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MAGMA HBA

I applied MAGMA to the Alzheimer's GWAS of Bellenguez et al.1 using scRNAseq data from the Human Brain Atlas2 as a reference.

Results

The results are plotted below:

hba-magma-alz

The x-axis corresponds to HBA cluster number, while the y-axis corresponds to the \(-\log_{10}(p)\) score produced by MAGMA. Clusters are colored according to their HBA supercluster. The dotted line denotes the Bonferroni significance threshold.

Almost all of the Bonferroni-significant cell types are in the microglia supercluster. The only exception is a single monocyte cell type. This is consistent with the theory of Alzheimer's as a primarily microglia-driven disease (see pg. 1205 of Kandel et al.3).

Applying a stepwise selection algorithm similar to the one describe in Watanabe et al.4 identifies only a single independently significant cluster: Cluster 12, which consists of microglial cells.

  1. Céline Bellenguez, Fahri Küçükali, Iris E Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C Naj, Rafael Campos-Martin, Benjamin Grenier-Boley, Victor Andrade, and others. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nature Genetics, 54(4):412–436, 2022. URL: https://www.nature.com/articles/s41588-022-01024-z. ↩

  2. Kimberly Siletti, Rebecca Hodge, Alejandro Mossi Albiach, Ka Wai Lee, Song-Lin Ding, Lijuan Hu, Peter Lönnerberg, Trygve Bakken, Tamara Casper, Michael Clark, and others. Transcriptomic diversity of cell types across the adult human brain. Science, 382(6667):eadd7046, 2023. URL: https://www.science.org/doi/abs/10.1126/science.add7046. ↩

  3. Eric R. Kandel, John D. Koester, and Steven A. Mack, Sarah H. Siegelbaum. Principles of neural science 6th edition. Elsevier New York, 2021. URL: https://www.amazon.ca/Principles-Neural-Science-Sixth-Kandel-ebook-dp-B08LNXDCS3/dp/B08LNXDCS3. ↩

  4. Kyoko Watanabe, Maša Umićević Mirkov, Christiaan A de Leeuw, Martijn P van den Heuvel, and Danielle Posthuma. Genetic mapping of cell type specificity for complex traits. Nature Communications, 10(1):3222, 2019. URL: https://www.nature.com/articles/s41467-019-11181-1. ↩