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Browsing by Author "Jacobson, Tanner"
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Item Integrative analysis of eQTL and GWAS summary statistics reveals transcriptomic alteration in Alzheimer brains(BMC, 2022-04-23) Varathan, Pradeep; Gorijala, Priyanka; Jacobson, Tanner; Chasioti, Danai; Nho, Kwangsik; Risacher, Shannon L.; Saykin, Andrew J.; Yan, Jingwen; Radiology and Imaging Sciences, School of MedicineBackground: Large-scale genome-wide association studies have successfully identified many genetic variants significantly associated with Alzheimer's disease (AD), such as rs429358, rs11038106, rs723804, rs13591776, and more. The next key step is to understand the function of these SNPs and the downstream biology through which they exert the effect on the development of AD. However, this remains a challenging task due to the tissue-specific nature of transcriptomic and proteomic data and the limited availability of brain tissue.In this paper, instead of using coupled transcriptomic data, we performed an integrative analysis of existing GWAS findings and expression quantitative trait loci (eQTL) results from AD-related brain regions to estimate the transcriptomic alterations in AD brain. Results: We used summary-based mendelian randomization method along with heterogeneity in dependent instruments method and were able to identify 32 genes with potential altered levels in temporal cortex region. Among these, 10 of them were further validated using real gene expression data collected from temporal cortex region, and 19 SNPs from NECTIN and TOMM40 genes were found associated with multiple temporal cortex imaging phenotype. Conclusion: Significant pathways from enriched gene networks included neutrophil degranulation, Cell surface interactions at the vascular wall, and Regulation of TP53 activity which are still relatively under explored in Alzheimer's Disease while also encouraging a necessity to bind further trans-eQTL effects into this integrative analysis.Item Serum triglycerides in Alzheimer disease: Relation to neuroimaging and CSF biomarkers(Wolters Kluwer, 2020-05-01) Bernath, Megan M.; Bhattacharyya, Sudeepa; Nho, Kwangsik; Barupal, Dinesh Kumar; Fiehn, Oliver; Baillie, Rebecca; Risacher, Shannon L.; Arnold, Matthias; Jacobson, Tanner; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; Kaddurah-Daouk, Rima; Saykin, Andrew J.; Consortium for the Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Metabolomics; Medicine, School of MedicineObjective To investigate the association of triglyceride (TG) principal component scores with Alzheimer disease (AD) and the amyloid, tau, neurodegeneration, and cerebrovascular disease (A/T/N/V) biomarkers for AD. Methods Serum levels of 84 TG species were measured with untargeted lipid profiling of 689 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including 190 cognitively normal older adults (CN), 339 with mild cognitive impairment (MCI), and 160 with AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]fluorodeoxyglucose-PET) were assessed with a generalized linear model approach. In both cases, the Bonferroni method of adjustment was used to correct for multiple comparisons. Results The 84 TGs yielded 9 principal components, 2 of which, consisting of long-chain, polyunsaturated fatty acid–containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying the APOE ε4 allele, these principal components were significantly associated with CSF β-amyloid1–42 values and entorhinal cortical thickness. Conclusion This study shows that PUTG component scores were significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE ε4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.