Journal article
Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained
PLoS genetics, Vol.9(3), e1003379
03/2013
DOI: 10.1371/journal.pgen.1003379
PMCID: PMC3605054
PMID: 23555291
Abstract
Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
Details
- Title: Subtitle
- Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained
- Creators
- Ying Wu - University of North Carolina at Chapel HillLindsay L WaiteAnne U JacksonWayne H-H SheuSteven BuyskeDevin AbsherDonna K ArnettEric BoerwinkleLori L BonnycastleCara L CartyIona Cheng - University of Hawaiʻi at MānoaBarbara CochranDamien C Croteau-ChonkaLogan DumitrescuCharles B EatonNora FranceschiniXiuqing GuoBrian E HendersonLucia A HindorffEric KimLeena KinnunenPirjo KomulainenWen-Jane LeeLoic Le MarchandYi LinJaana LindströmOddgeir Lingaas-HolmenSabrina L MitchellNarisu NarisuJennifer G RobinsonFred SchumacherAlena StančákováJouko SundvallYun-Ju SungAmy J SwiftWen-Chang WangLynne WilkensTom WilsgaardAlicia M YoungLinda S AdairChristie M BallantynePetra BůžkováAravinda ChakravartiFrancis S CollinsDavid DugganAlan B FeranilYi-Jen HungSteven C HuntKristian HveemJyh-Ming J JuangAntero Y KesäniemiJohanna KuusistoMarkku LaaksoTimo A LakkaI-Te Lee - Taichung Veterans General HospitalMark F LeppertTara C MatiseLeena MoilanenInger NjølstadUlrike PetersThomas QuertermousRainer RauramaaJerome I RotterJouko SaramiesJaakko TuomilehtoMatti UusitupaTzung-Dau WangMichael BoehnkeChristopher A HaimanYii-Der I ChenCharles KooperbergThemistocles L AssimesChao A HsiungKari E NorthLow-Tone Ho - National Taiwan UniversityDana C CrawfordKaren L Mohlke
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.9(3), e1003379
- DOI
- 10.1371/journal.pgen.1003379
- PMID
- 23555291
- PMCID
- PMC3605054
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- United States
- Grant note
- DK072193 / NIDDK NIH HHS\r\nHL54472 / NHLBI NIH HHS\r\nU01HG004798 / NHGRI NIH HHS\r\nR01 DK072193 / NIDDK NIH HHS\r\n32108-9 / PHS HHS\r\nES10126 / NIEHS NIH HHS\r\nN01-HC-55022 / NHLBI NIH HHS\r\n42129-32 / PHS HHS\r\nN01-HC-55018 / NHLBI NIH HHS\r\n42107-26 / PHS HHS\r\nP30 ES010126 / NIEHS NIH HHS\r\nDK093757 / NIDDK NIH HHS\r\nN01-HC-55015 / NHLBI NIH HHS\r\nHL54497 / NHLBI NIH HHS\r\nU01HG004801 / NHGRI NIH HHS\r\nDK062370 / NIDDK NIH HHS\r\n1Z01-HG000024 / NHGRI NIH HHS\r\nHL087647 / NHLBI NIH HHS\r\n24152 / PHS HHS\r\nT32 GM007092 / NIGMS NIH HHS\r\n32122 / PHS HHS\r\n32111-13 / PHS HHS\r\n32115 / PHS HHS\r\n44221 / PHS HHS\r\n2 R01 HL55673-12 / NHLBI NIH HHS\r\nTW05596 / FIC NIH HHS\r\nHL54471 / NHLBI NIH HHS\r\nN01-HC-55019 / NHLBI NIH HHS\r\nDK56350 / NIDDK NIH HHS\r\nP01CA33619 / NCI NIH HHS\r\nP30 DK063491 / NIDDK NIH HHS\r\nN01-HC-55016 / NHLBI NIH HHS\r\nRR20649 / NCRR NIH HHS\r\nHL54496 / NHLBI NIH HHS\r\nU01HG004790 / NHGRI NIH HHS\r\nU01HG004803 / NHGRI NIH HHS\r\nR01 CA63 / NCI NIH HHS\r\n32105-6 / PHS HHS\r\nU01HG004801-01 / NHGRI NIH HHS\r\nHL085144 / NHLBI NIH HHS\r\n32118-32119 / PHS HHS\r\nDK078150 / NIDDK NIH HHS\r\nU01CA98758 / NCI NIH HHS\r\nHL54473 / NHLBI NIH HHS\r\nR24 HD050924 / NICHD NIH HHS\r\nUL1 TR000124 / NCATS NIH HHS\r\nN01-HC-55020 / NHLBI NIH HHS\r\nR01 DK093757 / NIDDK NIH HHS\r\nHL54495 / NHLBI NIH HHS\r\nHL54515 / NHLBI NIH HHS\r\nU01HG004802 / NHGRI NIH HHS\r\nP30 DK020572 / NIDDK NIH HHS\r\n32100-2 / PHS HHS\r\nHL54509 / NHLBI NIH HHS\r\nR01 HG000376 / NHGRI NIH HHS\r\nN01-HC-55021 / NHLBI NIH HHS\r\nU01 HG004790 / NHGRI NIH HHS\r\nN01WH22110 / WHI NIH HHS\r\nR37CA54281 / NCI NIH HHS\r\nU01CA136792 / NCI NIH HHS
- Language
- English
- Date published
- 03/2013
- Academic Unit
- Epidemiology; Internal Medicine
- Record Identifier
- 9983995017202771
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