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HBA MAGMA

I applied MAGMA to the heart rate recovery GWAS of Verweiji et al.1 using scRNAseq data from the Human Brain Atlas as a reference.

In the plot below, 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. A single independent cluster was found, which is labeled in the plot and listed in detail the table below.

verweiji_independent_plot

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
Cluster398 1.5129e-07 Splatter NEUR VGLUT2 ADCYAP CART CBLN CCK CHGA CHGB GAL NAMPT NUCB NXPH SCG TAC UBL VGF proSAAS 0 Medulla: 86.6%, Pons: 12.8%, Midbrain: 0.2% PHOX2B-AS1, PHOX2B, LINC00682, HOXB3, SLC5A7, SLC6A2, GAL, TH, PHOX2A, HOTAIRM1

This result is striking. Notice that the cell type in the table above is found mostly in the medulla oblongata, a region of the brainstem. The brainstem is a center of autonomic nervous system control. Given that the autonomic nervous system is key to the control of heart rate, it makes physiologic sense that genes associated with heart rate recovery after exercise should be expressed in an autonomic control center.

  1. Niek Verweij, Yordi J van de Vegte, and Pim van der Harst. Genetic study links components of the autonomous nervous system to heart-rate profile during exercise. Nature Communications, 9(1):898, 2018. ↩

  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. ↩