Conceived and designed the experiments: KM CMB SK DJR. Performed the experiments: KM SPRR. Analyzed the data: KM SPRR GL. Contributed reagents/materials/analysis tools: JGW KAV MYT HAT PJS JIR SSR SR BMP GJP JMO KL RMK NLG SBG MF LAC SGB EB. Wrote the paper: KM.
The authors have declared that no competing interests exist.
Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.
We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring
We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.
Plasma concentrations of lipids and lipoproteins [low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG)] are heritable risk factors for cardiovascular disease
As promising as these observations may be, several critical questions remain – How many of the previously reported loci are genuine causal determinants of plasma lipid levels? Are there more loci associated with plasma lipids that are discoverable with techniques besides genome-wide association mapping? Do any of these loci confer effects on lipids in an ethnic-specific manner? To address these questions, we utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) comprising more than 40,000 individuals from nine prospective cohorts with measured lipid phenotypes and genotype information obtained using the “ITMAT-Broad-CARe” array, or IBC array, with ∼50,000 polymorphisms from ∼2,000 candidate genes/loci
We initiated this study with specific hypotheses: (1) Common DNA sequence variants in previously reported genes and loci, as well as additional novel loci, are associated with plasma lipids; (2) At some of these loci, the specific variants related to plasma lipids differ between ethnic groups. To test these hypotheses, we performed association analyses of the polymorphisms on the IBC array in 25,000 European Americans and 9,000 African Americans in CARe.
All participants in each of the CARe cohorts gave informed written consent. The Institutional Review Boards (IRBs) of each CARe cohort (i.e., the IRBs for each cohort’s field centers, coordinating center, and laboratory center) have reviewed and approved the cohort’s interaction with CARe. The study described in this manuscript was approved by the Committee on the Use of Humans as Experimental Subjects (COUHES) of the Massachusetts Institute of Technology.
A full description of the CARe Study is found elsewhere
All DNA samples passing initial quality checks were interrogated with the IBC v2 chip for genotyping of 49,320 total single nucleotide polymorphisms (SNPs). Samples with overall genotyping success rate <95%, individual SNPs with genotyping success rate <95% within a cohort, monomorphic SNPs, and SNPs mapping to multiple genomic loci were removed. An inbreeding coefficient was calculated for each sample as a measure of heterozygosity, with those samples exceeding 4 standard deviations from the mean (suggesting poor DNA quality if too low, or sample contamination if too high) being removed. In cases of identical DNA samples, the sample with the lowest genotyping success rate was removed. Samples that shared 5% or more of their genome with many other samples were also removed. Additional outlier samples as determined by multidimensional scaling were also removed. SNPs for which genotype missingness could be predicted by surrounding haplotypes were removed, as were any SNPs found to be associated with chemistry plates. Pedigrees and SNPs not conforming to Mendelian expectations were identified and, where appropriate, samples were removed. These analyses were all performed with PLINK
Because different ethnic groups were represented, with the expectation of differing genotype frequencies and admixture, no filters were applied for minor allele frequency or Hardy-Weinberg
About 2,000 ancestry-informative markers were included in the IBC v2 chip
We modeled the lipid phenotypes in the following ways. LDL-C was calculated according to Friedewald’s formula: LDL-C = total cholesterol – HDL-C – (TG ÷ 5). If a TG value was >400 mg/dL, LDL-C was treated as a missing value. For individuals on lipid-lowering therapy, the LDL-C value was multiplied by 1.42 to model a 30% reduction in LDL-C on therapy. This represents the average expected reduction in LDL-C with a first-generation statin, the most commonly used lipid-lowering medication during the study periods of most of the cohorts
For each of the three traits, we used linear regression to test SNP-phenotype associations in each stratum of cohort and ethnicity assuming an additive genetic model, using the ten calculated principal components as covariates: phenotype ∼ genotype + PC1+ PC2+ PC3+ PC4+ PC5+ PC6+ PC7+ PC8+ PC9+ PC10. These association analyses were performed in PLINK. Genotype-phenotype associations within each ethnic group were assessed by weighted z-score-based fixed-effects meta-analysis and effect size estimates (β values) generated by inverse-variance weighted meta-analysis, both using METAL (G. Abecasis, University of Michigan). Genomic control correction was applied to each cohort individually prior to meta-analysis, and a final genomic control correction was applied to each ethnicity’s meta-analysis dataset. For all cross-ethnic comparisons, only SNPs available in all cohorts (12 total) were considered. We considered
We performed sensitivity analyses for two cohorts for which there were significant numbers of related individuals–CFS and FHS–to account for family relationships, using a linear mixed effects (LME) model to analyze the lipid residuals, with the SNP genotype treated as a fixed effect, and a random effect according to the degree of relatedness within a family
To identify SNPs exerting sex-specific effects, we added sex as a covariate in the above linear regression model and tested for a formal SNP×sex interaction; the results were meta-analyzed as described above. Similarly, to test for SNP×SNP interactions among the most strongly associated SNPs at each of the identified loci, we added the minor allele count for each SNP as a covariate, in turn, into the above model (with sex removed), testing for a formal interaction between each SNP pair combination.
For those loci containing IBC-significant SNPs in both ethnicities, we performed SNP conditional analyses. These were conducted by adding SNP allele counts as extra covariates to the initial linear regression model described above. The conditional analyses were performed iteratively, with additional independent SNPs identified at each step in each locus added to the model. Adjusted
Nineteen lipid-associated loci that were reported in an early set of lipid GWAS studies of individuals of European ancestry were included in the IBC v2 array–these loci harbor the genes
Gene(s) of interest in associated interval | Trait | SNP | Chr | Position | Alleles | European American MAF | African American MAF | European American |
African American |
European American β | African American β | Direction (EA, AA) |
|
LDL | rs11591147 | 1 | 55278235 | T, G | 0.016 | 0.0033 |
|
0.00011 | –0.44 | –0.51 | – – |
rs11806638 | 1 | 55290748 | A, C | 0.056 | 0.33 | 0.012 |
|
–0.054 | –0.11 | – – | ||
|
TG | rs1748197 | 1 | 62828700 | A, G | 0.34 | 0.34 |
|
0.012 | –0.053 | –0.042 | – – |
|
LDL | rs7528419 | 1 | 109618715 | A, G | 0.22 | 0.28 |
|
1.34×10−16 | 0.18 | 0.15 | + + |
rs12740374 | 1 | 109619113 | T, G | 0.22 | 0.26 | 2.90×10−51 |
|
–0.18 | –0.17 | – – | ||
|
HDL | rs4846918 | 1 | 228367209 | T, C | 0.15 | 0.14 |
|
0.45 | 0.069 | 0.016 | + + |
|
LDL | rs934197 | 2 | 21120966 | A, G | 0.32 | 0.12 |
|
0.0081 | 0.13 | 0.065 | + + |
rs562338 | 2 | 21141826 | A, G | 0.18 | 0.39 | 7.60×10−34 |
|
–0.15 | –0.092 | – – | ||
HDL | rs673548 | 2 | 21091049 | A, G | 0.21 | 0.22 |
|
0.044 | 0.068 | 0.037 | + + | |
TG | rs1042034 | 2 | 21078786 | T, C | 0.21 | 0.16 |
|
0.00031 | 0.068 | 0.079 | + + | |
|
TG | rs1260326 | 2 | 27584444 | T, C | 0.41 | 0.14 |
|
8.23×10−5 | 0.037 | 0.088 | + + |
|
LDL | rs4953023 | 2 | 43927504 | A, G | 0.070 | 0.078 |
|
0.0011 | –0.11 | –0.10 | – – |
|
LDL | rs12916 | 5 | 74692295 | T, C | 0.41 | 0.25 |
|
0.099 | –0.075 | –0.031 | – – |
|
LDL | rs10455872 | 6 | 160930108 | A, G | 0.067 | 0.010 |
|
0.24 | –0.14 | –0.081 | – – |
|
LDL | rs17725246 | 7 | 44548511 | T, C | 0.19 | 0.25 |
|
0.025 | –0.061 | –0.041 | – – |
|
TG | rs17145750 | 7 | 72664314 | T, C | 0.15 | 0.11 |
|
0.12 | –0.0017 | –0.040 | – – |
|
HDL | rs3211938 | 7 | 80138385 | T, G | 0.00010 | 0.083 | 0.030 |
|
–1.31 | –0.1931 | – – |
|
HDL | rs3916027 | 8 | 19869148 | A, G | 0.26 | 0.41 |
|
1.93×10−7 | 0.13 | 0.082 | + + |
rs13702 | 8 | 19868772 | T, C | 0.29 | 0.48 | 2.14×10−28 |
|
–0.12 | –0.10 | – – | ||
TG | rs3916027 | 8 | 19869148 | A, G | 0.26 | 0.41 |
|
2.65×10−8 | –0.0072 | –0.089 | – – | |
rs327 | 8 | 19863816 | T, G | 0.27 | 0.41 | 2.72×10−36 |
|
0.0026 | 0.097 | + + | ||
|
LDL | rs6982636 | 8 | 126548497 | A, G | 0.47 | 0.36 |
|
1.0 | –0.059 | –0.00 | – – |
HDL | rs2980880 | 8 | 126550154 | A, G | 0.31 | 0.32 |
|
0.46 | 0.052 | 0.012 | + + | |
TG | rs2980875 | 8 | 126550929 | A, G | 0.47 | 0.37 |
|
0.19 | 0.057 | 0.023 | + + | |
|
HDL | rs1883025 | 9 | 106704122 | T, C | 0.26 | 0.34 |
|
0.031 | –0.055 | –0.036 | – – |
rs2515629 | 9 | 106634185 | A, G | 0.17 | 0.17 | 0.53 |
|
0.0079 | 0.11 | + + | ||
|
HDL | rs1535 | 11 | 61354548 | A, G | 0.33 | 0.15 |
|
0.00055 | 0.059 | 0.074 | + + |
|
HDL | rs10750097 | 11 | 116169250 | A, G | 0.21 | 0.43 |
|
0.55 | 0.10 | –0.0094 | + – |
TG | rs2075290 | 11 | 116158506 | T, C | 0.070 | 0.055 |
|
0.00044 | –0.064 | –0.12 | – – | |
rs9804646 | 11 | 116170289 | T, C | 0.079 | 0.36 | 0.011 |
|
–0.039 | –0.083 | – – | ||
|
HDL | rs2075440 | 12 | 108343483 | A, G | 0.45 | 0.35 |
|
0.45 | –0.048 | –0.013 | – – |
|
HDL | rs2070895 | 15 | 56511231 | A, G | 0.21 | 0.47 |
|
|
0.12 | 0.097 | + + |
|
HDL | rs17231506 | 16 | 55552029 | T, C | 0.32 | 0.14 |
|
1.54×10−8 | 0.24 | 0.12 | + + |
rs17231520 | 16 | 55553328 | A, G | – | 0.070 | – |
|
– | 0.50 | 0+ | ||
|
HDL | rs2107369 | 16 | 66673519 | T, G | 0.14 | 0.26 |
|
0.58 | –0.076 | –0.010 | – – |
rs255052 | 16 | 66582496 | A, G | 0.15 | 0.22 | 6.63×10−7 |
|
0.069 | 0.11 | + + | ||
|
LDL | rs2000999 | 16 | 70665594 | A, G | 0.20 | – |
|
– | 0.069 | – | +0 |
|
HDL | rs1943981 | 18 | 45423813 | A, T | 0.16 | 0.05 |
|
0.41 | –0.095 | –0.027 | – – |
|
HDL | rs2278236 | 19 | 8337581 | A, G | 0.48 | 0.47 |
|
0.96 | 0.048 | –0.00060 | + – |
|
LDL | rs5030359 | 19 | 10249462 | A, G | – | 0.0086 | – |
|
– | –0.52 | 0– |
|
LDL | rs6511720 | 19 | 11063306 | T, G | 0.12 | 0.14 |
|
|
–0.23 | –0.20 | – – |
|
TG | rs3794991 | 19 | 19471596 | T, C | 0.090 | 0.066 |
|
0.98 | –0.084 | 0.0012 | – + |
|
LDL | rs12721046 | 19 | 50113094 | A, G | 0.15 | 0.030 |
|
0.00098 | 0.16 | 0.16 | + + |
rs389261 | 19 | 50112183 | A, G | – | 0.25 | – |
|
– | 0.15 | 0+ | ||
HDL | rs12721046 | 19 | 50113094 | A, G | 0.15 | 0.030 |
|
0.056 | –0.075 | –0.087 | – – | |
TG | rs439401 | 19 | 50106291 | T, C | 0.37 | 0.14 |
|
0.88 | –0.022 | –0.0046 | – – | |
rs12721054 | 19 | 50114427 | A, G | 0.00047 | 0.12 | 0.60 |
|
0.33 | 0.26 | + + | ||
|
HDL | rs4810479 | 20 | 43978455 | T, C | 0.25 | 0.40 |
|
0.00013 | 0.067 | 0.062 | + + |
AA = African American; EA = European American; MAF = major allele frequency. Minor allele frequencies all derived from ARIC (largest cohort for both African Americans and European Americans). Bold indicates the most highly associated SNP (lowest
We also found significant associations for a number of IBC SNPs chosen for their proximity to candidate genes selected from the literature. Of these, eight loci–
Finally, one locus harbors an IBC-significant variant that has not previously been reported to be associated with lipid traits–
Comparing each index SNP in each of the lipid loci in European Americans to African Americans, we noted quite varied patterns of association. In some cases, the effect size estimates and minor allele frequencies (MAFs) are quite similar in two ethnicities. An example is SNP rs6511720 in the
Other index SNPs diverged considerably in the two ethnicities. Some of the SNPs displayed considerable differences in their estimated effect sizes despite similar MAFs. Notable examples include rs2278236 in the
We took advantage of the dense genotyping in each locus on the IBC v2 array to perform more detailed comparisons of the 11 loci that harbored IBC-significant SNPs for both ethnicities (
Gene(s) of interest in associated interval | Trait | SNP | Chr | Position | Alleles | European American MAF | African American MAF | European American |
African American |
Direction (EA, AA) | European American SNP |
African American SNP |
European American Locus |
African American Locus |
|
LDL | rs11591147 | 1 | 55278235 | T, G | 0.016 | 0.0033 | 1.73×10−28 * | 0.00025 | – – | 0.007 | 0.005 | 0.011 | 0.003 |
rs11806638 | 1 | 55290748 | A, C | 0.056 | 0.33 | 0.012 | 4.65×10−11 * | – – | 0.000 | 0.002 | ||||
rs499883 | 1 | 55291762 | A, G | 0.40 | – | 1.45×10−11 ** | – | +0 | 0.004 | – | ||||
rs505151 | 1 | 55301775 | A, G | – | 0.2457 | – | 9.88×10−10 ** | 0– | – | 0.002 | ||||
|
LDL | rs7528419 | 1 | 109618715 | A, G | 0.22 | 0.28 | 1.69×10−51 * | 4.98×10−17 | + + | 0.013 | 0.005 | 0.013 | 0.006 |
rs12740374 | 1 | 109619113 | T, G | 0.22 | 0.26 | 2.89×10−51 | 2.32×10−20 * | – – | 0.013 | 0.006 | ||||
|
LDL | rs5742904 | 2 | 21082665 | T, C | 0.00068 | – | 7.53×10−14 *** | – | +0 | 0.004 | – | 0.016 | 0.004 |
rs934197 | 2 | 21120966 | A, G | 0.32 | 0.12 | 2.88×10−34 * | 0.0076 | + + | 0.007 | 0.001 | ||||
rs562338 | 2 | 21141826 | A, G | 0.18 | 0.39 | 7.60×10−34 ** | 1.08×10−8 * | – – | 0.008 | 0.004 | ||||
|
HDL | rs268 | 8 | 19857809 | A, G | 0.020 | 0.0031 | 4.55×10−11 ** | 0.040 | + + | 0.003 | 0.000 | 0.009 | 0.006 |
rs13702 | 8 | 19868772 | T, C | 0.29 | 0.48 | 2.14×10−28 | 1.43×10−10 * | – – | 0.005 | 0.006 | ||||
rs3916027 | 8 | 19869148 | A, G | 0.26 | 0.41 | 1.01×10−31 * | 7.99×10−7 | + + | 0.006 | 0.003 | ||||
rs10503669 | 8 | 19891970 | A, C | 0.098 | 0.057 | 3.77×10−28 *** | 0.00084 | + + | 0.005 | 0.001 | ||||
|
TG | rs268 | 8 | 19857809 | A, G | 0.020 | 0.0031 | 9.49×10−13 ** | 0.5053 | – – | 0.003 | 0.000 | 0.012 | 0.004 |
rs327 | 8 | 19863816 | T, G | 0.27 | 0.41 | 2.72×10−36 | 1.03×10−9 * | + + | 0.008 | 0.004 | ||||
rs12679834 | 8 | 19864713 | T, C | 0.10 | 0.082 | 1.29×10−32 *** | 3.65×10−8 | ++ | 0.006 | 0.004 | ||||
rs3916027 | 8 | 19869148 | A, G | 0.26 | 0.41 | 1.20×10−40 * | 2.65×10−8 | – – | 0.009 | 0.004 | ||||
|
HDL | rs2515629 | 9 | 106634185 | A, G | 0.17 | 0.17 | 0.53 | 2.98×10−7 * | + + | 0.000 | 0.004 | 0.002 | 0.004 |
rs2472449 | 9 | 106644018 | T, G | 0.34 | 0.22 | 1.40×10−6 ** | 9.50×10−5 | + + | 0.001 | 0.002 | ||||
rs1883025 | 9 | 106704122 | T, C | 0.26 | 0.34 | 6.25×10−7 * | 0.031 | – – | 0.001 | 0.000 | ||||
|
TG | rs180327 | 11 | 116128869 | T, C | 0.37 | 0.49 | 3.44×10−23 | 1.79×10−5 ** | – – | 0.008 | 0.000 | 0.025 | 0.003 |
rs2075290 | 11 | 116158506 | T, C | 0.070 | 0.055 | 8.14×10−51 * | 0.00044 | – – | 0.013 | 0.000 | ||||
rs12287066 | 11 | 116167541 | T, G | 0.068 | 0.17 | 3.54×10−34 ** | 0.031 | + + | 0.010 | 0.000 | ||||
rs9804646 | 11 | 116170289 | T, C | 0.079 | 0.36 | 0.011 | 4.81×10−7 * | – – | 0.001 | 0.003 | ||||
|
HDL | rs4775041 | 15 | 56461987 | C, G | 0.29 | 0.13 | 2.69×10−20 ** | 0.21 | + + | 0.004 | 0.000 | 0.011 | 0.005 |
rs2070895 | 15 | 56511231 | A, G | 0.21 | 0.47 | 3.91×10−24 * | 1.35×10−10 * | + + | 0.007 | 0.005 | ||||
|
HDL | rs17231506 | 16 | 55552029 | T, C | 0.32 | 0.14 | 1.50×10−120 * | 2.41×10−8 | + + | 0.025 | 0.005 | 0.036 | 0.050 |
rs4783961 | 16 | 55552395 | A, G | 0.499 | 0.43 | 3.58×10−31 | 1.17×10−43 ** | + + | 0.006 | 0.026 | ||||
rs17231520 | 16 | 55553328 | A, G | – | 0.070 | – | 2.46×10−56 * | 0+ | – | 0.037 | ||||
rs7499892 | 16 | 55564091 | T, C | 0.17 | 0.39 | 4.20×10−78 | 1.04×10−26 *** | – – | 0.017 | 0.012 | ||||
rs5883 | 16 | 55564854 | T, C | 0.058 | 0.11 | 2.66×10−8 *** | 1.72×10−12 | + + | 0.000 | 0.006 | ||||
rs11076176 | 16 | 55564947 | T, G | 0.17 | – | 8.88×10−67 ** | – | +0 | 0.013 | – | ||||
rs5880 | 16 | 55572592 | C, G | 0.050 | 0.0096 | 7.28×10−33 **** | 0.0044 | – – | 0.007 | 0.001 | ||||
|
HDL | rs35673026 | 16 | 66534352 | T, C | – | 0.0038 | – | 1.54×10−6 ** | 0+ | – | 0.004 | 0.002 | 0.011 |
rs255052 | 16 | 66582496 | A, G | 0.15 | 0.22 | 6.64×10−7 | 5.02×10−9 * | + + | 0.002 | 0.007 | ||||
rs2107369 | 16 | 66673519 | T, G | 0.14 | 0.26 | 9.23×10−8 * | 0.70 | – – | 0.002 | 0.000 | ||||
|
LDL | rs6511720 | 19 | 11063306 | T, G | 0.12 | 0.14 | 1.39×10−49 * | 2.29×10−18 * | – – | 0.008 | 0.009 | 0.010 | 0.012 |
rs17242787 | 19 | 11063460 | A, T | – | 0.019 | – | 2.19×10−9 ** | 0– | – | 0.003 | ||||
rs688 | 19 | 11088602 | T, C | 0.43 | 0.10 | 1.66×10−11 ** | 0.0014 | + + | 0.002 | 0.003 | ||||
|
LDL | rs8106922 | 19 | 50093506 | A, G | 0.39 | 0.24 | 7.25×10−5 | 5.75×10−6 *** | – – | 0.000 | 0.003 | 0.010 | 0.019 |
rs405509 | 19 | 50100676 | T, G | 0.49 | 0.26 | 1.93×10−11 | 1.89×10−12 ** | + + | 0.002 | 0.005 | ||||
rs769450 | 19 | 50102284 | A, G | 0.40 | 0.37 | 6.93×10−7 *** | 0.00015 | + + | 0.001 | 0.003 | ||||
rs389261 | 19 | 50112183 | A, G | – | 0.25 | – | 2.72×10−14 * | 0+ | – | 0.003 | ||||
rs12721046 | 19 | 50113094 | A, G | 0.15 | 0.030 | 2.23×10−29 * | 0.0017 | + + | 0.006 | 0.003 | ||||
rs12721109 | 19 | 50139061 | A, G | 0.022 | 0.0028 | 7.72×10−27 ** | 0.023 | – – | 0.004 | 0.000 | ||||
|
TG | rs439401 | 19 | 50106291 | T, C | 0.37 | 0.14 | 1.85×10−15 * | 0.88 | – – | 0.003 | 0.000 | 0.003 | 0.012 |
rs12721054 | 19 | 50114427 | A, G | 0.00047 | 0.12 | 0.60 | 3.73×10−25 * | + + | 0.000 | 0.012 |
AA = African American; EA = European American; MAF = major allele frequency. Minor allele frequencies and R2 values all derived from ARIC (largest cohort for both African Americans and European Americans). Direction is modeled on the first allele listed in “Alleles” column. Independent SNPs (when they exist) are indicated as: * = lowest
For each ethnicity we performed conditional analyses with the most highly associated SNPs in each of the 11 loci to uncover any additional, independently associated SNPs (at IBC significance) in the same gene regions (
For many gene regions, the independent SNPs did not colocalize in the two ethnicities. For example, in the
Notably, for two loci/trait combinations–
We investigated whether any SNP×SNP interactions existed between any of the most significant SNPs identified at each of the 19 above-mentioned loci for their respective traits; none were identified (
Similarly, no IBC-significant SNP×sex interactions were observed among the SNPs identified in
In this work, we identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies of two ethnicities. Specifically, the results of these studies support each of our hypotheses.
We found that all 19 lipid-associated loci identified in early GWAS studies replicated in the combined CARe European American cohorts (∼25,000 individuals), and 10 of the loci replicated in the combined CARe African American cohorts (∼9,000 individuals). It is likely that with genotyping in additional African American individuals, increased power will ultimately allow replication of many of the remaining nine loci. We identified an additional 10 loci associated with one or more lipid traits at Bonferroni-corrected statistical significance. Eight of these loci were mapped in GWAS studies subsequent to the design of the IBC array, and one locus had been identified in a prior non-GWAS study. The remaining locus,
These findings give a high degree of confidence that most, if not all, of the reported GWAS lipid loci harbor authentic determinants of plasma lipid levels deserving of further functional investigation, and that many of the loci are relevant not just in European American populations but more generally in global populations.
We were able to use the dense SNP genotyping in loci available via the IBC array to analyze lipid-associated loci in an unprecedented level of detail, particularly in African Americans. Our analyses demonstrate that at many loci there are major differences in genetic architecture between European Americans and African Americans. These differences manifest in at least three ways.
First, some of the most highly associated SNPs in one ethnicity are rare or absent in the other ethnicity. This is a well-established phenomenon; for example, truncation mutations in
Second, some of the most highly associated SNPs in one ethnicity are poorly associated in the other ethnicity despite similar MAFs in both groups. An example is rs2515629 in the
Third, in some gene regions there are differences in the distributions of independent lipid-associated SNPs. Presumably these independent SNPs reflect the presence of independent causal variants. For example, in the
A previous analysis of lipid-associated loci in the Jackson Heart Study identified several loci–
Finally, while it has been assumed that differing patterns of linkage disequilibrium in European Americans and African Americans could be helpful in localizing shared, causal DNA variants, for the reasons stated above this may not often be the case. Of the 29 loci we studied, only in 4 cases did association signals in the two ethnicities appear to unambiguously converge (
In the
In the
Rs6511720 is located in intron 1 of the
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The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, and field staff.