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MAGMA HBA Analysis

I applied MAGMA to the Diastolic Blood Pressure GWAS of Keaton et al.1 using scRNAseq data from the Human Brain Atlas2 as a reference.

Results

The results are plotted below:

hba_magma_indep_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 3 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
Cluster20 7.291e-13 Vascular VSMC 0 AGT NAMPT UBL 0 Thalamus: 21.8%, Cerebral cortex: 13.7%, Medulla: 12.4% MYL9, CARMN, ADIRF, FHL5, ACTA2, VIM, TBX18, MUSTN1, TBX2, NOTCH3
Cluster57 4.5477e-08 Astrocyte ASTRO 0 AGT 0 Astro Hippocampus: 66.8%, Basal forebrain: 25.3%, Cerebral cortex: 4.0% CD38, OBI1-AS1, FGFR3, AL627316.1, AC012405.1, AL137139.2, TNC, LINC02649, GLI3, SLC14A1
Cluster16 1.4648e-07 Vascular ENDO 0 NAMPT NUCB CAP Endo Cerebral cortex: 25.5%, Hippocampus: 17.8%, Midbrain: 8.4% CLDN5, MECOM, VWF, FLT1, ABCG2, FLI1, NOSTRIN, LINC02147, TGM2, CFH

The significance of Cluster20 and Cluster16, which are auto-annotated as vascular smooth muscle cells (VSMC) and endothelial cells (ENDO) is unsurprising: the importance of vascular cell types to blood pressure is well-known. This finding probably does not reflect brain-specific physiology, but rather the general causal connection between vascular cells and blood pressure.

In contrast, the significance of the astrocyte cell type does reflect brain-specific physiology. As seen in the neuropeptide auto-annotation column in the table above, astrocytes are producers of angiotensinogen (AGT), precursor to angiotensin, which in turn is a key blood-pressure-modulating hormone. There are numerous confirmatory experimental studies demonstrating the role of astrocytes in the control of blood pressure56.

  1. Jacob M Keaton, Zoha Kamali, Tian Xie, Ahmad Vaez, Ariel Williams, Slavina B Goleva, Alireza Ani, Evangelos Evangelou, Jacklyn N Hellwege, Loic Yengo, and others. Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits. Nature Genetics, 56(5):778–791, 2024. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC11096100/. ↩

  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. ↩

  5. Javier E Stern, Sookjin Son, Vinicia C Biancardi, Hong Zheng, Neeru Sharma, and Kaushik P Patel. Astrocytes contribute to angiotensin II stimulation of hypothalamic neuronal activity and sympathetic outflow. Hypertension, 68(6):1483–1493, 2016. URL: https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.116.07747. ↩

  6. Himanshu Verma and Yumei Feng Earley. Emerging roles of astrocytes in autonomic control of blood pressure and hypertension. American Journal of Physiology-Cell Physiology, 329(6):C2013–C2021, 2025. URL: https://journals.physiology.org/doi/full/10.1152/ajpcell.00587.2025. ↩