We identified 10 loci that influence lipid levels in this cohort of African Americans. Of these, 7 were identified through testing the reported SNP while an additional 3 loci were identified using an LD-based strategy employed to account for the potential non-transfer of association signals across populations with different ancestral background . Teslovich et al. assessed the generalizability of their findings by attempting replication in ~8,000 African Americans in the CARe consortium . Of the 75 out of 95 loci for which the index SNP-trait association was investigated, 29 successfully replicated (see Supplementary Table 11 of that paper). A subset of these loci, along with replication of other lipid GWAS signals in the CARe African Americans, was also reported by Lettre et al.). The PAGE study, which included ~9,000 African Americans, investigated 9 of 95 loci (all also included in CARe) and replicated 6 . Of note, these were not independent samples, with both CARe and PAGE drawing participants from the ARIC and CARDIA cohorts. Of the 20 associations for which replication had not yet been attempted in an African American cohort, we were able to evaluate 16 in HUFS. One of these, an association between rs7941030 and TC, was replicated in HUFS. Additionally, four other associations that did not replicate in CARe were replicated in HUFS: rs10401969 (CILP2/SF4) with TG, rs2081687 (CYP7A1) with LDL, rs2972146 (IRS1) with HDL, and rs4420638 (APOE) with HDL (this association replicated in PAGE). CARe, PAGE, and HUFS all support the association of two loci with HDL in African Americans: rs3764261 (CETP) and rs4420638 (APOE).
Possible explanations for the lack of transferability of findings include differences in allele frequencies (see Additional file 1) and differences in effect sizes by population. Wide variability between populations in the frequency of risk alleles associated with a range of traits in GWAS has been demonstrated . The correlation of effect sizes between GWAS-identified associations in European compared to African ancestry populations was only 0.27 (p = 0.2) in an evaluation of 24 SNPs with GWAS results for both ancestral groups. In fact, for 79% of the associations investigated, point estimates were in the opposite direction or differed by more than twofold in European vs. African ancestry comparisons . Both of these results favor ancestry-specific analyses.
Some of the loci highlighted in this work have known biological functions relevant to serum lipids. STARD3, associated with HDL, is a lipid-trafficking protein. LPL, associated with TG, is a triglyceride hydrolase and a ligand factor for receptor-mediated lipoprotein uptake; mutations causing LPL deficiency have been implicated in type I hyperlipoproteinemia (NCBI: LPL, 2011). ApoE, associated with HDL, is a main lipoprotein of the chylomicron and is involved in the catabolism of triglyceride-rich lipoprotein constituents; defects in the gene encoding this protein result in familial dysbetalipoproteinemia (NCBI: APOE, 2011). CETP, associated with HDL, plays multiple roles in HDL metabolism and in the reverse cholesterol transport pathway . A CETP SNP (rs247617) that was unlinked with the replicated SNP was one of the top hits for HDL in our discovery GWAS (Additional file 3), suggesting the presence of multiple functional variants at this locus. Based on searches of both the GWAS catalog  and PubMed, only one of the top SNPs from our discovery GWAS had been previously reported: rs247617, a variant 5 KB upstream of CETP, was also associated with HDL among Finns  and African Americans of the CARe consortium , with a consistent direction of effect. This variant appears to be a significant determinant of HDL concentration across ethnicities.
Our study has two main strengths and one main limitation. First, HUFS represents the general population of African Americans in the Washington, DC area. The lack of selection for disease status makes this an optimal study sample for drawing conclusions regarding transferability to a broader population of African Americans. Second, a local replication strategy was employed to evaluate transferability of the reported associations, in recognition of the well-known differences in LD structure across the genome between African and European ancestry individuals. The main limitation of this study is the modest sample size. In some instances, it is probable that the failure to replicate was a result of lack of power. For instance, rs9987289 (PPP1R3B) – HDL, which was replicated in the CARe consortium analysis, was not genotyped or imputed in this sample, but a local SNP, rs6601299 (r2 = 0.86) was associated in the same direction, but just above the significance level (p = 0.07). As the previous publication is a meta-analysis with a very large sample size, it was able to detect small effect sizes, which would be difficult to replicate in a GWAS with a more limited sample size. As a result, more accurate estimates of transferability will await the aggregation of African ancestry GWAS into a suitably large meta-analysis. Of the 10 replicated loci in this study, only 1 had been previously identified in an individual GWAS (rs3764261 and HDL in GWAS of Indian Asian men [25, 26], Finns , and Japanese ).