Immune cell-mediated causal relationship between DNA copy number and Alzheimer disease: a Mendelian randomization study_West China Medical Journal

Authors：

ZHU Yun ¹ , WEI Jiaming ¹ , ZENG Yidi ¹ , LIN Ruifang ¹ , LIU Yongjun ¹ ,  GUO Zhihua ^1,2,3,4

1. School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P. R. China;
2. First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P. R. China;
3. Hunan Key Laboratory of Colleges and Universities of Intelligent Traditional Chinese Medicine Diagnosis and Preventive Treatment of Chronic Diseases of Hunan Universities of Chinese Medicine, Changsha, Hunan 410208, P. R. China;
4. Internet + TCM Diagnosis and Treatment of Chronic Diseases and Intelligent Application of Health Care Joint Postgraduate Training Base, Changsha, Hunan 410208, P. R. China;

Corresponding author：

GUO Zhihua, Email: guozhihua112@163.com

Keywords：

DNA copy number; immune cells; Alzheimer disease; Mendelian randomization; mediation

DOI：

10.7507/1002-0179.202406232

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To explore the causal relationship between DNA copy number and the risk of Alzheimer disease (AD) using Mendelian randomization (MR) methods, as well as to investigate the potential mediating effects of immune cells. Methods The data related to 731 immune cell types, DNA copy number and AD from the Genome-Wide Association Study database were collected. A bidirectional MR analysis was conducted to explore the causal relationship between DNA copy number and AD, primarily using the inverse-variance weighted method and MR-Egger method. Additionally, a two-step mediation analysis was performed to identify potential mediating immune cells. Results A total of 134 single-nucleotide polymorphisms were included for bidirectional MR analysis. The MR methods results showed a negative causal relationship between DNA copy number and the risk of AD (P<0.05), while the reverse analysis showed no statistical significance. Sensitivity analysis confirmed the robustness of these results. The mediation analysis indicated that the immune cell phenotype (HVEM on CD45RA-CD4⁺) partially mediated the causal relationship between DNA copy numbers and the risk of AD, with a mediation effect proportion of 4.6%. Conclusion An increase in DNA copy numbers may reduce the risk of AD, and immune cells partially mediate this causal relationship.

Citation： ZHU Yun, WEI Jiaming, ZENG Yidi, LIN Ruifang, LIU Yongjun, GUO Zhihua. Immune cell-mediated causal relationship between DNA copy number and Alzheimer disease: a Mendelian randomization study. West China Medical Journal, 2024, 39(8): 1204-1211. doi: 10.7507/1002-0179.202406232 Copy

1.	Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet, 2021, 397(10284): 1577-1590.
2.	Chen Z, Balachandran YL, Chong WP, et al. Roles of cytokines in Alzheimer’s disease. Int J Mol Sci, 2024, 25(11): 5803.
3.	Woo J, Cho H, Seol Y, et al. Power failure of mitochondria and oxidative stress in neurodegeneration and its computational models. Antioxidants (Basel), 2021, 10(2): 229.
4.	Antonyová V, Kejík Z, Brogyányi T, et al. Role of mtDNA disturbances in the pathogenesis of Alzheimer’s and Parkinson’s disease. DNA Repair (Amst), 2020, 91-92: 102871.
5.	Harerimana NV, Paliwali D, Romero-Molina C, et al. The role of mitochondrial genome abundance in Alzheimer’s disease. Alzheimers Dement, 2023, 19(5): 2069-2083.
6.	Picard M. Blood mitochondrial DNA copy number: what are we counting?. Mitochondrion, 2021, 60: 1-11.
7.	Jin WN, Shi K, He W, et al. Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition. Nat Neurosci, 2021, 24(1): 61-73.
8.	Cerantonio A, Citrigno L, Greco BM, et al. The role of mitochondrial copy number in neurodegenerative diseases: present insights and future directions. Int J Mol Sci, 2024, 25(11): 6062.
9.	Kulkarni B, Kumar D, Cruz-Martins N, et al. Role of TREM2 in Alzheimer’s disease: a long road ahead. Mol Neurobiol, 2021, 58(10): 5239-5252.
10.	Wang Q, Dai H, Hou T, et al. Dissecting causal relationships between gut microbiota, blood metabolites, and stroke: a Mendelian randomization study. J Stroke, 2023, 25(3): 350-360.
11.	Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
12.	Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
13.	Chong M, Mohammadi-Shemirani P, Perrot N, et al. GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia. ELife, 2022(11): e70382.
14.	Longchamps RJ, Yang SY, Castellani CA, et al. Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation. Hum Genet, 2022, 141(1): 127-146.
15.	Hägg S, Jylhävä J, Wang Y, et al. Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance. Hum Genet, 2021, 140(6): 849-861.
16.	Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 2020, 52(10): 1036-1045.
17.	Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature, 2023, 613(7944): 508-518.
18.	Fei Y, Yu H, Wu Y, et al. The causal relationship between immune cells and ankylosing spondylitis: a bidirectional Mendelian randomization study. Arthritis Res Ther, 2024, 26(1): 24.
19.	Ran B, Qin J, Wu Y, et al. Causal role of immune cells in chronic obstructive pulmonary disease: Mendelian randomization study. Expert Rev Clin Immunol, 2024, 20(4): 413-421.
20.	Choi KW, Chen CY, Stein MB, et al. Assessment of bidirectional relationships between physical activity and depression among adults: a 2-sample Mendelian randomization study. JAMA Psychiatry, 2019, 76(4): 399-408.
21.	Yuan J, Xiong X, Zhang B, et al. Genetically predicted C-reactive protein mediates the association between rheumatoid arthritis and atlantoaxial subluxation. Front Endocrinol (Lausanne), 2022, 13: 1054206.
22.	Li YS, Xia YG, Liu YL, et al. Metabolic-dysfunction associated steatotic liver disease-related diseases, cognition and dementia: a two-sample Mendelian randomization study. PLoS One, 2024, 19(2): e0297883.
23.	Cheng ZX, Hua JL, Jie ZJ, et al. Genetic insights into the gut-lung axis: Mendelian randomization analysis on gut microbiota, lung function, and COPD. Int J Chron Obstruct Pulmon Dis, 2024, 19: 643-653.
24.	Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
25.	Huang YL, Zheng JM, Shi ZY, et al. Inflammatory proteins may mediate the causal relationship between gut microbiota and inflammatory bowel disease: a mediation and multivariable Mendelian randomization study. Medicine (Baltimore), 2024, 103(25): e38551.
26.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
27.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
28.	Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol, 2021, 36(5): 465-478.
29.	陈鑫, 王尤, 周福祥. 基于孟德尔随机化的血浆脂质与结直肠癌因果关系及代谢物中介研究. 武汉大学学报(医学版), 2024: 1-7.
30.	Klein HU, Trumpff C, Yang HS, et al. Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain. Mol Neurodegener, 2021, 16(1): 75.
31.	Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci, 2019, 20(3): 148-160.
32.	Mostafavi S, Gaiteri C, Sullivan SE, et al. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease. Nat Neurosci, 2018, 21(6): 811-819.
33.	Yin J, Reiman EM, Beach TG, et al. Effect of ApoE isoforms on mitochondria in Alzheimer disease. Neurology, 2020, 94(23): e2404-e2411.
34.	Filograna R, Mennuni M, Alsina D, et al. Mitochondrial DNA copy number in human disease: the more the better?. FEBS Lett, 2021, 595(8): 976-1002.
35.	Wei W, Keogh MJ, Wilson I, et al. Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains. Acta Neuropathol Commun, 2017, 5(1): 13.
36.	Lynch MT, Taub MA, Farfel JM, et al. Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease. Sci Rep, 2023, 13(1): 14747.
37.	Gate D, Saligrama N, Leventhal O, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature, 2020, 577(7790): 399-404.
38.	Unger MS, Li E, Scharnagl L, et al. CD8⁺ T-cells infiltrate Alzheimer’s disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain Behav Immun, 2020, 89: 67-86.
39.	Zenaro E, Pietronigro E, Della Bianca V, et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med, 2015, 21(8): 880-886.
40.	Yoon JH, Shin P, Joo J, et al. Increased capillary stalling is associated with endothelial glycocalyx loss in subcortical vascular dementia. J Cereb Blood Flow Metab, 2022, 42(8): 1383-1397.
41.	Bawa KK, Krance SH, Herrmann N, et al. A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer’s disease. J Neuroinflammation, 2020, 17(1): 84.
42.	Lopez-Rodriguez AB, Hennessy E, Murray CL, et al. Acute systemic inflammation exacerbates neuroinflammation in Alzheimer’s disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimers Dement, 2021, 17(10): 1735-1755.
43.	Ito M, Komai K, Mise-Omata S, et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature, 2019, 565(7738): 246-250.
44.	Gate D, Tapp E, Leventhal O, et al. CD4+ T cells contribute to neurodegeneration in Lewy body dementia. Science, 2021, 374(6569): 868-874.
45.	Tait Wojno ED, Hunter CA, et al. The Immunobiology of the interleukin-12 family: room for discovery. Immunity, 2019, 50(4): 851-870.
46.	Yang HS, Zhang C, Carlyle BC, et al. Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults. Alzheimers Dement, 2022, 18(4): 645-653.
47.	Nitsch L, Schneider L, Zimmermann J, et al. Microglia-derived interleukin 23: a crucial cytokine in Alzheimer’s disease?. Front Neurol, 2021, 12: 639353.
48.	Xu C, Wu J, Wu Y, et al. TNF-α-dependent neuronal necroptosis regulated in Alzheimer’s disease by coordination of RIPK1-p62 complex with autophagic UVRAG. Theranostics, 2021, 11(19): 9452-9469.
49.	Xiong LL, Xue LL, Du RL, et al. Single-cell RNA sequencing reveals B cell-related molecular biomarkers for Alzheimer’s disease. Exp Mol Med, 2021, 53(12): 1888-1901.
50.	Shui JW, Kronenberg M. HVEM is a TNF receptor with multiple regulatory roles in the mucosal immune system. Immune Netw, 2014, 14(2): 67-72.
51.	Hokuto D, Sho M, Yamato I, et al. Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma. Eur J Cancer, 2015, 51(2): 157-165.
52.	Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation, 2014, 11: 98.

1. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet, 2021, 397(10284): 1577-1590.
2. Chen Z, Balachandran YL, Chong WP, et al. Roles of cytokines in Alzheimer’s disease. Int J Mol Sci, 2024, 25(11): 5803.
3. Woo J, Cho H, Seol Y, et al. Power failure of mitochondria and oxidative stress in neurodegeneration and its computational models. Antioxidants (Basel), 2021, 10(2): 229.
4. Antonyová V, Kejík Z, Brogyányi T, et al. Role of mtDNA disturbances in the pathogenesis of Alzheimer’s and Parkinson’s disease. DNA Repair (Amst), 2020, 91-92: 102871.
5. Harerimana NV, Paliwali D, Romero-Molina C, et al. The role of mitochondrial genome abundance in Alzheimer’s disease. Alzheimers Dement, 2023, 19(5): 2069-2083.
6. Picard M. Blood mitochondrial DNA copy number: what are we counting?. Mitochondrion, 2021, 60: 1-11.
7. Jin WN, Shi K, He W, et al. Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition. Nat Neurosci, 2021, 24(1): 61-73.
8. Cerantonio A, Citrigno L, Greco BM, et al. The role of mitochondrial copy number in neurodegenerative diseases: present insights and future directions. Int J Mol Sci, 2024, 25(11): 6062.
9. Kulkarni B, Kumar D, Cruz-Martins N, et al. Role of TREM2 in Alzheimer’s disease: a long road ahead. Mol Neurobiol, 2021, 58(10): 5239-5252.
10. Wang Q, Dai H, Hou T, et al. Dissecting causal relationships between gut microbiota, blood metabolites, and stroke: a Mendelian randomization study. J Stroke, 2023, 25(3): 350-360.
11. Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
12. Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
13. Chong M, Mohammadi-Shemirani P, Perrot N, et al. GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia. ELife, 2022(11): e70382.
14. Longchamps RJ, Yang SY, Castellani CA, et al. Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation. Hum Genet, 2022, 141(1): 127-146.
15. Hägg S, Jylhävä J, Wang Y, et al. Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance. Hum Genet, 2021, 140(6): 849-861.
16. Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 2020, 52(10): 1036-1045.
17. Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature, 2023, 613(7944): 508-518.
18. Fei Y, Yu H, Wu Y, et al. The causal relationship between immune cells and ankylosing spondylitis: a bidirectional Mendelian randomization study. Arthritis Res Ther, 2024, 26(1): 24.
19. Ran B, Qin J, Wu Y, et al. Causal role of immune cells in chronic obstructive pulmonary disease: Mendelian randomization study. Expert Rev Clin Immunol, 2024, 20(4): 413-421.
20. Choi KW, Chen CY, Stein MB, et al. Assessment of bidirectional relationships between physical activity and depression among adults: a 2-sample Mendelian randomization study. JAMA Psychiatry, 2019, 76(4): 399-408.
21. Yuan J, Xiong X, Zhang B, et al. Genetically predicted C-reactive protein mediates the association between rheumatoid arthritis and atlantoaxial subluxation. Front Endocrinol (Lausanne), 2022, 13: 1054206.
22. Li YS, Xia YG, Liu YL, et al. Metabolic-dysfunction associated steatotic liver disease-related diseases, cognition and dementia: a two-sample Mendelian randomization study. PLoS One, 2024, 19(2): e0297883.
23. Cheng ZX, Hua JL, Jie ZJ, et al. Genetic insights into the gut-lung axis: Mendelian randomization analysis on gut microbiota, lung function, and COPD. Int J Chron Obstruct Pulmon Dis, 2024, 19: 643-653.
24. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
25. Huang YL, Zheng JM, Shi ZY, et al. Inflammatory proteins may mediate the causal relationship between gut microbiota and inflammatory bowel disease: a mediation and multivariable Mendelian randomization study. Medicine (Baltimore), 2024, 103(25): e38551.
26. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
27. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
28. Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol, 2021, 36(5): 465-478.
29. 陈鑫, 王尤, 周福祥. 基于孟德尔随机化的血浆脂质与结直肠癌因果关系及代谢物中介研究. 武汉大学学报(医学版), 2024: 1-7.
30. Klein HU, Trumpff C, Yang HS, et al. Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain. Mol Neurodegener, 2021, 16(1): 75.
31. Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci, 2019, 20(3): 148-160.
32. Mostafavi S, Gaiteri C, Sullivan SE, et al. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease. Nat Neurosci, 2018, 21(6): 811-819.
33. Yin J, Reiman EM, Beach TG, et al. Effect of ApoE isoforms on mitochondria in Alzheimer disease. Neurology, 2020, 94(23): e2404-e2411.
34. Filograna R, Mennuni M, Alsina D, et al. Mitochondrial DNA copy number in human disease: the more the better?. FEBS Lett, 2021, 595(8): 976-1002.
35. Wei W, Keogh MJ, Wilson I, et al. Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains. Acta Neuropathol Commun, 2017, 5(1): 13.
36. Lynch MT, Taub MA, Farfel JM, et al. Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease. Sci Rep, 2023, 13(1): 14747.
37. Gate D, Saligrama N, Leventhal O, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature, 2020, 577(7790): 399-404.
38. Unger MS, Li E, Scharnagl L, et al. CD8⁺ T-cells infiltrate Alzheimer’s disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain Behav Immun, 2020, 89: 67-86.
39. Zenaro E, Pietronigro E, Della Bianca V, et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med, 2015, 21(8): 880-886.
40. Yoon JH, Shin P, Joo J, et al. Increased capillary stalling is associated with endothelial glycocalyx loss in subcortical vascular dementia. J Cereb Blood Flow Metab, 2022, 42(8): 1383-1397.
41. Bawa KK, Krance SH, Herrmann N, et al. A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer’s disease. J Neuroinflammation, 2020, 17(1): 84.
42. Lopez-Rodriguez AB, Hennessy E, Murray CL, et al. Acute systemic inflammation exacerbates neuroinflammation in Alzheimer’s disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimers Dement, 2021, 17(10): 1735-1755.
43. Ito M, Komai K, Mise-Omata S, et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature, 2019, 565(7738): 246-250.
44. Gate D, Tapp E, Leventhal O, et al. CD4+ T cells contribute to neurodegeneration in Lewy body dementia. Science, 2021, 374(6569): 868-874.
45. Tait Wojno ED, Hunter CA, et al. The Immunobiology of the interleukin-12 family: room for discovery. Immunity, 2019, 50(4): 851-870.
46. Yang HS, Zhang C, Carlyle BC, et al. Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults. Alzheimers Dement, 2022, 18(4): 645-653.
47. Nitsch L, Schneider L, Zimmermann J, et al. Microglia-derived interleukin 23: a crucial cytokine in Alzheimer’s disease?. Front Neurol, 2021, 12: 639353.
48. Xu C, Wu J, Wu Y, et al. TNF-α-dependent neuronal necroptosis regulated in Alzheimer’s disease by coordination of RIPK1-p62 complex with autophagic UVRAG. Theranostics, 2021, 11(19): 9452-9469.
49. Xiong LL, Xue LL, Du RL, et al. Single-cell RNA sequencing reveals B cell-related molecular biomarkers for Alzheimer’s disease. Exp Mol Med, 2021, 53(12): 1888-1901.
50. Shui JW, Kronenberg M. HVEM is a TNF receptor with multiple regulatory roles in the mucosal immune system. Immune Netw, 2014, 14(2): 67-72.
51. Hokuto D, Sho M, Yamato I, et al. Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma. Eur J Cancer, 2015, 51(2): 157-165.
52. Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation, 2014, 11: 98.

Previous Article
Causal association between gut microbiota and tic disorder: a Mendelian randomization study
Next Article
Psoriasis and Alzheimer disease: a two-sample two-way Mendelian randomization study

West China Medical Journal

Immune cell-mediated causal relationship between DNA copy number and Alzheimer disease: a Mendelian randomization study

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content