Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration

Meta-analyses of European populations has successfully identified genetic variants in over 150 loci associated with lipid levels, but results from additional ethnicities remain limited. Previously, we reported two novel lipid loci identified in a sample of 7,657 African Americans using a gene-centric array including 50,000 SNPs in 2,100 candidate genes. Initial discovery and follow-up of signals with P < 10−5 in additional African American samples confirmed CD36 and ICAM1. Using an additional 8,244 African American female samples from the Women's Health Initiative SNP Health Association Resource genome-wide association study dataset, we further examined the previous meta-analyses results by attempting to replicate 20 additional putative lipid signals with P < 10−4. Replication confirmed rs868213, located in a splice donor region of exocyst complex component 3-like 1 (EXOC3L1) as a novel signal for HDL (additive allelic effect β = 0.02; P = 1.4 × 10−8; meta-analyses of discovery and replication). EXOC3L1 is strongly expressed in vascular endothelium and forms part of the exocyst complex, a key facilitator of the trafficking of lipid receptors. Increasing sample sizes for genetic studies in nonEuropean populations will continue to improve our understanding of lipid metabolism. Meta-analyses of European populations has successfully identified genetic variants in over 150 loci associated with lipid levels, but results from additional ethnicities remain limited. Previously, we reported two novel lipid loci identified in a sample of 7,657 African Americans using a gene-centric array including 50,000 SNPs in 2,100 candidate genes. Initial discovery and follow-up of signals with P < 10−5 in additional African American samples confirmed CD36 and ICAM1. Using an additional 8,244 African American female samples from the Women's Health Initiative SNP Health Association Resource genome-wide association study dataset, we further examined the previous meta-analyses results by attempting to replicate 20 additional putative lipid signals with P < 10−4. Replication confirmed rs868213, located in a splice donor region of exocyst complex component 3-like 1 (EXOC3L1) as a novel signal for HDL (additive allelic effect β = 0.02; P = 1.4 × 10−8; meta-analyses of discovery and replication). EXOC3L1 is strongly expressed in vascular endothelium and forms part of the exocyst complex, a key facilitator of the trafficking of lipid receptors. Increasing sample sizes for genetic studies in nonEuropean populations will continue to improve our understanding of lipid metabolism. Greater than 150 lipid-associated loci have been discovered using genome-wide association studies (GWASs) mainly based on individuals of European ancestry (1Willer C.J. Schmidt E.M. Sengupta S. Peloso G.M. Gustafsson S. Kanoni S. Ganna A. Chen J. Buchkovich M.L. Mora S. et al.Global Lipids Genetics Consortium.Discovery and refinement of loci associated with lipid levels.Nat. Genet. 2013; 45: 1274-1283Google Scholar, 2Asselbergs F.W. Guo Y. van Iperen E.P. Sivapalaratnam S. Tragante V. Lanktree M.B. Lange L.A. Almoguera B. Appelman Y.E. Barnard J. et al.Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.Am. J. Hum. Genet. 2012; 91: 823-838Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). The number of variants discovered and the power to detect variants of lower allele frequency and effect size is directly proportional to the number of participants in the study, demonstrated by the success of gradually larger meta-analyses (1Willer C.J. Schmidt E.M. Sengupta S. Peloso G.M. Gustafsson S. Kanoni S. Ganna A. Chen J. Buchkovich M.L. Mora S. et al.Global Lipids Genetics Consortium.Discovery and refinement of loci associated with lipid levels.Nat. Genet. 2013; 45: 1274-1283Google Scholar). Genetic variants generally appear to exert similar effects across ethnicities if tested in a sufficiently powered cohort, but differences in allele frequency and regional linkage disequilibrium (LD) between ethnicities allows for the identification of novel contributors to lipid metabolism (3Buyske S. Wu Y. Carty C.L. Cheng I. Assimes T.L. Dumitrescu L. Hindorff L.A. Mitchell S. Ambite J.L. Boerwinkle E. et al.Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.PLoS One. 2012; 7: e35651Crossref PubMed Scopus (57) Google Scholar, 4Teo Y.Y. Small K.S. Kwiatkowski D.P. Methodological challenges of genome-wide association analysis in Africa.Nat. Rev. Genet. 2010; 11: 149-160Crossref PubMed Scopus (156) Google Scholar, 5Rosenberg N.A. Huang L. Jewett E.M. Szpiech Z.A. Jankovic I. Boehnke M. Genome-wide association studies in diverse populations.Nat. Rev. Genet. 2010; 11: 356-366Crossref PubMed Scopus (419) Google Scholar). While efforts to identify additional variants associated with blood lipids in African-American populations have been successful (3Buyske S. Wu Y. Carty C.L. Cheng I. Assimes T.L. Dumitrescu L. Hindorff L.A. Mitchell S. Ambite J.L. Boerwinkle E. et al.Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.PLoS One. 2012; 7: e35651Crossref PubMed Scopus (57) Google Scholar, 6Elbers C.C. Guo Y. Tragante V. van Iperen E.P. Lanktree M.B. Castillo B.A. Chen F. Yanek L.R. Wojczynski M.K. Li Y.R. et al.Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.PLoS One. 2012; 7: e50198Crossref PubMed Scopus (37) Google Scholar, 7Musunuru K. Romaine S.P. Lettre G. Wilson J.G. Volcik K.A. Tsai M.Y. Taylor H.A. Schreiner P.J. Rotter J.I. Rich S.S. et al.Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project.PLoS One. 2012; 7: e36473Crossref PubMed Scopus (38) Google Scholar, 8Coram M.A. Duan Q. Hoffmann T.J. Thornton T. Knowles J.W. Johnson N.A. Ochs-Balcom H.M. Donlon T.A. Martin L.W. Eaton C.B. et al.Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations.Am. J. Hum. Genet. 2013; 92: 904-916Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), the identification of novel genetic loci in nonEuropean populations has been hampered by inadequate power due to limited sample size and genotyping platform designs made for optimal SNP coverage of European populations (3Buyske S. Wu Y. Carty C.L. Cheng I. Assimes T.L. Dumitrescu L. Hindorff L.A. Mitchell S. Ambite J.L. Boerwinkle E. et al.Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.PLoS One. 2012; 7: e35651Crossref PubMed Scopus (57) Google Scholar, 9Keating B.J. Tischfield S. Murray S.S. Bhangale T. Price T.S. Glessner J.T. Galver L. Barrett J.C. Grant S.F. Farlow D.N. et al.Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.PLoS One. 2008; 3: e3583Crossref PubMed Scopus (322) Google Scholar). The Institute for Translational Medicine and Therapeutics (ITMAT)-Broad-Candidate Gene Association Resource (IBC) array [also referred to as the CardioChip or HumanCVD Beadchip (Illumina)] was specifically designed to capture ∼50,000 SNPs across ∼2,100 loci, with pathways known or postulated to have roles in lipid traits captured at higher density than conventional GWAS arrays (9Keating B.J. Tischfield S. Murray S.S. Bhangale T. Price T.S. Glessner J.T. Galver L. Barrett J.C. Grant S.F. Farlow D.N. et al.Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.PLoS One. 2008; 3: e3583Crossref PubMed Scopus (322) Google Scholar). SNPs were specifically selected from African HapMap samples to be included on the array to ensure coverage of African populations (9Keating B.J. Tischfield S. Murray S.S. Bhangale T. Price T.S. Glessner J.T. Galver L. Barrett J.C. Grant S.F. Farlow D.N. et al.Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.PLoS One. 2008; 3: e3583Crossref PubMed Scopus (322) Google Scholar). Results of genetic associations with total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and TG concentrations in European-derived cohorts using the IBC array, as well as meta-analysis of multi-ethnic cohorts, have been published (2Asselbergs F.W. Guo Y. van Iperen E.P. Sivapalaratnam S. Tragante V. Lanktree M.B. Lange L.A. Almoguera B. Appelman Y.E. Barnard J. et al.Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.Am. J. Hum. Genet. 2012; 91: 823-838Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 6Elbers C.C. Guo Y. Tragante V. van Iperen E.P. Lanktree M.B. Castillo B.A. Chen F. Yanek L.R. Wojczynski M.K. Li Y.R. et al.Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.PLoS One. 2012; 7: e50198Crossref PubMed Scopus (37) Google Scholar). Follow-up replication of signals with P < 10−5 from the discovery cohort in African American samples confirmed two previously unreported lipid loci (CD36 and ICAM1) (6Elbers C.C. Guo Y. Tragante V. van Iperen E.P. Lanktree M.B. Castillo B.A. Chen F. Yanek L.R. Wojczynski M.K. Li Y.R. et al.Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.PLoS One. 2012; 7: e50198Crossref PubMed Scopus (37) Google Scholar), which have since been validated independently (8Coram M.A. Duan Q. Hoffmann T.J. Thornton T. Knowles J.W. Johnson N.A. Ochs-Balcom H.M. Donlon T.A. Martin L.W. Eaton C.B. et al.Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations.Am. J. Hum. Genet. 2013; 92: 904-916Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). We sought to improve the power to detect novel signals in African American populations by increasing sample size for meta-analyses using additional independent study samples. A meta-analysis of the original six African American populations (n = 7,657) and the replication population (n = 8,244) yielded a total sample size of 15,901. SNPs selected for replication in additional African Americans had 10−4 < P < 10−5 in our previous analysis (6Elbers C.C. Guo Y. Tragante V. van Iperen E.P. Lanktree M.B. Castillo B.A. Chen F. Yanek L.R. Wojczynski M.K. Li Y.R. et al.Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.PLoS One. 2012; 7: e50198Crossref PubMed Scopus (37) Google Scholar) and independence from known lipid-related loci calculated by a minor allele frequency-specific r2 threshold (r2 < 0.3 if minor allele frequency > 1%, r2 < 0.6 if minor allele frequency < 1%). The six discovery cohorts [Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), Cardiovascular Health Study (CHS), Multi-Ethnic Study of Atherosclerosis (MESA), Women's Health Initiative (WHI), and Jackson Heart Study (JHS)] were included from our previous report (6Elbers C.C. Guo Y. Tragante V. van Iperen E.P. Lanktree M.B. Castillo B.A. Chen F. Yanek L.R. Wojczynski M.K. Li Y.R. et al.Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.PLoS One. 2012; 7: e50198Crossref PubMed Scopus (37) Google Scholar), and all studies contributed individual-level IBC array genotypes and phenotypes (see Table 1). Summary level statistics for SNPs selected for replication were provided from a second independent cohort of African American females genotyped from the WHI SNP Health Association Resource (SHARe) GWAS dataset, termed here WHI-SHARe. There was no sample overlap between the WHI and WHI-SHARe genotyping initiatives. Further details of the populations, genotyping, and quality control analysis have been published elsewhere (6Elbers C.C. Guo Y. Tragante V. van Iperen E.P. Lanktree M.B. Castillo B.A. Chen F. Yanek L.R. Wojczynski M.K. Li Y.R. et al.Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.PLoS One. 2012; 7: e50198Crossref PubMed Scopus (37) Google Scholar, 8Coram M.A. Duan Q. Hoffmann T.J. Thornton T. Knowles J.W. Johnson N.A. Ochs-Balcom H.M. Donlon T.A. Martin L.W. Eaton C.B. et al.Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations.Am. J. Hum. Genet. 2013; 92: 904-916Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). All participants provided informed written consent. Institutional Review Boards of each Candidate Gene Association Resource (CARe) cohort reviewed and approved the cohort's interaction with CARe. The study described here was approved by the Committee on the Use of Humans as Experimental Subjects of the Massachusetts Institute of Technology.TABLE 1Participating studiesStudyStudy DesignParticipant Age (years)NIndividual-Level DataGenotyping ArrayDiscoveryARICProspective cohort, asymptomatic randomly collected in four US centers45–642,687YesIBC arrayCARDIAProspective cohort examining young adults collected in four US centers18–301,024YesIBC arrayCHSProspective cohort of asymptomatic older adults collected in four US centers65–80701YesIBC arrayMESAProspective cohort of asymptomatic participants45–841,584YesIBC arrayWHIProspective cohort of postmenopausal women from across US50–791,584YesIBC arrayJHSProspective cohort of asymptomatic adults collected in Jackson, MS21–481,118YesIBC arrayReplicationWHI-SHAReProspective cohort of postmenopausal women from across US50–798,153NoAffymetrix 6.0N, number of participants included in current study; ARIC, Atherosclerosis Risk in Communities; CARDIA, Coronary Artery Risk Development in Young Adults; CHS, Cardiovascular Health Study; MESA, Multi-Ethnic Study of Atherosclerosis; JHS, Jackson Heart Study; WHI-SHARe, second phase of Women's Health Initiative genotyping. Open table in a new tab N, number of participants included in current study; ARIC, Atherosclerosis Risk in Communities; CARDIA, Coronary Artery Risk Development in Young Adults; CHS, Cardiovascular Health Study; MESA, Multi-Ethnic Study of Atherosclerosis; JHS, Jackson Heart Study; WHI-SHARe, second phase of Women's Health Initiative genotyping. All participants were greater than 21 years of age. Lipid phenotypes were taken from baseline or first measurements for all fasting individuals, as described in the original reports. All measurements were converted to millimoles per liter, with TC and HDL-C measurements converted from milligrams per deciliter by dividing by 38.67, and TG measurements converted from milligrams per deciliter by dividing by 88.57. TG and HDL values were log-transformed to satisfy normality. LDL-C was calculated according to the Friedewald formula: L ∼ TC − HDL − kTG, where k is 0.45 for millimoles per liter (or 0.20 if measured in milligrams per deciliter) (10Friedewald W.T. Levy R.I. Fredrickson D.S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.Clin. Chem. 1972; 18: 499-502Crossref PubMed Scopus (64) Google Scholar). If TG values were >4.51 mmol/l (>400 mg/dl), then LDL-C was treated as a missing value. Gender stratified association analysis was performed in each participating study using an additive genetic model including age, sex, type 2 diabetes diagnosis, body mass index, and smoking history as covariates, as well as adjusting for 10 principal components of ancestry in PLINK (https://www.cog-genomics.org/plink2) (11Purcell S. Neale B. Todd-Brown K. Thomas L. Ferreira M.A. Bender D. Maller J. Sklar P. de Bakker P.I. Daly M.J. et al.PLINK: a tool set for whole-genome association and population-based linkage analyses.Am. J. Hum. Genet. 2007; 81: 559-575Abstract Full Text Full Text PDF PubMed Scopus (19629) Google Scholar). Principal components were calculated using Eigenstrat (12Price A.L. Patterson N.J. Plenge R.M. Weinblatt M.E. Shadick N.A. Reich D. Principal components analysis corrects for stratification in genome-wide association studies.Nat. Genet. 2006; 38: 904-909Crossref PubMed Scopus (6830) Google Scholar). Sensitivity analysis including and excluding covariates did not alter our findings. Meta-analyses were performed by two independent analysts using a fixed-effect inverse-variance approach in two different software packages, MANTEL (http://www.broadinstitute.org/~debakker/mantel.html) (13de Bakker P.I. Ferreira M.A. Jia X. Neale B.M. Raychaudhuri S. Voight B.F. Practical aspects of imputation-driven meta-analysis of genome-wide association studies.Hum. Mol. Genet. 2008; 17: R122-R128Crossref PubMed Scopus (417) Google Scholar) and METAL (http://www.sph.umich.edu/csg/abecasis/metal/) (14Willer C.J. Li Y. Abecasis G.R. METAL: fast and efficient meta-analysis of genomewide association scans.Bioinformatics. 2010; 26: 2190-2191Crossref PubMed Scopus (2615) Google Scholar). Results were highly concordant, reflecting a robust data analyses pipeline. Pruning of discovery cohort meta-analysis results for independence from previously reported loci and 10−4 < P <10−5 yielded three SNPs associated with plasma TC, three SNPs associated with LDL-C, six SNPs associated with HDL-C, and seven SNPs associated with TG (20 total lipid-SNP of SNPs was for replication in 8,244 WHI-SHARe African American The results for all 20 SNPs in the discovery and WHI-SHARe replication samples in Table the replication six SNPs were associated with the lipid and with the of effect as the discovery report with P < The association was exocyst complex component 3-like 1 (EXOC3L1) = × with HDL concentration = of discovery and replication studies to a genome-wide signal at the EXOC3L1 = 1.4 × for association with on the of is at The minor allele of is in the African American cohorts at HapMap populations allele of in in in in in with and European in with ancestry in and of in for replication and meta-analysis in African American × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × allele β Genome-wide is in Open table in a new tab allele β Genome-wide is in We then the lower minor allele frequency of in European populations for the of association from large-scale lipid GWAS The IBC lipid meta-analysis a association of the minor allele of with HDL in = P = (2Asselbergs F.W. Guo Y. van Iperen E.P. Sivapalaratnam S. Tragante V. Lanktree M.B. Lange L.A. Almoguera B. Appelman Y.E. Barnard J. et al.Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.Am. J. Hum. Genet. 2012; 91: 823-838Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). The larger Lipid Genetics that in individuals of European the minor allele of was associated with an of HDL = P = × (1Willer C.J. Schmidt E.M. Sengupta S. Peloso G.M. Gustafsson S. Kanoni S. Ganna A. Chen J. Buchkovich M.L. Mora S. et al.Global Lipids Genetics Consortium.Discovery and refinement of loci associated with lipid levels.Nat. Genet. 2013; 45: 1274-1283Google Scholar). SNPs were associated with HDL β = P = × but the was not identified as distinct from the associations with SNPs in due to higher levels of in European The is and in with in African Americans (r2 = additional and in with in African was associated with HDL = P = × in a CARe African American but was not identified as independent of G. Young T. F. A. A. et al.Genome-wide association study of and in African the NHLBI CARe Genet. 7: PubMed Scopus Google Scholar). further the independence of the association from in an African American a analysis was performed with the minor allele of included as a in the The SNP in the is in European and African American populations and has been associated with HDL The association for P = replication P = meta-analysis P = EXOC3L1 is highly expressed in human and studies have that the an in K. Y. A. T. S. et al.Genome-wide identification of in the 2012; PubMed Scopus Google Scholar). of identified that a putative splice of in with the by rs868213, according to analysis 1). we reviewed data for of and four of including and of the was of the to of the EXOC3L1 that for interaction with components of the exocyst complex and be the of to a for Scholar), of the remain SNPs in with the we reviewed for loci by and SNPs r2 > across a of using three for an was in a in four = = = and = T. P. S. M. A. S. M. K. et and of human and One. 2010; PubMed Scopus Google Scholar). were all associated the threshold = and a no data were to further the in lipid capture analysis F. Li Y. S. B. A of the in human 2013; PubMed Scopus Google Scholar) of the region no for interaction between and the further independence of the association from There was of interaction between the and the previous genetic association we to replicate associated variants in a larger meta-analysis including African The was the genome-wide association of with in a region of SNPs were to be associated with HDL in meta-analyses of European populations, but were due to with allele frequency and lower between and SNPs in African Americans power to detect the novel association with HDL in the current of the association for the effect of SNP further an independent analysis identified that is located an EXOC3L1 putative splice with a analysis for an the capture analysis of the region no for interaction between and the further independence of the association from EXOC3L1 is for the of from β and is and expressed in with type 2 diabetes T. P. S. E. E. C.L. C.B. L. et al.Genome-wide analysis of human from type 2 and identifies candidate that influence Genet. PubMed Scopus Google Scholar). et I. J. T. K. J. complex component 3-like 2 with the exocyst complex and of Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) reported that the is expressed in the and studies that 2 and of EXOC3L1 and of the exocyst complex as were located in EXOC3L1 using the tool A. D. T. F. M. and for Chem. 2012; PubMed Scopus Google Scholar), the for of EXOC3L1 of all data across the we EXOC3L1 to be the candidate on the of and EXOC3L1 is a component of the exocyst complex, an complex in trafficking and to the plasma M. the exocyst 2012; PubMed Scopus Google Scholar). The exocyst complex has an in trafficking of specifically including the LDL E. complex is to and to the in Full Text Full Text PDF PubMed Scopus Google Scholar) and the HDL T.A. S. A. I. M. van et density lipoprotein to HDL cholesterol Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). all the genetic and we that in EXOC3L1 in the vascular endothelium where is to exocyst HDL The current study three for of genetic association studies in lipid GWAS meta-analysis results and be as a and in replication examining putative as power to detect variants of effect size has be in to differences between and due to and additional of African populations be for additional signals GWAS signals from we efforts to continue to population from additional greater than 150 lipid loci identified in meta-analyses of the of of effect between cohorts and ethnicities of additional variants variants and to be discovered (1Willer C.J. Schmidt E.M. Sengupta S. Peloso G.M. Gustafsson S. Kanoni S. Ganna A. Chen J. Buchkovich M.L. Mora S. et al.Global Lipids Genetics Consortium.Discovery and refinement of loci associated with lipid levels.Nat. Genet. 2013; 45: 1274-1283Google Scholar). associated is to multiple and variants which independently to the of the multiple different a be to of the of variants and will improve our and the and the of genetic efforts to and samples will to the of nonEuropean the current meta-analysis of African Americans identified an association between in EXOC3L1 and The Candidate Gene Association Resource (CARe) to the of the and Institute and the of the study and study The the contributors and of the WHI-SHARe a The WHI-SHARe GWAS had data and performed at the in with Candidate Gene Association Resource loci exocyst complex component 3-like 1 genome-wide association study HDL cholesterol Institute for Translational Medicine and Therapeutics (ITMAT)-Broad-Candidate Gene Association Resource linkage disequilibrium LDL cholesterol SNP Health Association Resource total cholesterol Women's Health Initiative

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