Defining functional variants associated with Alzheimer’s disease in the induced immune response

Harwood, Janet; Leonenko, Ganna; Sims, Rebecca; Escott‐Price, Valentina; Williams, Julie; Holmans, Peter

doi:10.1093/braincomms/fcab083

Cited by 21 publications

(19 citation statements)

References 71 publications

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“…The fourth replicated protein, poliovirus receptor ( PVR ), has multiple roles in the immune response, including mediating NK cell adhesion and triggering their effector functions. PVR has been found to be associated with bipolar disorder, schizophrenia [ 39 ], and Alzheimer’s disease [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Discovery and replication of blood-based proteomic signature of PTSD in 9/11 responders

et al. 2023

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Proteomics provides an opportunity to develop biomarkers for the early detection and monitoring of post-traumatic stress disorder (PTSD). However, research to date has been limited by small sample sizes and a lack of replication. This study performed Olink Proseek Multiplex Platform profiling of 81 proteins involved in neurological processes in 936 responders to the 9/11 disaster (mean age at blood draw = 55.41 years (SD = 7.93), 94.1% white, all men). Bivariate correlations and elastic net regressions were used in a discovery subsample to identify concurrent associations between PTSD symptom severity and the profiled proteins, and to create a multiprotein composite score. In hold-out subsamples, nine bivariate associations between PTSD symptoms and differentially expressed proteins were replicated: SKR3, NCAN, BCAN, MSR1, PVR, TNFRSF21, DRAXIN, CLM6, and SCARB2 (|r| = 0.08–0.17, p < 0.05). There were three replicated bivariate associations between lifetime PTSD diagnosis and differentially expressed proteins: SKR3, SIGLEC, and CPM (OR = 1.38–1.50, p < 0.05). The multiprotein composite score retained 38 proteins, including 10/11 proteins that replicated in bivariate tests. The composite score was significantly associated with PTSD symptom severity (β = 0.27, p < 0.001) and PTSD diagnosis (OR = 1.60, 95% CI: 1.17–2.19, p = 0.003) in the hold-out subsample. Overall, these findings suggest that PTSD is characterized by altered expression of several proteins implicated in neurological processes. Replicated associations with TNFRSF21, CLM6, and PVR support the neuroinflammatory signature of PTSD. The multiprotein composite score substantially increased associations with PTSD symptom severity over individual proteins. If generalizable to other populations, the current findings may inform the development of PTSD biomarkers.

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Section: Discussionmentioning

confidence: 99%

Discovery and replication of blood-based proteomic signature of PTSD in 9/11 responders

et al. 2023

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“…We observed colocalization with only two of these loci: 1) between AD and the expression of FNBP4 in memory B cells (H4 = 0.913) and in CD8+ T cells (H4 = 0.85 and 0.84, for effector and naïve CD8+ T cells, respectively), and 2) between PD and the expression of ARSA in CD8+ effector T cells (H4 = 0.88). FNBP4 (situated approximately 15,000 base pairs away from CELF1) has been previously identified as an AD risk locus (Karch et al, 2016), but in a more recent transcriptome-wide association study (TWAS) of AD, this gene was discarded in conditional analyses (Harwood et al, 2021). ARSA has been previously investigated as a PD risk locus in a Chinese population, in which no significant associations were found with PD susceptibility (Pan et al, 2022).…”

Section: Gene Expression Levels Of Immune-related Genes Share Causal ...mentioning

confidence: 99%

Regional genetic correlations highlight relationships between neurodegenerative diseases and the immune system

Lona-Durazo

Scholz

Ryten

et al. 2022

Preprint

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Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD) and amyotrophic lateral sclerosis (ALS), are devastating complex diseases that result in a physical and psychological burden to patients and their families. There have been significant efforts to understand the genetic basis of neurodegenerative diseases resulting in the identification of disease risk-associated variants involved in several molecular mechanisms, including those that influence immune-related pathways. Regional genetic correlations, in contrast to genome-wide correlations, between pairs of immune and neurodegenerative traits have not been comprehensively explored, but such a regional assessment could shed light on additional immune-mediated risk-associated loci. Here, we systematically assessed the potential role of the immune system in five neurodegenerative diseases, by estimating regional genetic correlations between neurodegenerative diseases and immune-cell-derived single-cell expression quantitative trait loci (sc-eQTLs), using the recently developed method of Local Analysis of [co]Variant Association (LAVA). We used the most recently published genome-wide association studies (GWASes) for five neurodegenerative diseases and publicly available sc-eQTLs derived from 982 individuals from the OneK1K Consortium, capturing aspects of the innate and adaptive immune systems. Additionally, we tested GWASes from well-established immune-mediated diseases, Crohn's disease (CD) and ulcerative colitis (UC), the immune-mediated neurodegenerative disease, multiple sclerosis (MS) and a well-powered GWAS with strong signal in the HLA region, schizophrenia (SCZ), as positive controls. Finally, we also performed regional genetic correlations between diseases and protein levels. We observed significant (FDR < 0.01) regional genetic correlations between sc-eQTLs and neurodegenerative diseases across 151 unique genes, spanning both the innate and adaptive immune systems, across most diseases tested (except for frontotemporal dementia (FTD) and LBD). Colocalization analyses on followed-up regional correlations highlighted immune-related candidate causal risk genes associated with neurodegenerative diseases. We also observed significant regional correlations with protein levels across 156 unique proteins, across all diseases tested, except for FTD. The outcomes of this study will improve our understanding of the immune component of neurodegeneration, which can be potentially used to repurpose existing immunotherapies used in clinical care for other immune-mediated diseases, to slow the progression of neurodegenerative diseases.

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“…To link our preclinical findings in adipose tissue to humans, we overlapped adipose tissue DEGs in the different mice models and with adipose tissue DEGs of women with PCOS (Divoux et al, 2022). The result showed that altered MS4A6E gene expression is shared by all PCOS-like models, a gene that has been shown to be involved in neurodegenerative disorders (Harwood et al, 2021) . Moreover, we found that adult androgen programming has highest number of common DEGs between the ovary and adipose tissue with the lowest number of common DEGs in maternal obesity followed by PNA mouse models.…”

Section: Transcriptomic Interaction Among Hypothalamus Ovary Adipose ...mentioning

confidence: 99%

Transcriptomic mapping of key reproductive and metabolic tissues and oocytes in mouse models of polycystic ovary syndrome

Deng

Yu²,

Risal³

et al. 2022

Preprint

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Excessive androgen production and obesity are key to Polycystic ovary syndrome (PCOS) pathogenesis. PCOS-like mouse models induced by androgen exposure include the prenatal androgenized (PNA), peripubertal androgenized, and overexpression of nerve growth factor in theca cells (17NF), as well as the effect of diet-induced maternal obesity model on offspring. To reveal the molecular features of these models, we performed transcriptomic profiling of the hypothalamus, adipose tissue, ovary, and MII oocytes. The largest number of differentially expressed genes (DEGs) were found in the ovaries of 17NF and in the adipose tissues of peripubertal androgenized models. In contrast, the hypothalamus is most affected in PNA and maternal obesity models suggesting fetal programming effects. The Ms4a6e gene, membrane-spanning 4-domains subfamily A member 6E, a DEG identified in the adipose tissue in all PCOS-like mouse models is also differently expressed in adipose tissue of women with PCOS women, highlighting a conservative disease mechanism. Our comprehensive transcriptomic mapping of key target tissues of the PCOS pathology provides a unique resource when investigating molecular mechanisms induced by androgen exposure and highlights that there are critical windows for androgen administration and maternal obesity.

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Defining functional variants associated with Alzheimer’s disease in the induced immune response

Cited by 21 publications

References 71 publications

Discovery and replication of blood-based proteomic signature of PTSD in 9/11 responders

Discovery and replication of blood-based proteomic signature of PTSD in 9/11 responders

Regional genetic correlations highlight relationships between neurodegenerative diseases and the immune system

Transcriptomic mapping of key reproductive and metabolic tissues and oocytes in mouse models of polycystic ovary syndrome

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