Abstract
Late onset Alzheimer’s disease (LOAD) is a genetically complex and clinically heterogeneous disease. Recent large-scale genome wide association studies (GWAS) have identified more than twenty loci that modify risk for AD. Despite the identification of these loci, little progress has been made in identifying the functional variants that explain the association with AD risk. Thus, we sought to determine whether the novel LOAD GWAS single nucleotide polymorphisms (SNPs) alter expression of LOAD GWAS genes and whether expression of these genes is altered in AD brains. The majority of LOAD GWAS SNPs occur in gene dense regions under large linkage disequilibrium (LD) blocks, making it unclear which gene(s) are modified by the SNP. Thus, we tested for brain expression quantitative trait loci (eQTLs) between LOAD GWAS SNPs and SNPs in high LD with the LOAD GWAS SNPs in all of the genes within the GWAS loci. We found a significant eQTL between rs1476679 and PILRB and GATS, which occurs within the ZCWPW1 locus. PILRB and GATS expression levels, within the ZCWPW1 locus, were also associated with AD status. Rs7120548 was associated with MTCH2 expression, which occurs within the CELF1 locus. Additionally, expression of several genes within the CELF1 locus, including MTCH2, were highly correlated with one another and were associated with AD status. We further demonstrate that PILRB, as well as other genes within the GWAS loci, are most highly expressed in microglia. These findings together with the function of PILRB as a DAP12 receptor supports the critical role of microglia and neuroinflammation in AD risk.
Highlights
Late onset Alzheimer’s disease (LOAD) is a complex, heterogeneous disease with a strong genetic component
Despite the identification of additional, novel genome wide association studies (GWAS) loci that modulate LOAD risk, we still know little of the functional impact of LOAD GWAS single nucleotide polymorphisms (SNPs) and the role of these genes in AD pathogenesis
Three independent datasets demonstrate that rs1476679 is associated with altered PILRB expression in multiple brain regions. These datasets provide evidence for a much more complex picture of AD genetic risk than was previously reported in the original International Genomics of Alzheimer's Project (IGAP) GWAS: (1) the majority of IGAP GWAS SNPs do not significantly affect expression of nearby genes in brain homogenates and (2) eQTLs occur in genes that are near the IGAP SNP but not that have been named as an IGAP gene
Summary
Late onset Alzheimer’s disease (LOAD) is a complex, heterogeneous disease with a strong genetic component (reviewed in [1]). We found that expression levels of some LOAD GWAS genes that were identified in early GWAS [3,4,5,6,7,8], including ABCA7, BIN1, CD33, CLU, CR1, and MS4A6E, are associated with clinical and/or neuropathological aspects of AD [15] but failed to identify strong expression quantitative trait loci (eQTLs) [15, 17]. The expression of several genes within the CELF1 locus, including MTCH2, were highly correlated and were associated with AD status. These significant eQTLs and expression differences in LOAD brains were observed in genes that occur within the IGAP GWAS loci but not the named IGAP GWAS gene. Our findings demonstrate that several LOAD risk variants modify expression of nearby genes and may contribute to LOAD risk
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