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Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.


ABSTRACT: Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.

SUBMITTER: Iotchkova V 

PROVIDER: S-EPMC5279872 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

Iotchkova Valentina V   Huang Jie J   Morris John A JA   Jain Deepti D   Barbieri Caterina C   Walter Klaudia K   Min Josine L JL   Chen Lu L   Astle William W   Cocca Massimilian M   Deelen Patrick P   Elding Heather H   Farmaki Aliki-Eleni AE   Franklin Christopher S CS   Franberg Mattias M   Gaunt Tom R TR   Hofman Albert A   Jiang Tao T   Kleber Marcus E ME   Lachance Genevieve G   Luan Jian'an J   Malerba Giovanni G   Matchan Angela A   Mead Daniel D   Memari Yasin Y   Ntalla Ioanna I   Panoutsopoulou Kalliope K   Pazoki Raha R   Perry John R B JRB   Rivadeneira Fernando F   Sabater-Lleal Maria M   Sennblad Bengt B   Shin So-Youn SY   Southam Lorraine L   Traglia Michela M   van Dijk Freerk F   van Leeuwen Elisabeth M EM   Zaza Gianluigi G   Zhang Weihua W   Amin Najaf N   Butterworth Adam A   Chambers John C JC   Dedoussis George G   Dehghan Abbas A   Franco Oscar H OH   Franke Lude L   Frontini Mattia M   Gambaro Giovanni G   Gasparini Paolo P   Hamsten Anders A   Issacs Aaron A   Kooner Jaspal S JS   Kooperberg Charles C   Langenberg Claudia C   Marz Winfried W   Scott Robert A RA   Swertz Morris A MA   Toniolo Daniela D   Uitterlinden Andre G AG   van Duijn Cornelia M CM   Watkins Hugh H   Zeggini Eleftheria E   Maurano Mathew T MT   Timpson Nicholas J NJ   Reiner Alexander P AP   Auer Paul L PL   Soranzo Nicole N  

Nature genetics 20160926 11


Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5  ...[more]

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