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bioRxiv · 10.1101/583286

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

Li, Z.·Farias, F. G.·Dube, U.·Del Aguila, J. L. L.·Mihindukulasuriya, K. A.·Fernandez, M.-V. V.·Ibanez, L.·Budde, J. P.·Wang, F.·Lake, A. M.·Robles, Y.·Perez, J.·Yang, C.·Bradley, J.·Davenport, R.·Bergmann, K.·Benitez, B. A. A.·Dougherty, J. D.·Harari, O.·Cruchaga, C.
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Abstract

BackgroundIn previous studies, we observed decreased neuronal and increased astrocyte proportions in AD cases in parietal brain cortex by using a deconvolution method for bulk RNA-seq. These findings suggested that genetic risk factors associated with AD etiology have a specific effect in the cellular composition of AD brains. The goal of this study is to investigate if there are genetic determinants for brain cell compositions.\n\nMethodsUsing cell type composition inferred from transcriptome as a disease status proxy, we performed cell type association analysis to identify novel loci related to cellular population changes in disease cohort. We imputed and merged genotyping data from seven studies in total of 1,669 samples and derived major CNS cell type proportions from cortical RNAseq data. We also inferred RNA transcript integrity number (TIN) to account for RNA quality variances. The model we performed in the analysis was: normalized neuronal proportion [~] SNP + Age + Gender + PC1 + PC2 + median TIN.\n\nResultsA variant rs1990621 located in the TMEM106B gene region was significantly associated with neuronal proportion (p=6.40x10-07) and replicated in an independent dataset. The association became more significant as we combined both discovery and replication datasets in multi-tissue meta-analysis (p=9.42x10-09) and joint analysis (p=7.66x10-10). This variant is in high LD with rs1990622 (r2 = 0.98) which was previously identified as a protective variant in FTD cohorts. Further analyses indicated that this variant is associated with increased neuronal proportion in participants with neurodegenerative disorders, not only in AD cohort but also in cognitive normal elderly cohort. However, this effect was not observed in a younger schizophrenia cohort with a mean age of death < 65. The second most significant loci for neuron proportion was APOE, which suggested that using neuronal proportion as an informative endophenotype could help identify loci associated with neurodegeneration.\n\nConclusionThis result suggested a common pathway involving TMEM106B shared by aging groups in the present or absence of neurodegenerative pathology may contribute to cognitive preservation and neuronal protection.

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Li, Z., Farias, F. G., Dube, U., Del Aguila, J. L. L., Mihindukulasuriya, K. A., Fernandez, M.-V. V., Ibanez, L., Budde, J. P., Wang, F., Lake, A. M., Robles, Y., Perez, J., Yang, C., Bradley, J., Davenport, R., Bergmann, K., Benitez, B. A. A., Dougherty, J. D., Harari, O., Cruchaga, C.. 2019-03-20. The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion. https://doi.org/10.1101/583286

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