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RNA sequencing of whole blood reveals early alterations in immune cells and gene expression in Parkinson’s disease

Nature Aging volume 1, pages 734–747 (2021)Cite this article

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Abstract

Changes in the blood-based RNA transcriptome have the potential to inform biomarkers of Parkinson’s disease (PD) progression. Here we sequenced a discovery set of whole-blood RNA species in 4,871 longitudinally collected samples from 1,570 clinically phenotyped individuals from the Parkinson’s Progression Marker Initiative (PPMI) cohort. Samples were sequenced to an average of 100 million read pairs to create a high-quality transcriptome. Participants with PD in the PPMI had significantly altered RNA expression (>2,000 differentially expressed genes), including an early and persistent increase in neutrophil gene expression, with a concomitant decrease in lymphocyte cell counts. This was validated in a cohort from the Parkinson’s Disease Biomarkers Program (PDBP) consisting of 1,599 participants and by alterations in immune cell subtypes. This publicly available transcriptomic dataset, coupled with available detailed clinical data, provides new insights into PD biological processes impacting whole blood and new paths for developing diagnostic and prognostic PD biomarkers.

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Fig. 1: Samples and analysis overview and QC.
Fig. 2: Variance analysis by covariates.
Fig. 3: Differential expression in patients with PD versus controls.
Fig. 4: Cell count percentage in the PPMI cohort and genes enriched in neutrophils and lymphocytes in the PPMI and PDBP cohorts.
Fig. 5: Cell count percentage and genes enriched in neutrophils and in different types of PD represented in the PPMI cohort.
Fig. 6: Neutrophil gene expression increases over time in prodromal participants.

Data availability

Raw sequencing data (FASTQ files), alignment files (BAM files), TPM data and counts for each sample are available at the LONI IDA. (https://fairsharing.org/, IDA; LONI IDA, https://doi.org/10.25504/FAIRsharing.r4ph5f). Data are also available through the AMP PD (https://amp-pd.org/). These are the requirements for downloading from the AMP PD: (1) personal and institutional or company details; (2) description of intended data use, for example, proposed analyses; (3) institutional signature on the AMP PD Data Use Agreement (for researchers requesting access to individual-level, ’omics data). Additional data, including but not limited to study arm, motor assessments, DaTscan and MRI imaging, genetic testing results, whole-exome and genome sequencing data, patient history and standardized techniques and protocols for data collection are also available through the IDA. To access complete data, researchers need to fill out a data-use agreement. Data are available in a public (institutional, general or participant-specific) repository that does not issue datasets with DOIs (non-mandated deposition).

Code availability

All code used for data analysis is available at GitHub: https://github.com/tgen/ppmi-qc-wt-paper and https://github.com/tgen/ppmi-rnaseq-wb-paper.

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Acknowledgements

This research was supported and funded by the MJFF under grant numbers 12749 (K.V.K.-J.), 12749.01 (K.V.K.-J., M.R.C.) and 14696 (K.V.K.-J., A.K., D.W.C.). Many MJFF staff assisted in harmonizing and transferring data. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Data used in the preparation of this article were obtained from the PPMI database (https://www.ppmi-info.org/data). For up-to-date information on the study, visit https://www.ppmi-info.org/. We also acknowledge industry partners of the PPMI: AbbVie, Allergan, Amathus Therapeutics, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol Myers Squibb, Celgene, Denali, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily and Voyager Therapeutics. We also thank the AMP PD for allowing us access to PDBP data. The PDBP consortium is supported by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/policy. PDBP investigators have not participated in reviewing the data analysis or content of the text. Data used in the preparation of this article were obtained from the AMP PD Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org. The AMP PD, a public–private partnership, is managed by the FNIH and funded by Celgene, GlaxoSmithKline, the MJFF, the National Institute of Neurological Disorders and Stroke, Pfizer, Sanofi and Verily. We thank all people with PD and families for participating in the study and donating their samples and time. We would like to thank the group at IU for RNA isolation, QC metrics and safe shipment of samples. We thank the group at the HAIB for running sequencing and sample tracking.

Author information

Author notes

  1. These authors contributed equally: David W. Craig, Elizabeth Hutchins.

  2. A full list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Institute of Translational Genomics, University of Southern California, Los Angeles, CA, USA

    David W. Craig & Ivo Violich

  2. Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA

    Elizabeth Hutchins, Eric Alsop, Timothy G. Whitsett, Kendall Van Keuren-Jensen & Kendall Van Keuren-Jensen

  3. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    J. Raphael Gibbs & Mark R. Cookson

  4. HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA

    Shawn Levy, Madison Robison & Nripesh Prasad

  5. Indiana University, Indianapolis, IN, USA

    Tatiana Foroud

  6. Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    Karen L. Crawford & Arthur W. Toga

  7. Center for Computational Systems Biology, Department of Electrical and Computer Engineering, Roy G. Perry College of Engineering, Prairie View A&M University, Prairie View, TX, USA

    Seungchan Kim

  8. The Michael J. Fox Foundation for Parkinson’s Research, New York, NY, USA

    Bradford Casey, Alyssa Reimer, Samantha J. Hutten, Mark Frasier & Samantha Hutten

  9. Chair for Clinical Bioinformatics, Saarland University, Saarbrücken, Germany

    Fabian Kern, Tobias Fehlman & Andreas Keller

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Consortia

Parkinson Progression Marker Initiative

  • David W. Craig
  • , Tatiana Foroud
  • , Karen L. Crawford
  • , Arthur W. Toga
  • , Bradford Casey
  • , Alyssa Reimer
  • , Samantha Hutten
  • , Mark Frasier
  • , Mark R. Cookson
  •  & Kendall Van Keuren-Jensen

Contributions

D.W.C., E.H., I.V., E.A., J.R.G., T.G.W., B.C., A.R., S.H., M.F., A.K., M.R.C. and K.V.K.-J. each contributed to the overall study design. D.W.C., E.H., I.V., E.A., S.K., F.K., T. Fehlman, A.K., M.R.C. and K.V.K.-J. each contributed to primary data analysis, including statistical evaluation. D.W.C., E.H., I.V., E.A., K.L.C. and A.W.T. contributed to data organization and data storage. T. Foroud, S.L. and M.R. each contributed to nucleic acid isolation and sequencing. D.W.C., E.H., T.G.W., M.R.C. and K.V.K.-J. each substantially contributed to writing the manuscript. All authors contributed to data interpretation and review and editing of the manuscript.

Corresponding author

Correspondence to Kendall Van Keuren-Jensen.

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Competing interests

B.C., S.H., A.R. and M.F. are employees of the MJFF. E.H., D.W.C., I.V., E.A., K.L.C., A.W.T. and K.V.K.-J. are funded by the MJFF. The other authors declare no competing interests.

Additional information

Peer review information Nature Aging thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

PPMI author list and Supplementary Methods, Figs. 1–10 and Table 2.

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Supplementary Tables 1 and 3–11.

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Craig, D.W., Hutchins, E., Violich, I. et al. RNA sequencing of whole blood reveals early alterations in immune cells and gene expression in Parkinson’s disease. Nat Aging 1, 734–747 (2021). https://doi.org/10.1038/s43587-021-00088-6

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