markku Laakso @@aut@@ Kristian Hveem @@aut@@ Jaakko Tuomilehto @@aut@@ Timo A Lakka @@aut@@ Rainer Rauramaa @@aut@@ Michael Boehnke @@aut@@ Francesco Cucca @@aut@@ Manuela Uda @@aut@@ David Schlessinger @@aut@@ Ramaiah Nagaraja @@aut@@ Gonçalo R Abecasis @@aut@@
publishDateDaySort_date	2011-01-01T00:00:00Z
hierarchy_top_id	485248026
id	DOAJ037150588
language_de	englisch
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author	Serena Sanna
spellingShingle	Serena Sanna misc QH426-470 misc Genetics Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.
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topic_title	QH426-470 Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability
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title	Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.
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title_full	Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability
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title_sort	fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability
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title_auth	Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.
abstract	Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.
abstractGer	Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.
abstract_unstemmed	Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.
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title_short	Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.
url	https://doi.org/10.1371/journal.pgen.1002198 https://doaj.org/article/b7f4549516ff4fdfb01e7c55dac19995 http://europepmc.org/articles/PMC3145627?pdf=render https://doaj.org/toc/1553-7390 https://doaj.org/toc/1553-7404
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Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.

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