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MAGMA HBA Analysis

I applied MAGMA1 to the GWAS of whole brainstem volume of Xue et al.2 using scRNAseq data from the Human Brain Atlas3 as a reference.

The results are plotted below:

Result of HBA MAGMA applied to Xue et al.'s whole brainstem volume GWAS. The x-axis corresponds to HBA cluster number, while the y-axis corresponds to the negative log p value generated by MAGMA. Clusters are colored according to their HBA supercluster. The dotted line denotes the Bonferroni significance threshold.

I also used a conditional analysis approach based on the one described in Watanabe et al.4 to identify independent clusters. These clusters are shown in the table and plot below.

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
Cluster288 3.5812e-09 CGE interneuron NEUR GABA CBLN CCK CHGA CHGB CORT CRH IGF NAMPT NUCB NXPH SCG UBL proSAAS INT-LAMP5 Lamp5 Cerebral cortex: 70.6%, Amygdala: 13.7%, Hippocampus: 6.3% HAPLN1, AC137770.1, LINC00298, AC132803.1, KIT, PKP2, EYA4, ROR2, NXPH2, GRPR
Cluster56 6.7711e-08 Astrocyte ASTRO 0 AGT 0 Astro Hypothalamus: 30.0%, Thalamus: 21.5%, Amygdala: 14.3% TNC, GFAP, OBI1-AS1, FGFR3, GJA1, AC012405.1, EFEMP1, AQP4, SLC14A1, ETNPPL
Cluster262 2.4462e-07 MGE interneuron NEUR GABA CCK CHGA CHGB CORT IGF NAMPT NMU NPPC NUCB NXPH PNOC SCG TAC UBL VGF proSAAS INT-PVALB Pvalb Cerebral cortex: 94.5%, Basal forebrain: 2.1%, Hippocampus: 1.8% RNF144B, AL136114.1, PRDM1, SULF1, LRRC38, TCIM, WNT16, MYO5B, KCNS3, AL096865.1
Cluster42 1.9051e-06 Committed oligodendrocyte precursor OLIGO 0 0 0 Thalamus: 92.7%, Midbrain: 2.3%, Pons: 1.5% CNDP1, LINC01608, GREM1, OPALIN, FA2H, AC110285.1, MYRF, CD22, LINC01792, LINC00906
Cluster37 1.3184e-05 Committed oligodendrocyte precursor OLIGO 0 NXPH proSAAS COP OPC Cerebral cortex: 35.6%, Hippocampus: 19.5%, Amygdala: 8.2% GPR17, AL512308.1, TNS3, BCAS1, MIR503HG, AC008080.4, NKX2-2, GPNMB, INAVA, FIBIN

xue_indep_cluster_plot

One would expect that the key cell types determining brainstem volume would be substantially over-represented in the brainstem. This does not seem to be the case. Instead, MAGMA has found 5 independently significant cell types: two interneuron types found mainly in the cerebral cortex, two oligodendrocyte precursor cell types found mostly in the thalamus and cerebral cortex, and one astrocyte cell type found mainly in the thalamus and hypothalamus. Since the GWAS considered here is of overall brainstem volume, it is possible that these results reflect correlation between brain regions. i.e. the GWAS has identified genes that contribute to the volume of multiple brain regions, of which the brainstem is only one.

  1. Christiaan A De Leeuw, Joris M Mooij, Tom Heskes, and Danielle Posthuma. MAGMA: generalized gene-set analysis of GWAS data. PLoS Computational Biology, 11(4):e1004219, 2015. URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004219. ↩

  2. Hui Xue, Jilian Fu, Zuojun Geng, Jingliang Cheng, Meiyun Wang, Longjiang Zhang, Guangbin Cui, Yongqiang Yu, Weihua Liao, Hui Zhang, and others. The genetic architecture of brainstem structures. Nature Communications, 2025. URL: https://www.nature.com/articles/s41467-025-67221-6_reference.pdf. ↩

  3. 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. ↩

  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. ↩