TY - JOUR
T1 - The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion
AU - Li, Zeran
AU - Farias, Fabiana H.G.
AU - Dube, Umber
AU - Del-Aguila, Jorge L.
AU - Mihindukulasuriya, Kathie A.
AU - Fernandez, Maria Victoria
AU - Ibanez, Laura
AU - Budde, John P.
AU - Wang, Fengxian
AU - Lake, Allison M.
AU - Deming, Yuetiva
AU - Perez, James
AU - Yang, Chengran
AU - Bahena, Jorge A.
AU - Qin, Wei
AU - Bradley, Joseph L.
AU - Davenport, Richard
AU - Bergmann, Kristy
AU - Morris, John C.
AU - Perrin, Richard J.
AU - Benitez, Bruno A.
AU - Dougherty, Joseph D.
AU - Harari, Oscar
AU - Cruchaga, Carlos
N1 - Funding Information:
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. Acknowledgements
Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - Complex traits
KW - Cortex
KW - Deconvolution
KW - GWAS
KW - Neurodegeneration
KW - QTL
UR - http://www.scopus.com/inward/record.url?scp=85071644728&partnerID=8YFLogxK
U2 - 10.1007/s00401-019-02066-0
DO - 10.1007/s00401-019-02066-0
M3 - Article
C2 - 31456032
AN - SCOPUS:85071644728
SN - 0001-6322
VL - 139
SP - 45
EP - 61
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 1
ER -