Jarod Evert Rutledge

All Publications

• Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell Piehl, N., van Olst, L., Ramakrishnan, A., Teregulova, V., Simonton, B., Zhang, Z., Tapp, E., Channappa, D., Oh, H., Losada, P. M., Rutledge, J., Trelle, A. N., Mormino, E. C., Elahi, F., Galasko, D. R., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., Gate, D. 2022

  Abstract

  Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 Tcells. Clonal CD8T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific Tcell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

  View details for DOI 10.1016/j.cell.2022.11.019

  View details for PubMedID 36516855

• Measuring biological age using omics data. Nature reviews. Genetics Rutledge, J., Oh, H., Wyss-Coray, T. 2022

  Abstract

  Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the ageing process itself to 'rejuvenate' physiological functioning. However, achieving this aim requires measures of biological age and rates of ageing at the molecular level. Spurred by recent advances in high-throughput omics technologies, a new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution. Epigenomic, transcriptomic, proteomic and metabolomic data can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing.

  View details for DOI 10.1038/s41576-022-00511-7

  View details for PubMedID 35715611

• Publisher Correction: Limited proteolysis-mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures. Nature aging Shuken, S. R., Rutledge, J., Iram, T., Losada, P. M., Wilson, E. N., Andreasson, K. I., Leib, R. D., Wyss-Coray, T. 2022; 2 (5): 455

  View details for DOI 10.1038/s43587-022-00225-9

  View details for PubMedID 37118077

• Limited proteolysis-mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures (vol 2, pg 379, 2022) NATURE AGING Shuken, S. R., Rutledge, J., Iram, T., Losada, P., Wilson, E. N., Andreasson, K. I., Leib, R. D., Wyss-Coray, T. 2022; 2 (5): 455

  View details for DOI 10.1038/s43587-022-00225-9

  View details for Web of Science ID 000916578300018

• Limited proteolysis–mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures Nature Aging Shuken, S. R., Rutledge, J., Iram, T., Moran Losada, P., Wilson, E. N., Andreasson, K. I., Leib, R. D., Wyss-Coray, T. 2022

  View details for DOI 10.1038/s43587-022-00196-x

• Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics. American journal of human genetics He, Z., Le Guen, Y., Liu, L., Lee, J., Ma, S., Yang, A. C., Liu, X., Rutledge, J., Losada, P. M., Song, B., Belloy, M. E., Butler, R. R., Longo, F. M., Tang, H., Mormino, E. C., Wyss-Coray, T., Greicius, M. D., Ionita-Laza, I. 2021

  Abstract

  Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in biobank-scale whole-genome sequencing and whole-genome imputed datasets. We propose a scalable knockoff-based method for the analysis of common and rare variants across the genome, KnockoffScreen-AL, that is applicable to biobank-scale studies with hundreds of thousands of samples and millions of genetic variants. The application of KnockoffScreen-AL to the analysis of Alzheimer disease (AD) in 388,051 WG-imputed samples from the UK Biobank resulted in 31 significant loci, including 14 loci that are missed by conventional association tests on these data. We perform replication studies in an independent meta-analysis of clinically diagnosed AD with 94,437 samples, and additionally leverage single-cell RNA-sequencing data with 143,793 single-nucleus transcriptomes from 17 control subjects and AD-affected individuals, and proteomics data from 735 control subjects and affected indviduals with AD and related disorders to validate the genes at these significant loci. These multi-omics analyses show that 79.1% of the proximal genes at these loci and 76.2% of the genes at loci identified only by KnockoffScreen-AL exhibit at least suggestive signal (p < 0.05) in the scRNA-seq or proteomics analyses. We highlight a potentially causal gene in AD progression, EGFR, that shows significant differences in expression and protein levels between AD-affected individuals and healthy control subjects.

  View details for DOI 10.1016/j.ajhg.2021.10.009

  View details for PubMedID 34767756