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MAGMA HBA Analysis

I applied MAGMA to the Liu et al.1 GWAS of inflammatory bowel disease using scRNAseq data from the Human Brain Atlas as a reference.

Results

The results are plotted below:

hba-ibd-magma-plot

The x-axis corresponds to HBA cluster number2, 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. I used a conditional analysis approach based on the one described in Wanatabe et al.3 to identify independent clusters. These 2 independent clusters are labeled in plot. I have also listed them in the table below, together with some cluster-annotations from Duncan et al.4.

Retained_clusters P Supercluster Class auto-annotation Neurotransmitter auto-annotation Neuropeptide auto-annotation Subtype auto-annotation Transferred MTG Label Top three regions Top Enriched Genes
Cluster4 4.6356e-14 Microglia MGL 0 NAMPT 0 Micro-PVM Spinal cord: 31.8%, Pons: 26.0%, Medulla: 13.2% SRGN, RGS1, GPR183, CD69, HLA-DRA, OLR1, TNFRSF1B, IFI30, CXCR4, CD74
Cluster1 3.3757e-10 Miscellaneous TCELL 0 0 0 Midbrain: 15.0%, Basal forebrain: 14.0%, Pons: 13.2% CD2, IL7R, PTPRC, SLFN12L, IL32, CCL5, GRAP2, RUNX3, CD69, CD3E
  • Cluster2 (T-cells) is consistent with the known biology of inflammatory bowel disease. The importance of T-cells to inflammatory bowel disease is well known.
  • Cluster4 (Microglia) is more surprising. While there are some ("Gut-Brain-Axis") theories that give a role to the CNS in the development of Crohn's disease, it seems to me more likely that the significance of this cluster in MAGMA analysis is an artifact. Probably, IBD is associated with certain myeloid transcriptional programs, and microglia are the best representatives of these transcriptional programs in the human brain atlas dataset.

  1. Zhanju Liu, Ruize Liu, Han Gao, Seulgi Jung, Xiang Gao, Ruicong Sun, Xiaoming Liu, Yongjae Kim, Ho-Su Lee, Yosuke Kawai, and others. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries. Nature Genetics, 55(5):796–806, 2023. URL: https://www.nature.com/articles/s41588-023-01384-0. ↩

  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. 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. ↩

  4. Laramie E Duncan, Tayden Li, Madeleine Salem, Will Li, Leili Mortazavi, Hazal Senturk, Naghmeh Shahverdizadeh, Sam Vesuna, Hanyang Shen, Jong Yoon, and others. Mapping the cellular etiology of schizophrenia and complex brain phenotypes. Nature Neuroscience, 28(2):248–258, 2025. URL: https://www.nature.com/articles/s41593-024-01834-w. ↩