Background: Peripheral metabolic disturbance is a known component of Alzheimer’s Disease (AD), however predictive genetic markers, as well as the associated pathways, remain to be determined. Two AD studies, ROSMAP and ADNI, have generated Whole Genome Sequencing (WGS) and ante-mortem serum metabolic biomarker samples. A previous study utilizing ROSMAP data has identified the metabolite tetradecadienylcarnitine, C14:2, as protective against incident AD in both brain and serum data (Brain and blood metabolome for Alzheimer’s dementia: Findings from a targeted metabolomics analysis; Huo et. al).
Method: After standard QC procedure, WGS data from ROSMAP participants was prioritized to include only variants within +/- 1000 bp of 584 AD prioritized genes identified on the AD Knowledge Portal’s Agora Platform (https://agora.adknowledgeportal.org/genes/(genes-router:genes-list)), resulting in a subset of 401,415 variants. A metabolite quantitative trait locus (mQTL) study was performed (N=67) investigating associations between these variants of interest and the C14:2 metabolite measurements collected from the ROSMAP cohort by Biocrates p180 flow injection analysis. A subsequent single-variant targeted mQTL analysis (N=464) utilizing ADNI-GO/2 WGS and C14:2 metabolic data (Biocrates p180 flow injection analysis) was performed. Age, gender and education were used as covariates in both analyses.
Result: A novel locus, rs147667251, showed significance to the C14:2 metabolic biomarker in both ROSMAP and ADNI serum mQTL analyses. In ROSMAP data, rs147667251 was identified as most significant to the C14:2 biomarker with a p-value of 5.507e-10 (threshold=1.2e-7). In a single test mQTL of ADNI C14:2 data, the rs147667251 locus had a significant p-value of 0.02415 (threshold=0.05). The locus lies on chromosome two and is an intron variant of the DPP10 gene. The DPP10 gene encodes a type II membrane protein and is known to have altered transcript and protein expression linked to AD.
Conclusion: In this AD prioritized mQTL study, a single genetic locus, rs147667251, within the AD nominated gene DPP10 has been identified as associated with serum levels of C14:2. DPP10 is known to be dysregulated in AD and a previous study has identified the C14:2 metabolite as protective against AD, warranting further investigation into the regulatory impact of rs147667251 on DPP10 expression and the C14:2 metabolic pathway.
Sophia TumSuden, Brian Lee, Jingxuan Bao, Jaesik Kim, Ryoma Kawakami, Dokyoon Kim, Li Shen (2022). "Metabolite QTL analysis of ROSMAP and ADNI prioritized sequencing data identifies C14:2 genetic locus on Chr 2." Alzheimer’s Association International Conference 2022.