Alzheimer’s Disease Risk Polymorphisms Regulate Gene Expression in the <i>ZCWPW1</i> and the <i>CELF1</i> Loci

<div><p>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 <i>PILRB</i> and <i>GATS</i>, which occurs within the <i>ZCWPW1</i> locus. <i>PILRB</i> and <i>GATS</i> expression levels, within the <i>ZCWPW1</i> locus, were also associated with AD status. Rs7120548 was associated with <i>MTCH2</i> expression, which occurs within the <i>CELF1</i> locus. Additionally, expression of several genes within the <i>CELF1</i> locus, including <i>MTCH2</i>, were highly correlated with one another and were associated with AD status. We further demonstrate that <i>PILRB</i>, 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.</p>