Genome-wide association study of CSF biomarkers A 1-42, t-tau, and p-tau181p in the ADNI cohort

Objectives: CSF levels of Aβ 1-42 , t-tau, and p-tau 181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ 1-42 , t-tau, p-tau 181p , p-tau 181p /Aβ 1-42 , and t-tau/Aβ 1-42 ). Methods: A total of 374 non-Hispanic Caucasian participants in the Alzheimer9s Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p p −8 ) and secondarily examined SNPs with uncorrected p values less than 10 −5 to identify potential candidates. Results: Four SNPs in the regions of the APOE , LOC100129500, TOMM40 , and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134 , ABCG2 , SREBF2 , and NFATC4 , although not reaching genome-wide significance, were identified as potential candidates. Conclusions: In addition to known candidate genes, APOE , TOMM40 , and one hypothetical gene LOC100129500 partially overlapping APOE ; one novel gene, EPC2 , and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.