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...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2011-07-01
|
Series: | PLoS Genetics |
Online Access: | http://europepmc.org/articles/PMC3145627?pdf=render |
id |
doaj-b7f4549516ff4fdfb01e7c55dac19995 |
---|---|
record_format |
Article |
spelling |
doaj-b7f4549516ff4fdfb01e7c55dac199952020-11-25T01:29:11ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-07-0177e100219810.1371/journal.pgen.1002198Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.Serena SannaBingshan LiAntonella MulasCarlo SidoreHyun M KangAnne U JacksonMaria Grazia PirasGianluca UsalaGiuseppe ManincheddaAlessandro SassuFabrizio SerraMaria Antonietta PalmasWilliam H WoodInger NjølstadMarkku LaaksoKristian HveemJaakko TuomilehtoTimo A LakkaRainer RauramaaMichael BoehnkeFrancesco CuccaManuela UdaDavid SchlessingerRamaiah NagarajaGonçalo R AbecasisComplex 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.http://europepmc.org/articles/PMC3145627?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Serena Sanna Bingshan Li Antonella Mulas Carlo Sidore Hyun M Kang Anne U Jackson Maria Grazia Piras Gianluca Usala Giuseppe Maninchedda Alessandro Sassu Fabrizio Serra Maria Antonietta Palmas William H Wood Inger Njølstad Markku Laakso Kristian Hveem Jaakko Tuomilehto Timo A Lakka Rainer Rauramaa Michael Boehnke Francesco Cucca Manuela Uda David Schlessinger Ramaiah Nagaraja Gonçalo R Abecasis |
spellingShingle |
Serena Sanna Bingshan Li Antonella Mulas Carlo Sidore Hyun M Kang Anne U Jackson Maria Grazia Piras Gianluca Usala Giuseppe Maninchedda Alessandro Sassu Fabrizio Serra Maria Antonietta Palmas William H Wood Inger Njølstad Markku Laakso Kristian Hveem Jaakko Tuomilehto Timo A Lakka Rainer Rauramaa Michael Boehnke Francesco Cucca Manuela Uda David Schlessinger Ramaiah Nagaraja Gonçalo R Abecasis Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genetics |
author_facet |
Serena Sanna Bingshan Li Antonella Mulas Carlo Sidore Hyun M Kang Anne U Jackson Maria Grazia Piras Gianluca Usala Giuseppe Maninchedda Alessandro Sassu Fabrizio Serra Maria Antonietta Palmas William H Wood Inger Njølstad Markku Laakso Kristian Hveem Jaakko Tuomilehto Timo A Lakka Rainer Rauramaa Michael Boehnke Francesco Cucca Manuela Uda David Schlessinger Ramaiah Nagaraja Gonçalo R Abecasis |
author_sort |
Serena Sanna |
title |
Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. |
title_short |
Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. |
title_full |
Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. |
title_fullStr |
Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. |
title_full_unstemmed |
Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. |
title_sort |
fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2011-07-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3145627?pdf=render |
work_keys_str_mv |
AT serenasanna finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT bingshanli finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT antonellamulas finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT carlosidore finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT hyunmkang finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT anneujackson finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT mariagraziapiras finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT gianlucausala finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT giuseppemaninchedda finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT alessandrosassu finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT fabrizioserra finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT mariaantoniettapalmas finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT williamhwood finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT ingernjølstad finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT markkulaakso finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT kristianhveem finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT jaakkotuomilehto finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT timoalakka finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT rainerrauramaa finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT michaelboehnke finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT francescocucca finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT manuelauda finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT davidschlessinger finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT ramaiahnagaraja finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability AT goncalorabecasis finemappingoffivelociassociatedwithlowdensitylipoproteincholesteroldetectsvariantsthatdoubletheexplainedheritability |
_version_ |
1725098019713449984 |