Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients

Kimberly C Paul; Cynthia Kusters; Melissa Furlong; Keren Zhang; Yu Yu; Aline Duarte Folle; Irish Del Rosario; Adrienne Keener; Jeff Bronstein; Janet S Sinsheimer; Steve Horvath; Beate Ritz

doi:10.1016/j.bbih.2022.100530

Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients

Brain Behav Immun Health. 2022 Oct 3:26:100530. doi: 10.1016/j.bbih.2022.100530. eCollection 2022 Dec.

Authors

Kimberly C Paul¹, Cynthia Kusters², Melissa Furlong³, Keren Zhang⁴, Yu Yu⁵, Aline Duarte Folle⁴, Irish Del Rosario⁴, Adrienne Keener¹, Jeff Bronstein¹, Janet S Sinsheimer^{2

6}, Steve Horvath^{2

6}, Beate Ritz^{1

4}

Affiliations

¹ Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA.
² Departments of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, USA.
³ University of Arizona, Mel and Enid Zuckerman College of Public Health, Tucson, AZ, USA.
⁴ Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
⁵ Center for Health Policy Research, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
⁶ Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA.

Abstract

Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS<5). For PD patients with a history of clinical depression compared to those without, we found no differences in immune cell composition. However, a history of clinical depression among patients was associated with differentially methylated CpGs. Epigenome-wide association analysis (EWAS) revealed 35 CpGs associated at an FDR≤0.05 (569 CpGs at FDR≤0.10, 1718 CpGs at FDR≤0.15). Gene set enrichment analysis implicated immune system pathways, including immunoregulatory interactions between lymphoid and non-lymphoid cells (p-adj = 0.003) and cytokine-cytokine receptor interaction (p-adj = 0.004). Based on functional genomics, 25 (71%) of the FDR≤0.05 CpGs were associated with genetic variation at 45 different methylation quantitative trait loci (meQTL). Twenty-six of the meQTLs were also expression QTLs (eQTLs) associated with the abundance of 53 transcripts in blood and 22 transcripts in brain (substantia nigra, putamen basal ganglia, or frontal cortex). Notably, cg15199181 was strongly related to rs823114 (SNP-CpG p-value = 3.27E-310), a SNP identified in a PD meta-GWAS and related to differential expression of PM20D1, RAB29, SLC41A1, and NUCKS1. The entire set of genes detected through functional genomics was most strongly overrepresented for interferon-gamma-mediated signaling pathway (enrichment ratio = 18.8, FDR = 4.4e-03) and T cell receptor signaling pathway (enrichment ratio = 13.2, FDR = 4.4e-03). Overall, the current study provides evidence of immune system involvement in depression among Parkinson's patients.

Keywords: DNA methylation; Depression; Inflammation; Methylation QTLs; Neutrophil-to-lymphocyte ratio; Parkinson's disease.

Abstract

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