zongchangli / H-MAGMA

H-MAGMA

Authors: Nancy Sey and Hyejung Won Created: 06/14/2019 Updated: 11/26/2019

H_MAGMA.sh

• This file is to run Hi-C coupled MAGMA or H-MAGMA to assign non-coding SNPs to cognate genes. Follow the detailed script below to run H-MAGMA for fetal brain, adult brain and iPSC derived neurons and astrocyte.
  • magma/1.07b/bin/magma: We used MAGMA version 1.07b, downloaded from [MAGMA v1.07b (https://ctg.cncr.nl/software/magma)]
  • --bfiile g1000_eur: Reference file for European population, downloaded from [Reference data (https://ctg.cncr.nl/software/magma)]
  • --pval disorder1_GWAS.txt: P-values from GWAS summary statistics, see below.
  • use=rsid,P: use rsid and P columns in GWAS summary statistics for SNP IDs and P-values, respectively.
  • ncol=N: use N column in GWAS summary statistics for the sample size
  • --gene-annot Fetal_brain.genes.annot: gene-SNP pairs based on the fetal brain Hi-C (provided in this repository in Input_Files folder as Fetal_brain.genes.annot).
  • --gene-annot Adult_brain.genes.annot: gene-SNP pairs based on the adult brain Hi-C (provided in this repository in Input_Files folder as Adult_brain.genes.annot).
  • --gene-annot Neuron.genes.annot: gene-SNP pairs based on the neuronal Hi-C (provided in this repository in Input_Files folder as Neuro.genes.annot).
  • --gene-annot Astro.genes.annot: gene-SNP pairs based on the astrocytic brain Hi-C (provided in this repository in Input_Files folder as Astro.genes.annot).
  • --gene-annot MAGMA.genes.annot: gene-SNP pairs based on conventional MAGMA (provided in this repository in Input_Files folder as MAGMAdefault.genes.annot.gz)
  • --out disorder1_FB: output file name

GWAS summary statistics

• GWAS Reference

  • Attention deficit/hyperactivity disorder (ADHD): Demontis, D. et al.(2019) PMID:30478444

  • Autism spectrum disorder (ASD): Grove, J. et al.(2019) PMID: 30804558

  • Bipolar disorder (BD): Stahl, E. et al.(2019) PMID: 31043756

  • Schizophrenia (SCZ): Pardiñas, A. F. et al.(2018) PMID: 29483656

  • Major depressive disorder (MDD): Howard, D. M. et al.(2019) PMID: 30718901

  • Alzheimer’s disease (AD): Jansen, I. E. et al.(2019) PMID: 30617256

  • Parkinson’s disease (PD): Nalls, M. A. et al.(2019) bioRxiv 388165 doi:10.1101/388165

  • Multiple sclerosis (MS): Andlauer, T. F. M. et al.(2016) PMID: 27386562

  • Amyotrophic lateral sclerosis (ALS): van Rheenen, W. et al.(2016) PMID: 27455348

MAGMA output files

• Output files from H_MAGMA.sh are provided in Output_Files folder as H-MAGMA_Fetal_brain_output.xlsx.; H-MAGMA_Adult_brain_output.xlsx.; H-MAGMA_Neuron_output.xlsx.; H-MAGMA_Astrocyte_output.xlsx.
• Output files from MAGMAdefault.sh are provided in Output_Files folder as MAGMAdefault_output.xlsx.
• Columns
  • GENE: Gene ID
  • CHR: Chromosomal location
  • START: Chromosomal start location of gene
  • STOP: Chromosomal stop location of gene
  • NSNPS: Number of SNPS annotated to gene
  • NPARAM: Number of relevant parameters used in the model
  • N: Sample size
  • ZSTAT: Z-scores derived from P-values
  • P: Gene level P-values

RRHO.R

• This script runs gene-level overlap between two disorders based on Z-scores from H-MAGMA outputs.
• Here we provide an example code using fetal brain Hi-C MAGMA outputs for ADHD and ASD.
• Input files are provided in RRHO_example_input folder as H-MAGMA_ADHD.FB.csv and H-MAGMA_ASD.FB.csv respectively.
  • alternative="enrichment" : One sided test
  • BY=TRUE : P-value corrected by the Benjamini and Yekutieli procedure
  • log10.ind=TRUE : P-value plotted in -log10

Pleiotropic_genes.R

• This file is to identify a set of genes shared among at least 4 disorders.
• To use this file, first run RRHO between pairs of disorders (e.g. ADHD vs ASD/BD/SCZ/MDD; ASD vs BD/SCZ/MDD; BD vs SCZ/MDD; SCZ vs MDD) to obtain most upregulated genes for each comparison. Then intersect gene lists to obtain pleiotropic genes (defined as genes shared in >3 disorder).
  • sharedlist : Most upregulated genes from RRHO. This list gives significantly associated genes in both disorders.
  • HGNC : We have provided geneAnno_allgenes.rda as an input file to convert ENSEMBL gene IDs to HGNC symbols.

Reference

Please cite this paper: Sey, N.Y.A., Hu, B., Mah, W. et al. A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles. Nat Neurosci (2020). https://doi.org/10.1038/s41593-020-0603-0

Adult brain Hi-C: Wang, D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 362, eaat8464 (2018).

Fetal brain Hi-C: Won, H. et al. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538, 523–527 (2016).

iPSC derived neurons and astrocyte : Rajarajan, P. et al. Neuron-specific Signatures in the Chromosomal Connectome Are Associated with Schizophrenia Risk. Science 362, eaat4311 (2018).