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  • Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3. Alzheimer's & dementia : the journal of the Alzheimer's Association Panyard, D. J., Reus, L. M., Ali, M., Liu, J., Deming, Y. K., Lu, Q., Kollmorgen, G., Carboni, M., Wild, N., Visser, P. J., Bertram, L., Zetterberg, H., Blennow, K., Gobom, J., Western, D., Sung, Y. J., Carlsson, C. M., Johnson, S. C., Asthana, S., Cruchaga, C., Tijms, B. M., Engelman, C. D., Snyder, M. P. 2024

    Abstract

    Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear.We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269).CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10-5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10-7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10-6) and CSF p-tau levels (P = 4.38 × 10-9).These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels.Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.

    View details for DOI 10.1002/alz.13848

    View details for PubMedID 38809917

  • Assessing the Biological Mechanisms Linking Smoking Behavior and Cognitive Function: A Mediation Analysis of Untargeted Metabolomics. Metabolites Choi, J. J., Koscik, R. L., Jonaitis, E. M., Panyard, D. J., Morrow, A. R., Johnson, S. C., Engelman, C. D., Schmitz, L. L. 2023; 13 (11)

    Abstract

    (1) Smoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which have both been linked to the development of Alzheimer's disease and related dementias (ADRD). This study identified potential mechanisms of the smoking-cognitive function relationship using metabolomics data from the longitudinal Wisconsin Registry for Alzheimer's Prevention (WRAP). (2) 1266 WRAP participants were included to assess the association between smoking status and four cognitive composite scores. Next, untargeted metabolomic data were used to assess the relationships between smoking and metabolites. Metabolites significantly associated with smoking were then tested for association with cognitive composite scores. Total effect models and mediation models were used to explore the role of metabolites in smoking-cognitive function pathways. (3) Plasma N-acetylneuraminate was associated with smoking status Preclinical Alzheimer Cognitive Composite 3 (PACC3) and Immediate Learning (IMM). N-acetylneuraminate mediated 12% of the smoking-PACC3 relationship and 13% of the smoking-IMM relationship. (4) These findings provide links between previous studies that can enhance our understanding of potential biological pathways between smoking and cognitive function.

    View details for DOI 10.3390/metabo13111154

    View details for PubMedID 37999250

    View details for PubMedCentralID PMC10673384

  • Unique genetic architecture of CSF and brain metabolites pinpoints the novel targets for the traits of human wellness. Research square Wang, C., Western, D., Yang, C., Ali, M., Wang, L., Gorijala, P., Timsina, J., Ruiz, A., Pastor, P., Fernandez, M., Panyard, D., Engelman, C., Deming, Y., Boada, M., Cano, A., García-González, P., Graff-Radford, N., Mori, H., Lee, J. H., Perrin, R., Sung, Y. J., Cruchaga, C. 2023

    Abstract

    Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson's Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions.

    View details for DOI 10.21203/rs.3.rs-2923409/v1

    View details for PubMedID 37333177

    View details for PubMedCentralID PMC10274943

  • Multi-omics microsampling for the profiling of lifestyle-associated changes in health. Nature biomedical engineering Shen, X., Kellogg, R., Panyard, D. J., Bararpour, N., Castillo, K. E., Lee-McMullen, B., Delfarah, A., Ubellacker, J., Ahadi, S., Rosenberg-Hasson, Y., Ganz, A., Contrepois, K., Michael, B., Simms, I., Wang, C., Hornburg, D., Snyder, M. P. 2023

    Abstract

    Current healthcare practices are reactive and use limited physiological and clinical information, often collected months or years apart. Moreover, the discovery and profiling of blood biomarkers in clinical and research settings are constrained by geographical barriers, the cost and inconvenience of in-clinic venepuncture, low sampling frequency and the low depth of molecular measurements. Here we describe a strategy for the frequent capture and analysis of thousands of metabolites, lipids, cytokines and proteins in 10 μl of blood alongside physiological information from wearable sensors. We show the advantages of such frequent and dense multi-omics microsampling in two applications: the assessment of the reactions to a complex mixture of dietary interventions, to discover individualized inflammatory and metabolic responses; and deep individualized profiling, to reveal large-scale molecular fluctuations as well as thousands of molecular relationships associated with intra-day physiological variations (in heart rate, for example) and with the levels of clinical biomarkers (specifically, glucose and cortisol) and of physical activity. Combining wearables and multi-omics microsampling for frequent and scalable omics may facilitate dynamic health profiling and biomarker discovery.

    View details for DOI 10.1038/s41551-022-00999-8

    View details for PubMedID 36658343

  • Liver-Specific Polygenic Risk Score Is Associated with Alzheimer's Disease Diagnosis JOURNAL OF ALZHEIMERS DISEASE Panyard, D. J., Deming, Y. K., Darst, B. F., Van Hulle, C. A., Zetterberg, H., Blennow, K., Kollmorgen, G., Suridjan, I., Carlsson, C. M., Johnson, S. C., Asthana, S., Engelman, C. D., Lu, Q. 2023; 92 (2): 395-409

    Abstract

    Our understanding of the pathophysiology underlying Alzheimer's disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models.We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers.We built 13 tissue-specific AD PRS and studied the scores' relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD.The AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS: n = 1,115; odds ratio = 2.15 (1.67-2.78), p = 3.62×10-9. The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ42:Aβ40 ratio, p = 3.53×10-6) and the phosphorylated tau:amyloid-β ratio (p = 1.45×10-5).These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.

    View details for DOI 10.3233/JAD-220599

    View details for Web of Science ID 000952023800002

    View details for PubMedID 36744333

    View details for PubMedCentralID PMC10050104

  • The metabolomics of human aging: Advances, challenges, and opportunities. Science advances Panyard, D. J., Yu, B., Snyder, M. P. 2022; 8 (42): eadd6155

    Abstract

    As the global population becomes older, understanding the impact of aging on health and disease becomes paramount. Recent advancements in multiomic technology have allowed for the high-throughput molecular characterization of aging at the population level. Metabolomics studies that analyze the small molecules in the body can provide biological information across a diversity of aging processes. Here, we review the growing body of population-scale metabolomics research on aging in humans, identifying the major trends in the field, implicated biological pathways, and how these pathways relate to health and aging. We conclude by assessing the main challenges in the research to date, opportunities for advancing the field, and the outlook for precision health applications.

    View details for DOI 10.1126/sciadv.add6155

    View details for PubMedID 36260671

  • Cerebrospinal Fluid Sphingomyelins in Alzheimer's Disease, Neurodegeneration, and Neuroinflammation. Journal of Alzheimer's disease : JAD Morrow, A., Panyard, D. J., Deming, Y. K., Jonaitis, E., Dong, R., Vasiljevic, E., Betthauser, T. J., Kollmorgen, G., Suridjan, I., Bayfield, A., Van Hulle, C. A., Zetterberg, H., Blennow, K., Carlsson, C. M., Asthana, S., Johnson, S. C., Engelman, C. D. 2022

    Abstract

    BACKGROUND: Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available.OBJECTIVE: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation.METHODS: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models.RESULTS: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, alpha-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs.CONCLUSION: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.

    View details for DOI 10.3233/JAD-220349

    View details for PubMedID 36155504