Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

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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.

Vyšlo v časopise: Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003379
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003379

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1. KathiresanS, MelanderO, GuiducciC, SurtiA, BurttNP, et al. (2008) Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40: 189–197.

2. WillerCJ, SannaS, JacksonAU, ScuteriA, BonnycastleLL, et al. (2008) Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40: 161–169.

3. AulchenkoYS, RipattiS, LindqvistI, BoomsmaD, HeidIM, et al. (2009) Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 41: 47–55.

4. KathiresanS, WillerCJ, PelosoGM, DemissieS, MusunuruK, et al. (2009) Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41: 56–65.

5. TeslovichTM, MusunuruK, SmithAV, EdmondsonAC, StylianouIM, et al. (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466: 707–713.

6. McCarthyMI, AbecasisGR, CardonLR, GoldsteinDB, LittleJ, et al. (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9: 356–369.

7. SannaS, LiB, MulasA, SidoreC, KangHM, et al. (2011) Fine mapping of five Loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet 7: e1002198 doi:10.1371/journal.pgen.1002198

8. HarituniansT, JonesMR, McGovernDP, ShihDQ, BarrettRJ, et al. (2011) Variants in ZNF365 isoform D are associated with Crohn's disease. Gut 60: 1060–1067.

9. BuyskeS, WuY, CartyCL, ChengI, AssimesTL, et al. (2012) Evaluation of the Metabochip Genotyping Array in African Americans and Implications for Fine Mapping of GWAS-Identified Loci: The PAGE Study. PLoS ONE 7: e35651 doi:10.1371/journal.pone.0035651

10. VoightBF, KangHM, DingJ, PalmerCD, SidoreC, et al. (2012) The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits. PLoS Genet 8: e1002793 doi:10.1371/journal.pgen.1002793

11. PedenJF, FarrallM (2011) Thirty-five common variants for coronary artery disease: the fruits of much collaborative labour. Hum Mol Genet 20: R198–205.

12. VoightBF, ScottLJ, SteinthorsdottirV, MorrisAP, DinaC, et al. (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42: 579–589.

13. SimX, OngRT, SuoC, TayWT, LiuJ, et al. (2011) Transferability of type 2 diabetes implicated Loci in multi-ethnic cohorts from southeast Asia. PLoS Genet 7: e1001363 doi:10.1371/journal.pgen.1001363

14. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437: 1299–1320.

15. HelgasonA, PalssonS, ThorleifssonG, GrantSF, EmilssonV, et al. (2007) Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 39: 218–225.

16. MusunuruK, RomaineSP, LettreG, WilsonJG, VolcikKA, et al. (2012) Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project. PLoS ONE 7: e36473 doi:10.1371/journal.pone.0036473

17. DumitrescuL, CartyCL, TaylorK, SchumacherFR, HindorffLA, et al. (2011) Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study. PLoS Genet 7: e1002138 doi:10.1371/journal.pgen.1002138

18. MusunuruK, StrongA, Frank-KamenetskyM, LeeNE, AhfeldtT, et al. (2010) From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466: 714–719.

19. TeoYY, SmallKS, KwiatkowskiDP (2010) Methodological challenges of genome-wide association analysis in Africa. Nat Rev Genet 11: 149–160.

20. CohenJ, PertsemlidisA, KotowskiIK, GrahamR, GarciaCK, et al. (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37: 161–165.

21. KotowskiIK, PertsemlidisA, LukeA, CooperRS, VegaGL, et al. (2006) A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 78: 410–422.

22. ZhaoZ, Tuakli-WosornuY, LagaceTA, KinchL, GrishinNV, et al. (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79: 514–523.

23. RallSCJr, WeisgraberKH, InnerarityTL, MahleyRW (1982) Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci U S A 79: 4696–4700.

24. WardH, MitrouPN, BowmanR, LubenR, WarehamNJ, et al. (2009) APOE genotype, lipids, and coronary heart disease risk: a prospective population study. Arch Intern Med 169: 1424–1429.

25. HuangYJ, LinYL, ChiangCI, YenCT, LinSW, et al. (2012) Functional importance of apolipoprotein A5 185G in the activation of lipoprotein lipase. Clin Chim Acta 413: 246–250.

26. TalmudPJ, PalmenJ, PuttW, LinsL, HumphriesSE (2005) Determination of the functionality of common APOA5 polymorphisms. J Biol Chem 280: 28215–28220.

27. McCarthyMI (2008) Casting a wider net for diabetes susceptibility genes. Nat Genet 40: 1039–1040.

28. ReesMG, WincovitchS, SchultzJ, WaterstradtR, BeerNL, et al. (2012) Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 55: 114–122.

29. BenjannetS, RhaindsD, HamelinJ, NassouryN, SeidahNG (2006) The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. J Biol Chem 281: 30561–30572.

30. FasanoT, SunXM, PatelDD, SoutarAK (2009) Degradation of LDLR protein mediated by ‘gain of function’ PCSK9 mutants in normal and ARH cells. Atherosclerosis 203: 166–171.

31. SullivanPM, MezdourH, QuarfordtSH, MaedaN (1998) Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2. J Clin Invest 102: 130–135.

32. PalmenJ, SmithAJ, DorfmeisterB, PuttW, HumphriesSE, et al. (2008) The functional interaction on in vitro gene expression of APOA5 SNPs, defining haplotype APOA52, and their paradoxical association with plasma triglyceride but not plasma apoAV levels. Biochim Biophys Acta 1782: 447–452.

33. ThompsonJF, LloydDB, LiraME, MilosPM (2004) Cholesteryl ester transfer protein promoter single-nucleotide polymorphisms in Sp1-binding sites affect transcription and are associated with high-density lipoprotein cholesterol. Clin Genet 66: 223–228.

34. ZambonA, DeebSS, PaulettoP, CrepaldiG, BrunzellJD (2003) Hepatic lipase: a marker for cardiovascular disease risk and response to therapy. Curr Opin Lipidol 14: 179–189.

35. HaasBE, Weissglas-VolkovD, Aguilar-SalinasCA, NikkolaE, VergnesL, et al. (2011) Evidence of how rs7575840 influences apolipoprotein B-containing lipid particles. Arterioscler Thromb Vasc Biol 31: 1201–1207.

36. NiermanMC, RipJ, KuivenhovenJA, SakaiN, KasteleinJJ, et al. (2007) Enhanced apoB48 metabolism in lipoprotein lipase X447 homozygotes. Atherosclerosis 194: 446–451.

37. ZhuH, TuckerHM, GrearKE, SimpsonJF, ManningAK, et al. (2007) A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol. Hum Mol Genet 16: 1765–1772.

38. MaillyF, TugrulY, ReymerPW, BruinT, SeedM, et al. (1995) A common variant in the gene for lipoprotein lipase (Asp9→Asn). Functional implications and prevalence in normal and hyperlipidemic subjects. Arterioscler Thromb Vasc Biol 15: 468–478.

39. KellerL, MurphyC, WangHX, FratiglioniL, OlinM, et al. (2010) A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations. Brain Res 1344: 185–191.

40. SmithAJ, AhmedF, NairD, WhittallR, WangD, et al. (2007) A functional mutation in the LDLR promoter (-139C>G) in a patient with familial hypercholesterolemia. Eur J Hum Genet 15: 1186–1189.

41. ReymerPW, GagneE, GroenemeyerBE, ZhangH, ForsythI, et al. (1995) A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis. Nat Genet 10: 28–34.

42. Acuna-AlonzoV, Flores-DorantesT, KruitJK, Villarreal-MolinaT, Arellano-CamposO, et al. (2010) A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans. Hum Mol Genet 19: 2877–2885.

43. KyriakouT, PontefractDE, ViturroE, HodgkinsonCP, LaxtonRC, et al. (2007) Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients. Hum Mol Genet 16: 1412–1422.

44. TaramelliR, PontoglioM, CandianiG, OttolenghiS, DieplingerH, et al. (1990) Lecithin cholesterol acyl transferase deficiency: molecular analysis of a mutated allele. Hum Genet 85: 195–199.

45. AouizeratBE, EnglerMB, NatanzonY, KulkarniM, SongJ, et al. (2006) Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia. J Lipid Res 47: 787–793.

46. EdmondsonAC, BrownRJ, KathiresanS, CupplesLA, DemissieS, et al. (2009) Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. J Clin Invest 119: 1042–1050.

47. KhetarpalSA, EdmondsonAC, RaghavanA, NeeliH, JinW, et al. (2011) Mining the LIPG allelic spectrum reveals the contribution of rare and common regulatory variants to HDL cholesterol. PLoS Genet 7: e1002393 doi:10.1371/journal.pgen.1002393

48. AdzhubeiIA, SchmidtS, PeshkinL, RamenskyVE, GerasimovaA, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7: 248–249.

49. Lango AllenH, EstradaK, LettreG, BerndtSI, WeedonMN, et al. (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467: 832–838.

50. HuangL, JakobssonM, PembertonTJ, IbrahimM, NyamboT, et al. (2011) Haplotype variation and genotype imputation in African populations. Genet Epidemiol 35: 766–780.

51. FriedlanderY, KarkJD, SteinY (1986) Heterogeneity in multifactorial inheritance of plasma lipids and lipoproteins in ethnically diverse families in Jerusalem. Genet Epidemiol 3: 95–112.

52. BeekmanM, HeijmansBT, MartinNG, PedersenNL, WhitfieldJB, et al. (2002) Heritabilities of apolipoprotein and lipid levels in three countries. Twin Res 5: 87–97.

53. IliadouA, SniederH, WangX, TreiberFA, DavisCL (2005) Heritabilities of lipids in young European American and African American twins. Twin Res Hum Genet 8: 492–498.

54. KaoJT, WenHC, ChienKL, HsuHC, LinSW (2003) A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia. Hum Mol Genet 12: 2533–2539.

55. WoodAR, HernandezDG, NallsMA, YaghootkarH, GibbsJR, et al. (2011) Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association. Hum Mol Genet 20: 4082–4092.

56. TrynkaG, HuntKA, BockettNA, RomanosJ, MistryV, et al. (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 43: 1193–1201.

57. SpencerC, HechterE, VukcevicD, DonnellyP (2011) Quantifying the underestimation of relative risks from genome-wide association studies. PLoS Genet 7: e1001337 doi:10.1371/journal.pgen.1001337

58. TeoYY, OngRT, SimX, TaiES, ChiaKS (2010) Identifying candidate causal variants via trans-population fine-mapping. Genet Epidemiol 34: 653–664.

59. TeoYY, SimX (2010) Patterns of linkage disequilibrium in different populations: implications and opportunities for lipid-associated loci identified from genome-wide association studies. Curr Opin Lipidol 21: 104–115.

60. LiuEY, BuyskeS, AragakiAK, PetersU, BoerwinkleE, et al. (2012) Genotype Imputation of MetabochipSNPs Using a Study-Specific Reference Panel of ∼4,000 Haplotypes in African Americans From the Women's Health Initiative. Genetic Epidemiology 36: 107–117.

61. RosenbergNA, HuangL, JewettEM, SzpiechZA, JankovicI, et al. (2010) Genome-wide association studies in diverse populations. Nat Rev Genet 11: 356–366.

62. The ARIC investigators (1989) The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol 129: 687–702.

63. KolonelLN, AltshulerD, HendersonBE (2004) The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer 4: 519–527.

64. The Woman's Health Initiative Study Group (1998) Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials 19: 61–109.

65. AndersonGL, MansonJ, WallaceR, LundB, HallD, et al. (2003) Implementation of the Women's Health Initiative study design. Ann Epidemiol 13: S5–17.

66. MatiseTC, AmbiteJL, BuyskeS, CarlsonCS, ColeSA, et al. (2011) The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. Am J Epidemiol 174: 849–859.

67. WilliamsRR, RaoDC, EllisonRC, ArnettDK, HeissG, et al. (2000) NHLBI family blood pressure program: methodology and recruitment in the HyperGEN network. Hypertension genetic epidemiology network. Ann Epidemiol 10: 389–400.

68. AdairLS, PopkinBM, AkinJS, GuilkeyDK, GultianoS, et al. (2011) Cohort profile: the Cebu longitudinal health and nutrition survey. Int J Epidemiol 40: 619–625.

69. ScottLJ, MohlkeKL, BonnycastleLL, WillerCJ, LiY, et al. (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316: 1341–1345.

70. StancakovaA, JavorskyM, KuulasmaaT, HaffnerSM, KuusistoJ, et al. (2009) Changes in insulin sensitivity and insulin release in relation to glycemia and glucose tolerance in 6,414 Finnish men. Diabetes 58: 1212–1221.

71. MidthjellK, KrugerO, HolmenJ, TverdalA, ClaudiT, et al. (1999) Rapid changes in the prevalence of obesity and known diabetes in an adult Norwegian population. The Nord-Trondelag Health Surveys: 1984–1986 and 1995–1997. Diabetes Care 22: 1813–1820.

72. JosephJ, SvartbergJ, NjolstadI, SchirmerH (2010) Incidence of and risk factors for type-2 diabetes in a general population: the Tromso Study. Scand J Public Health 38: 768–775.

73. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.

74. ChenMH, YangQ (2010) GWAF: an R package for genome-wide association analyses with family data. Bioinformatics 26: 580–581.

75. WillerCJ, LiY, AbecasisGR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26: 2190–2191.

76. PruimRJ, WelchRP, SannaS, TeslovichTM, ChinesPS, et al. (2010) LocusZoom: Regional visualization of genome-wide association scan results. Bioinformatics 26: 2336–2337.