Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.
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...
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2013-03-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003379&type=printable |
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| author | Ying Wu Lindsay L Waite Anne U Jackson Wayne H-H Sheu Steven Buyske Devin Absher Donna K Arnett Eric Boerwinkle Lori L Bonnycastle Cara L Carty Iona Cheng Barbara Cochran Damien C Croteau-Chonka Logan Dumitrescu Charles B Eaton Nora Franceschini Xiuqing Guo Brian E Henderson Lucia A Hindorff Eric Kim Leena Kinnunen Pirjo Komulainen Wen-Jane Lee Loic Le Marchand Yi Lin Jaana Lindström Oddgeir Lingaas-Holmen Sabrina L Mitchell Narisu Narisu Jennifer G Robinson Fred Schumacher Alena Stančáková Jouko Sundvall Yun-Ju Sung Amy J Swift Wen-Chang Wang Lynne Wilkens Tom Wilsgaard Alicia M Young Linda S Adair Christie M Ballantyne Petra Bůžková Aravinda Chakravarti Francis S Collins David Duggan Alan B Feranil Low-Tone Ho Yi-Jen Hung Steven C Hunt Kristian Hveem Jyh-Ming J Juang Antero Y Kesäniemi Johanna Kuusisto Markku Laakso Timo A Lakka I-Te Lee Mark F Leppert Tara C Matise Leena Moilanen Inger Njølstad Ulrike Peters Thomas Quertermous Rainer Rauramaa Jerome I Rotter Jouko Saramies Jaakko Tuomilehto Matti Uusitupa Tzung-Dau Wang Michael Boehnke Christopher A Haiman Yii-Der I Chen Charles Kooperberg Themistocles L Assimes Dana C Crawford Chao A Hsiung Kari E North Karen L Mohlke |
| author_facet | Ying Wu Lindsay L Waite Anne U Jackson Wayne H-H Sheu Steven Buyske Devin Absher Donna K Arnett Eric Boerwinkle Lori L Bonnycastle Cara L Carty Iona Cheng Barbara Cochran Damien C Croteau-Chonka Logan Dumitrescu Charles B Eaton Nora Franceschini Xiuqing Guo Brian E Henderson Lucia A Hindorff Eric Kim Leena Kinnunen Pirjo Komulainen Wen-Jane Lee Loic Le Marchand Yi Lin Jaana Lindström Oddgeir Lingaas-Holmen Sabrina L Mitchell Narisu Narisu Jennifer G Robinson Fred Schumacher Alena Stančáková Jouko Sundvall Yun-Ju Sung Amy J Swift Wen-Chang Wang Lynne Wilkens Tom Wilsgaard Alicia M Young Linda S Adair Christie M Ballantyne Petra Bůžková Aravinda Chakravarti Francis S Collins David Duggan Alan B Feranil Low-Tone Ho Yi-Jen Hung Steven C Hunt Kristian Hveem Jyh-Ming J Juang Antero Y Kesäniemi Johanna Kuusisto Markku Laakso Timo A Lakka I-Te Lee Mark F Leppert Tara C Matise Leena Moilanen Inger Njølstad Ulrike Peters Thomas Quertermous Rainer Rauramaa Jerome I Rotter Jouko Saramies Jaakko Tuomilehto Matti Uusitupa Tzung-Dau Wang Michael Boehnke Christopher A Haiman Yii-Der I Chen Charles Kooperberg Themistocles L Assimes Dana C Crawford Chao A Hsiung Kari E North Karen L Mohlke |
| author_sort | Ying Wu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7c2f637f03e140f7b69972b2a24b3451 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2013-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-7c2f637f03e140f7b69972b2a24b34512025-08-20T03:10:39ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-03-0193e100337910.1371/journal.pgen.1003379Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.Ying WuLindsay L WaiteAnne U JacksonWayne H-H SheuSteven BuyskeDevin AbsherDonna K ArnettEric BoerwinkleLori L BonnycastleCara L CartyIona ChengBarbara 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 FeranilLow-Tone HoYi-Jen HungSteven C HuntKristian HveemJyh-Ming J JuangAntero Y KesäniemiJohanna KuusistoMarkku LaaksoTimo A LakkaI-Te LeeMark F LeppertTara C MatiseLeena MoilanenInger NjølstadUlrike PetersThomas QuertermousRainer RauramaaJerome I RotterJouko SaramiesJaakko TuomilehtoMatti UusitupaTzung-Dau WangMichael BoehnkeChristopher A HaimanYii-Der I ChenCharles KooperbergThemistocles L AssimesDana C CrawfordChao A HsiungKari E NorthKaren L MohlkeGenome-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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003379&type=printable |
| spellingShingle | Ying Wu Lindsay L Waite Anne U Jackson Wayne H-H Sheu Steven Buyske Devin Absher Donna K Arnett Eric Boerwinkle Lori L Bonnycastle Cara L Carty Iona Cheng Barbara Cochran Damien C Croteau-Chonka Logan Dumitrescu Charles B Eaton Nora Franceschini Xiuqing Guo Brian E Henderson Lucia A Hindorff Eric Kim Leena Kinnunen Pirjo Komulainen Wen-Jane Lee Loic Le Marchand Yi Lin Jaana Lindström Oddgeir Lingaas-Holmen Sabrina L Mitchell Narisu Narisu Jennifer G Robinson Fred Schumacher Alena Stančáková Jouko Sundvall Yun-Ju Sung Amy J Swift Wen-Chang Wang Lynne Wilkens Tom Wilsgaard Alicia M Young Linda S Adair Christie M Ballantyne Petra Bůžková Aravinda Chakravarti Francis S Collins David Duggan Alan B Feranil Low-Tone Ho Yi-Jen Hung Steven C Hunt Kristian Hveem Jyh-Ming J Juang Antero Y Kesäniemi Johanna Kuusisto Markku Laakso Timo A Lakka I-Te Lee Mark F Leppert Tara C Matise Leena Moilanen Inger Njølstad Ulrike Peters Thomas Quertermous Rainer Rauramaa Jerome I Rotter Jouko Saramies Jaakko Tuomilehto Matti Uusitupa Tzung-Dau Wang Michael Boehnke Christopher A Haiman Yii-Der I Chen Charles Kooperberg Themistocles L Assimes Dana C Crawford Chao A Hsiung Kari E North Karen L Mohlke Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. PLoS Genetics |
| title | Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. |
| title_full | Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. |
| title_fullStr | Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. |
| title_full_unstemmed | Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. |
| title_short | Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. |
| title_sort | trans ethnic fine mapping of lipid loci identifies population specific signals and allelic heterogeneity that increases the trait variance explained |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003379&type=printable |
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