To our knowledge, the present study is the largest GWAS for the study of LOAD in African Americans ever assembled. Aside from SNPs associated with APOE, the top-ranked SNP observed in this study was located in ABCA7
(rs115550680) and had an effect size comparable with that of APOE
ε4. This observation differs from the previous GWAS in whites. The reported ABCA7
SNPs in non-Hispanic whites have lower effect sizes (rs3752246: OR, 1.13 [95% CI, 1.03-1.25]; rs3764650: OR, 1.23 [95% CI, 1.17-1.28]),3,5
as do all other genes reported in whites (CR1
It remains possible that this could be attributable to population differences in the frequencies of the causative variant(s) tagged by the associated SNPs (rs115550680 in ABCA7 is monomorphic in non-Hispanic whites; the MAF for rs3752246 is 0.04 in African Americans and 0.19 in non-Hispanic whites; the MAF for rs3764650 is 0.25 in African Americans and 0.11 in non-Hispanic whites) or the result of a bias in the estimated effect of a newly identified allele on disease (also termed “winner's curse”).
However, it is also possible that the large difference between whites and African Americans in the effect size of the ABCA7
locus on the relative odds of being diagnosed with LOAD is explained by population-specific causative variants with variable influence on protein structure or function. The linkage disequilibrium block in which rs115550680 is located spans across several introns and exons (), implying that rs115550680 is in dis-equilibrium with exonic variants that could be potentially causative. Thus, although the findings of this study require replication in an independent African American sample with enough power to detect small ORs as well as functional confirmation, support for our findings comes from the previous studies in whites observing ABCA7
as a risk locus in Alzheimer disease, albeit with marginal effects.3,5
If validated by future replication and functional studies, identification of ABCA7
as a risk gene in LOAD among African Americans not only may help elucidate the disease etiology but also may have major implications for developing targets for genetic testing, prevention, and treatment. ABCA7
is an integral transmembrane adenosine triphosphate–binding cassette transporter that belongs to the ABC family proteins and that mediates the biogenesis of high-density lipoprotein with cellular lipid and helical apolipoproteins.48
It binds apolipoprotein A1 and functions in apolipoprotein-mediated phospholipid and cholesterol efflux from cells.49
The findings of the current study suggest that lipid metabolism is a prominent pathway of LOAD in African Americans. This is consistent with the fact that cardiovascular and cerebrovascular diseases are more prominent in African Americans than in non-Hispanic whites.50
Moreover, dyslipidemia and cardiovascular and cerebrovascular diseases are well-recognized risk factors for LOAD,51,52
and the LOAD-related genes SORL1
, and APOE
are also involved in lipid metabolism. If confirmed, focusing on the role of lipid metabolism in LOAD may have significant effects on disease management.
also affects the transport of other important proteins, including amyloid precursor protein,49
through the cell membrane and is involved in host defense through effects on phagocytosis by macrophages of apoptotic cells.48
Thus, there are multiple ways in which ABCA7
might affect risk of LOAD.
Compared with the findings described in Naj et al5
among non-Hispanic whites, the area including significant SNP associations in the ABCA7
region was broader in the African American sample. It is possible that this broad region of association in African Americans is attributable to a large, ancestral risk haplotype recently introduced by admixture with white (“European”) Americans and has remained substantially intact within African Americans because of the relatively short time since its introduction. In contrast, the risk allele may exist on several different haplotypes in non-Hispanic whites (ie, may be older), only a subset of which was introduced into the African American population.
In a previous study,5
the ADGC reported genome-wide associations for variants in MSA4
, and EPHA1
among individuals of white European ancestry. A cohort-based consortium comprising whites from the United Kingdom, Europe, and the United States had similar findings and first reported the association between SNPs in ABCA7
and Alzheimer disease.3
Logue et al29
reported nominal significance for the ABCA7
SNP rs3764650 reported by Hollingworth et al3
in a well-characterized cohort of 513 African American persons with Alzheimer disease and 496 cognitively normal controls. As described above, the effect sizes for the association between ABCA7
and LOAD in these studies is small compared with the effect size observed in the current study. In the current study CR1
, and CD33
were replicated with significance in gene-based analyses. Differences in disease-associated SNPs in these loci between the white and African American consortium data sets also reflect differences in degree of variation and size of haplotype blocks, which in turn is helpful in identifying the true causative variants.
This study has limitations. Because of the paucity of available African American data sets for LOAD, we could not divide the assembled data sets into discovery and replication data sets but rather used the ADGC white race data set for replication. Thus, this study requires replication in an independent African American sample. In addition, we had limited power to detect associations with small effect sizes and associations with rare variants. Although all data sets included in the analytic sample used accepted clinical or pathological criteria to define LOAD, phenotypic heterogeneity between samples may have limited our ability to detect some associations.
In addition, the top-ranked SNP observed in ABCA7
was not directly genotyped but imputed in all data sets. However, several facts make it unlikely that the observed association was caused by imputation error. First, as stated above and shown in , rs115550680 is in linkage disequilibrium with the 2 ABCA7
SNPs reported by Naj et al5
and Hollingworth et al3
in non-Hispanic whites of European ancestry (rs3764650 and rs3752246, 0.8<D’ = 0.9) that make this finding plausible. Second, the imputation quality (R^2) of this SNP is high across all data sets (0.89<R^2<0.99) (eTable 3
). Third, the MAF of rs115550680 in our African American sample is 7%. Although in general the imputation error rate increases with decreasing MAF, several recent studies suggest that SNPs with MAFs less than 5% are especially prone to imputation errors.36
The recent study by Hancock et al,53
which specifically assessed genotype imputation performance using 1000 Genomes reference panels in African Americans, determined that the threshold for high imputation lies at MAF 2% or greater, applying the software and reference panel used in the present study.
The variant associations reported herein reflect a portion of the genetic influences of common alleles on LOAD in African Americans. Among these, ABCA7 and APOE genotype were the strongest risk factors that both substantially increased the risk of LOAD (OR, 1.79 and 2.31, respectively). Identification of the genetic risk variants by resequencing and validation by functional studies would allow refinement of risk estimates and diagnostic and predictive testing protocols specific for African Americans.