التفاصيل البيبلوغرافية
| العنوان: |
Gene‐level Association Study of Alzheimer's Disease on CHS and FRAM cohorts. |
| المؤلفون: |
Zhbannikov, Ilya, Ukraintseva, Svetlana, Wu, Deqing, Bagley, Olivia, Duan, Hongzhe, Holmes, Rachel, Yashin, Anatoliy I |
| المصدر: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2023 Supplement 24, Vol. 19, p1-3, 3p |
| مستخلص: |
Background: Experimental, clinical, and genetic epidemiological studies continue clarifying important aspects of Alzheimer's disease (AD) pathological development. Despite this progress the genetic mechanisms of AD regulation remain unclear. One problem that may contribute to slowing further progress in better understanding of these mechanisms deals with difficulties in replication of the results of genetic association studies. To overcome this problem the idea of using a gene‐based analysis in which all common variation within a candidate gene is considered jointly has been suggested. In this paper we investigate to what extent the use of gene‐based analyses resolves the non‐replication problem. Method: We performed gene‐level and meta‐analysis association studies for two cohorts: Cardiovascular Heart Study (CHS) and Framingham (FRAM) using Alzheimer's disease as a primary outcome. To support our findings, we also performed meta‐analysis following gene‐enrichment study for both cohorts. Analysis was performed separately for males and females and for both sexes. Additional covariates were age, smoking. Gene‐level analysis was performed with fastBAT and enrichment analysis with ClusterProfiler on KEGG database. Result: Our analysis identified a list of highly significant genes, such as TOMM40, APOC1 (all with FDR‐adjusted p‐value < 0.05) and pathways, such as Cholesterol metabolism, Fluid shear stress and atherosclerosis, Proteoglycans in cancer, Lipid and atherosclerosis showed statistically significant associations (FDR‐adjusted p‐value < 0.05) in both datasets and sexes. Meta‐analysis revealed TOMM40 (p‐value = 2.35E‐16), APOC1 (p‐value 4.46E‐13), ENSG00000259648 (p‐value = 8.88E‐06), PEX7 (p‐value = 4.40E‐05), ENSG00000287274 (p‐value = 5.38E‐05) genes for men and women combined; men exclusively revealed ENSG00000259648, TOMM40, and APOC1 (p‐value<1.75E‐05) and women TOMM40 and APOC1 (p‐value<6E‐08). Gene‐enrichment meta‐analysis revealed NOD‐like receptor signaling pathway (adjusted p‐value 3.23E‐07), Lipid and atherosclerosis (p‐value = 5.93E‐05), Yersinia (p‐value = 1.17E‐04) for men and women combined; for men only the pathways are Lipid and atherosclerosis (p‐value = 3.61E‐03), TGF‐beta signaling pathway (p‐value = 3.61E‐03), AGE‐RAGE signaling pathway in diabetic complications (p‐value = 5.18E‐03); and for women Cholesterol metabolism (p‐value = 3.49E‐07), Fatty acid degradation (p‐value = 1.04E‐06), PPAR signaling pathway (p‐value = 1.23E‐05). Conclusion: In this work we were able to identify statistically significant genes and pathways showed replication across the studies and are potentially useful for uncovering genetic mechanisms of AD. However, other things such as genetic heterogeneity may influence disease developing and needed further exploration. [ABSTRACT FROM AUTHOR] |
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