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The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion

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Abstract

Apart from amyloid β deposition and tau neurofibrillary tangles, Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and astrocytosis in the cerebral cortex. The goal of this study is to investigate genetic factors associated with the neuronal proportion in health and disease. To identify cell-autonomous genetic variants associated with neuronal proportion in cortical tissues, we inferred cellular population structure from bulk RNA-Seq derived from 1536 individuals. We identified the variant rs1990621 located in the TMEM106B gene region as significantly associated with neuronal proportion (p value = 6.40 × 10−07) and replicated this finding in an independent dataset (p value = 7.41 × 10−04) surpassing the genome-wide threshold in the meta-analysis (p value = 9.42 × 10−09). This variant is in high LD with the TMEM106B non-synonymous variant p.T185S (rs3173615; r2 = 0.98) which was previously identified as a protective variant for frontotemporal lobar degeneration (FTLD). We stratified the samples by disease status, and discovered that this variant modulates neuronal proportion not only in AD cases, but also several neurodegenerative diseases and in elderly cognitively healthy controls. Furthermore, we did not find a significant association in younger controls or schizophrenia patients, suggesting that this variant might increase neuronal survival or confer resilience to the neurodegenerative process. The single variant and gene-based analyses also identified an overall genetic association between neuronal proportion, AD and FTLD risk. These results suggest that common pathways are implicated in these neurodegenerative diseases, that implicate neuronal survival. In summary, we identified a protective variant in the TMEM106B gene that may have a neuronal protection effect against general aging, independent of disease status, which could help elucidate the relationship between aging and neuronal survival in the presence or absence of neurodegenerative disorders. Our findings suggest that TMEM106B could be a potential target for neuronal protection therapies to ameliorate cognitive and functional deficits.

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Data availability

The meta-analysis results can be accessed interactively through our Online Neurodegenerative Trait Integrative Multi-Omics Explorer (ONTIME): http://ngi.pub:5000/pheno/Neuron_QTL. Knight ADRC: https://www.synapse.org/#!Synapse:syn12181323. According to the data request terms, DIAN data are available upon request: http://dian.wustl.edu. Mayo: https://www.synapse.org/#!Synapse:syn5550404. MSSM: https://www.synapse.org/#!Synapse:syn3157743. ROSMAP: https://www.synapse.org/#!Synapse:syn3219045. CommonMind: https://www.synapse.org/#!Synapse:syn2759792. GTEx: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000424.v7.p2.

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Acknowledgements

We thank all the participants and their families, as well as the many institutions and their staff that provided support for the studies involved in this collaboration. We also thank Dr. Jae Hoon Sul for his help with the Meta-Tissue analysis applied in this study.

Funding

This work was supported by Grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, R01AG057777, and U01AG058922), the Alzheimer’s Association (NIRG-11-200110, BAND-14-338165, AARG-16-441560 and BFG-15-362540). BAB is supported by 2018 pilot funding from the Hope Center for Neurological Disorders and the Danforth Foundation Challenge at Washington University. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine. DIAN: Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer’s Network (DIAN, UF1AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), and the Raul Carrea Institute for Neurological Research (FLENI). Partial support was provided by the Research and Development Grants for Dementia from the Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI). This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. Mayo RNAseq: Study data were provided by the following sources: The Mayo Clinic Alzheimer’s Disease Genetic Studies, led by Dr. Nilufer Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer’s Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA Grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. MSBB: These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine.

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Author notes

  1. Oscar Harari and Carlos Cruchaga are contributed equally.

Authors and Affiliations

  1. Department of Psychiatry, BJC Institute of Heath, Washington University School of Medicine, 425 S. Euclid Ave., Box 8134, St. Louis, MO, 63110, USA

    Zeran Li, Fabiana H. G. Farias, Umber Dube, Jorge L. Del-Aguila, Kathie A. Mihindukulasuriya, Maria Victoria Fernandez, Laura Ibanez, John P. Budde, Fengxian Wang, James Perez, Chengran Yang, Jorge A. Bahena, Wei Qin, Joseph L. Bradley, Richard Davenport, Kristy Bergmann, John C. Morris, Richard J. Perrin, Bruno A. Benitez, Joseph D. Dougherty, Oscar Harari & Carlos Cruchaga

  2. NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, USA

    Zeran Li, Fabiana H. G. Farias, Umber Dube, Jorge L. Del-Aguila, Kathie A. Mihindukulasuriya, Maria Victoria Fernandez, Laura Ibanez, John P. Budde, Fengxian Wang, James Perez, Chengran Yang, Jorge A. Bahena, Joseph L. Bradley, Richard Davenport, Kristy Bergmann, Bruno A. Benitez, Oscar Harari & Carlos Cruchaga

  3. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA

    Zeran Li, Fabiana H. G. Farias, Umber Dube, Jorge L. Del-Aguila, Kathie A. Mihindukulasuriya, Maria Victoria Fernandez, Laura Ibanez, John P. Budde, Fengxian Wang, James Perez, Chengran Yang, Jorge A. Bahena, Joseph L. Bradley, Richard Davenport, Kristy Bergmann, Bruno A. Benitez, Oscar Harari & Carlos Cruchaga

  4. Vanderbilt University Medical Scientist Training Program, Nashville, TN, USA

    Allison M. Lake

  5. Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA

    Yuetiva Deming

  6. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China

    Wei Qin

  7. The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    John C. Morris & Richard J. Perrin

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  1. Zeran Li
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Contributions

ZL analyzed the data and wrote the manuscript. FGF performed the genotype QC, imputation, and merging. ZL, UB, JLD, KAM, JPB, OH, CC performed the RNA-Seq data preprocessing and QC. ZL, UB, JLD, KAM, JPB, FW, OH, CC performed the public data assembly and phenotype QC. ZL, FGF, UD, JLD, KAM, MVF, LI, JPB, AML, YD, JP, CY, JAB contributed to the analysis pipeline applied in the study. ZL, FGF, UD, JLD, KAM, MVF, LI, JPB, YD, JP, CY, JAB, QW, BAB, JDD, OH, CC contributed to the result interpretation. JLB, RD, KB, JPB, BAB contributed to the genotype and RNA-Seq data generation. JCM and PJP provided the Knight ADRC data. CC, OH, JDD, ZL designed the study. CC supervised the project. All authors read and approved the manuscript.

Corresponding author

Correspondence to Carlos Cruchaga.

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Conflict of interest

CC receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, interpretation of data; or in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of ADx Healthcare and Vivid Genomics.

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Li, Z., Farias, F.H.G., Dube, U. et al. The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion. Acta Neuropathol 139, 45–61 (2020). https://doi.org/10.1007/s00401-019-02066-0

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