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Pathway analysis based on GWAS data using Polygenic Risk Score

Introduction

Despite the considerable progress made in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving nearly 80,000 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS.

Overview

We have performed a three-stage study design to identify pathways and cell types relevant to ALS risk

Reference Dataset. A published GWAS study involving 12,577 ALS cases and 23,475 controls (Van Rheenen et al., 2016) https://www.ncbi.nlm.nih.gov/pubmed/27455348

Training Dataset. Plink Binary files containing individual-level data genotype consisting in 5,605 ALS cases and 24,110 control subjects (Nicolas et al., 2018). https://www.ncbi.nlm.nih.gov/pubmed/29566793

Replication Dataset. Plink Binary files containing individual-level data consisting in 2,411 ALS cases and 10,322 controls (Nicolas et al., 2018). https://www.ncbi.nlm.nih.gov/pubmed/29566793

Pathway analysis based on Polygenic Risk Scores using PRSice2

A detailed information about PRSice2 can be found in the following link: https://choishingwan.github.io/PRSice/

Citation: Choi SW, and O’Reilly PF. "PRSice-2: Polygenic Risk Score Software for Biobank-Scale Data." GigaScience 8, no. 7 (July 1, 2019). https://doi.org/10.1093/gigascience/giz082.

Requirements

  • PRSice2_Linux executable (v2.1.1)
  • PLINK v1.90b4.4 64-bit (www.cog-genomics.org/plink/1.9/)
  • PLINK binary files with PCAs and a covariate file. Due to the nature of PRS analysis, it is recommendable to include 20 PCs plus sex plus age.
  • R (version 3.2.3+)

PRSet Specific Input

  • MSigDB file: File containing name of each gene sets and the ID of genes within the gene set on each individual line. If MSigDB is provided, GTF file is required.
  • GTF file: A file contain the genome boundary of each individual gene

Base/Reference file

Summary Stats without overlapping samples with training dataset. We have used a previous published GWAS summary Stats (Van Rheenen et al., 2016) https://www.ncbi.nlm.nih.gov/pubmed/27455348

Training file

Training dataset: Raw genotype data of "target phenotype" in the form of PLINK binary https://www.ncbi.nlm.nih.gov/pubmed/29566793

Testing/Replication dataset: Raw genotype data of "target phenotype" in the form of PLINK binary https://www.ncbi.nlm.nih.gov/pubmed/29566793