Nothing
R/analyze.R
In xQTLbiolinks: An R Package for Integrative Analysis of Quantitative Trait Locus Data of 'xQTL'
Defines functions
xQTLanalyze_getSentinelSnp
Documented in
xQTLanalyze_getSentinelSnp
#' @title Detect sentinel SNPs for GWAS using summary statistics data
#' @description
#' Return sentinel snps whose pValue < 5e-8(default) and SNP-to-SNP distance > 1e6 bp.
#' @param gwasDF A data.frame or a data.table object. Five columns are required (arbitrary column names is supported):
#'
#' `Col 1`. "snps" (character), , using an rsID (e.g. "rs11966562").
#'
#' `Col 2`. "chromosome" (character), one of the chromosome from chr1-chr22.
#'
#' `Col 3`. "postion" (integer), genome position of snp.
#'
#' `Col 4`. "P-value" (numeric).
#'
#' `Col 5`. "MAF" (numeric). Allel frequency.
#'
#' `Col 6`. "beta" (numeric). effect size.
#'
#' `Col 7`. "se" (numeric). standard error.
#'
#' @param pValueThreshold Cutoff of gwas p-value. Default: 5e-8
#' @param centerRange SNP-to-SNP distance. Default:1e6
#' @param mafThreshold Cutoff of maf to remove rare variants.
#' @param genomeVersion Genome version of input file. "grch37" or "grch38" (default).
#' @param grch37To38 TRUE or FALSE, we recommend converting grch37 to grch38, or using a input file of grch38 directly. Package `rtracklayer` is required.
#' @import data.table
#' @import stringr
#' @importFrom GenomicRanges GRanges
#' @importFrom IRanges IRanges ranges
#' @importFrom GenomeInfoDb seqnames
#' @return A data.table object.
#' @export
#'
#' @examples
#' \donttest{
#' url<-"http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/GLGC.txt"
#' gwasDF <- data.table::fread(url)
#' gwasDF <- gwasDF[, .(rsid, chr, position, P, maf, beta, se)]
#' sentinelSnpDF <- xQTLanalyze_getSentinelSnp(gwasDF)
#' }
xQTLanalyze_getSentinelSnp <- function(gwasDF, pValueThreshold=5e-8, centerRange=1e6, mafThreshold = 0.01, genomeVersion="grch38", grch37To38 = FALSE){
position <- pValue <- maf <- rsid <- chr <- se <- NULL
.<-NULL
# Detect gene with sentinal SNP:
gwasDF <- gwasDF[,1:7]
data.table::setDT(gwasDF)
message("== Preparing GWAS dataset... ")
names(gwasDF) <- c("rsid", "chr", "position", "pValue", "maf", "beta", "se")
gwasDF <- na.omit(gwasDF)
# chromosome revise：
if( !str_detect(gwasDF[1,]$chr, regex("^chr")) ){
gwasDF$chr <- paste0("chr", gwasDF$chr)
}
# convert variable class:
gwasDF[,c("position", "pValue", "maf", "beta", "se")] <- gwasDF[,.(position=as.numeric(position), pValue=as.numeric(pValue), maf=as.numeric(maf), beta=as.numeric(beta), se=as.numeric(se))]
# MAF filter:
gwasDF <- gwasDF[maf > mafThreshold & maf<1,]
# 去重：
# gwasDF <- gwasDF[order(rsid, pValue)][!duplicated(rsid)]
# retain SNPs with rs id:
# gwasDF <- gwasDF[stringr::str_detect(rsid,stringr::regex("^rs")),]
####################### convert hg19 to hg38:
if(genomeVersion =="grch37" & grch37To38){
message("== Converting SNPs' coordinate to GRCH38... ")
if(suppressMessages(!requireNamespace("rtracklayer"))){
message("Package [rtracklayer] is not installed! please install [rtracklayer] with following: ")
message("---------")
message('\"if (!require("BiocManager", quietly = TRUE)); BiocManager::install("rtracklayer")\"')
message("---------")
}
path = system.file(package="xQTLbiolinks", "extdata", "hg19ToHg38.over.chain")
ch = rtracklayer::import.chain(path)
gwasRanges <- GenomicRanges::GRanges(gwasDF$chr,
IRanges::IRanges(gwasDF$position, gwasDF$position),
strand= "*",
gwasDF[,.(rsid, maf, pValue, beta, se)]
)
gwasRanges_hg38 <- unlist(rtracklayer::liftOver(gwasRanges, ch))
# retain the SNPs located in chromosome 1:22
gwasRanges_hg38 <- gwasRanges_hg38[which(as.character(GenomeInfoDb::seqnames(gwasRanges_hg38)) %in% paste0("chr", 1:22)),]
gwasDF <- cbind(data.table(rsid = gwasRanges_hg38$rsid, maf=gwasRanges_hg38$maf, pValue=gwasRanges_hg38$pValue, beta = gwasRanges_hg38$beta, se = gwasRanges_hg38$se),
data.table::data.table(chr = as.character(GenomeInfoDb::seqnames(gwasRanges_hg38)), position=as.data.table(IRanges::ranges(gwasRanges_hg38))$start ))
gwasDF <- gwasDF[,.(rsid, chr, position, pValue, maf, beta, se)]
message("== ",length(gwasRanges_hg38),"/",nrow(gwasDF)," left.")
rm(gwasRanges, gwasRanges_hg38)
}else if(genomeVersion =="grch38" & grch37To38){
stop("Only grch37 genome version can be converted to grch38!")
}else if(!genomeVersion %in% c("grch38", "grch37")){
stop("Paramater genomeVersion must be choosen from grch38 and grch37, default: grch38.")
}
####################### detect sentinel snp:
message("== Detecting sentinel SNPs... ")
# pValue filter:
gwasDFsub <- gwasDF[pValue<pValueThreshold, ]
gwasDFsub <- gwasDFsub[chr %in% paste0("chr", 1:22)]
chrAll <- unique(gwasDFsub$chr)
chrAll <- chrAll[order(as.numeric(str_remove(chrAll,"chr")))]
sentinelSnpDF <- data.table()
for(i in 1:length(chrAll)){
gwasDFsubChrom <- gwasDFsub[chr==chrAll[i],][order(pValue, position)]
tmp <- copy(gwasDFsubChrom)
sentinelSnps_count <- 0
while(nrow(tmp)>0){
sentinelSnps_count <- sentinelSnps_count+1
sentinelSnpDF <- rbind(sentinelSnpDF, tmp[1,])
startPos <- tmp[1,]$position-centerRange
endPos <- tmp[1,]$position+centerRange
tmp <- tmp[position<startPos | position>endPos][order(pValue, position)]
}
message(" In ",chrAll[i], ", ",sentinelSnps_count, " sentinel SNPs detected. ")
rm(tmp, sentinelSnps_count, startPos, endPos)
}
message("== Totally, [", nrow(sentinelSnpDF), "] sentinel SNPs located in [",length(unique(sentinelSnpDF$chr)) ,"] chromosomes have been detected!")
return(sentinelSnpDF)
}
#' @title Identify trait genes using sentinel SNPs generated from `xQTLanalyze_getSentinelSnp`
#' @param sentinelSnpDF A data.table. Better be the results from the function "xQTLanalyze_getSentinelSnp", seven columns are required, including "rsid", "chr", "position", "pValue", "maf", "beta" and "se".
#' @param detectRange A integer value. Trait genes that harbor sentinel SNPs located in the 1kb range upstream and downstream of gene. Default: 1e6 bp
#' @param tissueSiteDetail (character) details of tissues in GTEx can be listed using `tissueSiteDetailGTExv8` or `tissueSiteDetailGTExv7`
#' @param genomeVersion "grch38" or "grch37". Default: "grch38"
#' @param grch37To38 TRUE or FALSE, we recommend converting grch37 to grch38, or using a input file of grch38 directly. Package `rtracklayer` is required.
#' @param overlapWithEGene TRUE(default) of FALSE. take the intersection with eGenes, egene data.frame will be automatically download from GTEx, or can be provided by the parameter `egeneDF` specified the data.frame of one column of genecode ID. Default:TRUE
#' @param egeneDF A data.table object of one column of gencode ID. requiring overlapWithEGene is TRUE.
#' @import data.table
#' @import stringr
#' @importFrom GenomicRanges GRanges
#' @importFrom IRanges IRanges ranges
#' @importFrom GenomeInfoDb seqnames
#' @return A data.table object
#' @export
#'
#' @examples
#' \donttest{
#' # without a customized egene file,
#' URL1<-"https://gitee.com/stronghoney/exampleData/raw/master/gwas/GLGC_CG0052/sentinelSnpDF.txt"
#' sentinelSnpDF <- data.table::fread(URL1)
#' traitsAll <- xQTLanalyze_getTraits(sentinelSnpDF, detectRange=1e4,"Brain - Cerebellum",
#' genomeVersion="grch37", grch37To38=TRUE)
#' # with a egene file:
#' egeneFile <- "http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/egeneDF.txt"
#' egeneDF <- data.table::fread(egeneFile)
#' traitsAll <- xQTLanalyze_getTraits(sentinelSnpDF, detectRange=1e4,"Brain - Cerebellum",
#' genomeVersion="grch37", grch37To38=TRUE, egeneDF=egeneDF)
#' }
xQTLanalyze_getTraits <- function(sentinelSnpDF, detectRange=1e6, tissueSiteDetail="", genomeVersion="grch38", grch37To38=FALSE, overlapWithEGene=TRUE, egeneDF=NULL){
rsid <- maf <- strand <- pValue <- chr <- position <- chromosome <- NULL
. <-genes <- geneSymbol <- gencodeId <- geneType <- description<- NULL
data.table::setDT(sentinelSnpDF)
# if(overlapWithEGene){
# if( length(tissueSiteDetail)!=1 | tissueSiteDetail=="" | !(tissueSiteDetail %in% tissueSiteDetailGTExv8$tissueSiteDetail) ){
# stop("== \"tissueSiteDetail\" can not be null. Please choose the tissue from tissue list of tissueSiteDetailGTExv8")
# }
# }
# (未做) 由于下一步的 xQTLdownload_eqtlPost 函数只能 query 基于 hg38(v26) 的突变 1e6 bp附近的基因，所以如果输入的GWAS是 hg19 的突变坐标，需要进行转换为38，然后再进行下一步 eqtl sentinel snp filter.
# 由于从 EBI category 里获得的是 hg38(v26) 的信息，所以如果这一步是 hg19 的1e6范围内，则在 hg38里就会未必，所以需要这一步，如果是hg19，则对突变的坐标进行变换：
####################### convert hg19 to hg38:
if( genomeVersion =="grch37" & !grch37To38 & tissueSiteDetail!="" ){
stop("Because the genome version of eqtl associations only support GRCH38, sentinel SNP should be converted to GRCH38 before colocalization analysis if GRCH37 is provided.")
genecodeVersion = "v19"
datasetId="gtex_v7"
}else if(genomeVersion =="grch37" & !grch37To38 & tissueSiteDetail==""){
genecodeVersion = "v19"
datasetId="gtex_v7"
}else if( genomeVersion =="grch37" & grch37To38){
genecodeVersion = "v26"
datasetId="gtex_v8"
message("== Converting SNPs' coordinate to GRCH38... ")
if(suppressMessages(!requireNamespace("rtracklayer"))){
message("Package [rtracklayer] is not installed! please install [rtracklayer] with following: ")
message("---------")
message('\"if (!require("BiocManager", quietly = TRUE)); BiocManager::install("rtracklayer")\"')
message("---------")
}
path = system.file(package="xQTLbiolinks", "extdata", "hg19ToHg38.over.chain")
ch = rtracklayer::import.chain(path)
dataRanges <- GenomicRanges::GRanges(sentinelSnpDF$chr,
IRanges::IRanges(sentinelSnpDF$position, sentinelSnpDF$position),
strand= "*",
sentinelSnpDF[,.(rsid, maf, pValue)]
)
dataRanges_hg38 <- unlist(rtracklayer::liftOver(dataRanges, ch))
# retain the SNPs located in chromosome 1:22
dataRanges_hg38 <- dataRanges_hg38[which(as.character(GenomeInfoDb::seqnames(dataRanges_hg38)) %in% paste0("chr", 1:22)),]
message("== ",length(dataRanges_hg38),"/",nrow(sentinelSnpDF)," left.")
sentinelSnpDF <- cbind(data.table(rsid = dataRanges_hg38$rsid, maf=dataRanges_hg38$maf, pValue=dataRanges_hg38$pValue),
data.table::data.table(chr = as.character(GenomeInfoDb::seqnames(dataRanges_hg38)), position=as.data.table(IRanges::ranges(dataRanges_hg38))$start ))
sentinelSnpDF <- sentinelSnpDF[,.(rsid, chr, position, pValue, maf)]
rm(dataRanges, dataRanges_hg38)
}else if( genomeVersion =="grch38" & !grch37To38){
genecodeVersion = "v26"
datasetId="gtex_v8"
}else if( genomeVersion =="grch38" & grch37To38 ){
genecodeVersion = "v26"
datasetId="gtex_v8"
message("Genome version of grch38 is used!")
}else if(!genomeVersion %in% c("grch38", "grch37")){
stop("Paramater genomeVersion must be choosen from grch38 and grch37, default: grch38.")
}
###################### tissueSiteDetail="Brain - Cortex", maf_threshold=0.01
geneInfo <- extractGeneInfo(gencodeGeneInfoAllGranges, genomeVersion = genecodeVersion)
chrAll <- unique(sentinelSnpDF$chr)
chrAll <- chrAll[order(as.numeric(str_remove(chrAll,"chr")))]
########################## # 确保这些 SNPs 在 GTEx 里是有的， rsid 和 位置信息都一致才保留：
# message("== Validating variant in GTEx....")
# sentinelSnpDFNew <- data.table()
# for(i in 1:length(chrAll)){
# sentinelSnpChromRaw <- sentinelSnpDF[chr==chrAll[i],]
# snpTMP <- suppressMessages(xQTLquery_varPos(chrom = ifelse(datasetId=="gtex_v8", chrAll[i], str_remove(chrAll[i], "chr")), pos = sentinelSnpChromRaw$position, datasetId = datasetId))
# if( !exists("snpTMP") || is.null(snpTMP) ){
# stop("== Fail to fecth variant information, please check your network.")
# }
# # 使用 position 和 rsid 进行merge:， 因为 rsid 有可能有版本差异，而position可能有由于 liftover 转换产生差异。
# sentinelSnpChrom <- merge(sentinelSnpChromRaw, unique(snpTMP[,.(position=pos,rsid = snpId)]), by=c("rsid", "position"))
# if(nrow(sentinelSnpChrom)>0){
# sentinelSnpDFNew <- rbind(sentinelSnpDFNew, sentinelSnpChrom)
# }else{
# next()
# }
# message(" ", chrAll[i], ", ", nrow(sentinelSnpChrom),"/", nrow(sentinelSnpChromRaw) ," SNPs retained.")
# rm(sentinelSnpChromRaw, sentinelSnpChrom, snpTMP)
# }
# if(nrow(sentinelSnpDFNew)==0){
# stop("There is no shared variants found in your gwas dataset.")
# }else{
# message("== Totally, ",nrow(sentinelSnpDFNew), "/",nrow(sentinelSnpDF), " sentinel SNPs retained.")
# }
sentinelSnpDFNew <- copy(sentinelSnpDF)
######################## 1
message("== Detecting the trait genes of sentinel snps... ")
traitsAll <- data.table()
for(i in 1:length(chrAll)){
geneInfoChrom <- geneInfo[chromosome == chrAll[i]]
sentinelSnpChrom <- sentinelSnpDFNew[chr==chrAll[i],]
Traits <- rbindlist(lapply(1:nrow(geneInfoChrom), function(x){
tmp<-geneInfoChrom[x,];
startPos <- tmp$start - detectRange; endPos <- tmp$end + detectRange;
traits <- sentinelSnpChrom[position>=startPos & position<=endPos ];
traits$gencodeId <- tmp$gencodeId
return(traits)
}))
traitsAll <- rbind(traitsAll, Traits)
message(i," - ", chrAll[i]," - [",nrow(Traits),"] gene-SNP pairs of [",length(unique(Traits$gencodeId)),"] genes and [",length(unique(Traits$rsid)),"] SNPs." )
rm(sentinelSnpChrom, geneInfoChrom, Traits)
}
message("== Fetching [", length(unique(traitsAll$gencodeId)),"] genes' information from the GTEx...")
# geneAnnot <- xQTLquery_gene(unique(traitsAll$gencodeId), geneType = "gencodeId")
# if( datasetId=="gtex_v7" ){
# geneAnnot$chromosome <- paste0("chr",geneAnnot$chromosome)
# }
# if( exists("geneAnnot") && !is.null(geneAnnot) && nrow(geneAnnot)>0 ){
# traitsAll <- merge(geneAnnot[,.(genes, geneSymbol,gencodeId, geneType, description, chromosome, start,end ,strand)],traitsAll, by.x="genes",by.y="gencodeId", all.x=TRUE)[,-c("genes")]
# traitsAll <- traitsAll[,.( chromosome, geneStart=start, geneEnd=end, geneStrand=strand, geneSymbol, gencodeId, rsid, position, pValue, maf )][order(as.numeric(str_remove(chromosome, "chr")), pValue, position)]
# message("== Totally, [",nrow(traitsAll), "] associations between [",length(unique(traitsAll$gencodeId)),"] traits genes and [",length(unique(traitsAll$rsid)),"] SNPs are detected." )
# }
# Get the overlap with the eGgenes:
if(overlapWithEGene & is.null(egeneDF)){
egeneDF <- xQTLdownload_egene(tissueSiteDetail = tissueSiteDetail) #11240
traitsAll <- traitsAll[gencodeId %in% egeneDF$gencodeId | gencodeId %in% unlist(lapply(egeneDF$gencodeId, function(x){ str_split(x, fixed("."))[[1]][1] }))]
message("== After taking the intersection with egenes, [",nrow(traitsAll), "] associations between [",length(unique(traitsAll$gencodeId)),"] traits genes and [",length(unique(traitsAll$rsid)),"] SNPs are detected." )
}else if(overlapWithEGene & !(is.null(egeneDF))){
egeneDF <- egeneDF[,1]
names(egeneDF) <- "gencodeId"
traitsAll <- traitsAll[gencodeId %in% egeneDF$gencodeId | gencodeId %in% unlist(lapply(egeneDF$gencodeId, function(x){ str_split(x, fixed("."))[[1]][1] }))]
message("== ",nrow(egeneDF), " eGenes are provided...")
message(" After taking the intersection with egenes, [",nrow(traitsAll), "] associations between [",length(unique(traitsAll$gencodeId)),"] traits genes and [",length(unique(traitsAll$rsid)),"] SNPs are detected." )
}
return(traitsAll)
}
#' @title Conduct colocalization analysis with trait genes generated from `xQTLanalyze_getTraits`
#' @param gwasDF A data.frame or data.table objectof gwas.
#'
#' @param traitGene A gene symbol or a gencode id (versioned).
#' @param geneType (character) options: "auto","geneSymbol" or "gencodeId". Default: "auto".
#' @param genomeVersion "grch38" (default) or "grch37". Note: grch37 will be converted to grch38 automatically.
#' @param tissueSiteDetail (character) details of tissues in GTEx can be listed using `tissueSiteDetailGTExv8` or `tissueSiteDetailGTExv7`
#' @param study (character) name of studies can be listed using "ebi_study_tissues"
#' @param mafThreshold Cutoff of maf to remove rare variants.
#' @param population Supported population is consistent with the LDlink, which can be listed using function "LDlinkR::list_pop()"
#' @param gwasSampleNum Sample number of GWAS dataset. Default:50000.
#' @param token LDlink provided user token, default = NULL, register for token at https://ldlink.nci.nih.gov/?tab=apiaccess
#' @param method (character) options: "coloc"(default) or "hyprcoloc" (must be updated to the latest version from the github to use hyprcoloc ). Package `coloc` or `hyprcoloc` is required.
#' @param bb.alg For `hyprcoloc`, branch and bound algorithm: TRUE, employ BB algorithm; FALSE, do not. Default: FALSE.
#'
#' @return A list of coloc result and details.
#' @export
#'
#' @examples
#' \donttest{
#' url1 <- "http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/gwasDFsub_MMP7.txt"
#' gwasDF <- data.table::fread(url1)
#' output <- xQTLanalyze_coloc(gwasDF = gwasDF, traitGene= "MMP7", tissueSiteDetail="Prostate")
#' }
xQTLanalyze_coloc <- function(gwasDF, traitGene, geneType="auto", genomeVersion="grch38", tissueSiteDetail="", study="gtex_v8", mafThreshold=0.01, population="EUR", gwasSampleNum=50000, method="coloc", token="9246d2db7917", bb.alg=FALSE){
rsid <- chr <- position <- se <- pValue <- snpId <- maf <- pos <- i <- variantId <- se.eqtl <- se.gwas <-SNP.PP.H4 <- beta.eqtl <- beta.gwas <- posterior_prob <- regional_prob <-candidate_snp <- posterior_explained_by_snp <- NULL
qtl_group <- NULL
. <- NULL
# tissueSiteDetail="Brain - Cortex"
# geneType="geneSymbol"
# genomeVersion="grch37"
# gwasSampleNum=50000
# mafThreshold=0.01
# https://stackoverflow.com/questions/66849936/make-cran-r-package-suggest-github-r-package
population <- ""
token <- ""
if(method == "coloc" && !requireNamespace("coloc")){
stop("please install package \"coloc\" with install.packages(\"coloc\").")
}
# Automatically determine the type of variable:
if(geneType=="auto"){
if( all(unlist(lapply(traitGene, function(g){ stringr::str_detect(g, "^ENSG") }))) ){
geneType <- "gencodeId"
}else{
geneType <- "geneSymbol"
}
}
# eqtl dataset:
eqtlInfo <- xQTLdownload_eqtlAllAsso(traitGene, geneType = geneType, tissueLabel=tissueSiteDetail, study=study, withB37VariantId = FALSE)
if( !exists("eqtlInfo") || is.null(eqtlInfo)){
message(i," | gene", traitGene, "has no eqtl associations, next!")
message(" = None eQTL associations obtained of gene [",traitGene,"], please change the gene name or ENSEMBLE ID.")
return(NULL)
}
# 如果有有多个 qtl_group, 只保留第一个。
eqtlInfo <- eqtlInfo[ qtl_group ==eqtlInfo[1,]$qtl_group,]
eqtlInfo[,position:=.(pos)]
# chromosome:
P_chrom <- paste0("chr",eqtlInfo[1,]$chrom)
eqtlInfo<- eqtlInfo[maf>mafThreshold & maf <1,]
# 去重：
eqtlInfo <- eqtlInfo[order(snpId, pValue)][!duplicated(snpId)]
# subset:
eqtlInfo <- na.omit( eqtlInfo[,.(rsid=snpId, maf=as.numeric(maf), beta, se, pValue=as.numeric(pValue), position=as.numeric(position))] )
if(nrow(eqtlInfo)==0){
message("Number of eQTL association is <1")
return(NULL)
}
message("Data processing...")
##################### gwas dataset:
gwasDF <- gwasDF[,1:7]
data.table::setDT(gwasDF)
names(gwasDF) <- c("rsid", "chr", "position", "pValue", "maf", "beta", "se")
# gwas subset:
gwasDF <- na.omit(gwasDF)
p_chrom_tmp <- ifelse(stringr::str_detect(gwasDF[1,]$chr, "chr"),P_chrom, stringr::str_remove(P_chrom, "chr"))
gwasDF <- gwasDF[chr==p_chrom_tmp,]
# convert variable class:
gwasDF[,c("position", "pValue", "maf", "beta", "se"):=.(as.numeric(position), as.numeric(pValue), as.numeric(maf), as.numeric(beta), as.numeric(se))]
# MAF filter:
gwasDF <- gwasDF[maf > mafThreshold & maf<1,]
# 去重：
gwasDF <- gwasDF[order(rsid, pValue)][!duplicated(rsid)]
# retain SNPs with rs id:
gwasDF <- gwasDF[stringr::str_detect(rsid,stringr::regex("^rs")),]
# chromosome revise：
if( !str_detect(gwasDF[1,]$chr, stringr::regex("^chr")) ){
gwasDF$chr <- paste0("chr", gwasDF$chr)
}
##### convert to grch38:
if(genomeVersion == "grch37"){
message("== Converting GWAS coordinate to GRCH38... ")
if(suppressMessages(!requireNamespace("rtracklayer"))){
message("Package [rtracklayer] is not installed! please install [rtracklayer] with following: ")
message("---------")
message('\"if (!require("BiocManager", quietly = TRUE)); BiocManager::install("rtracklayer")\"')
message("---------")
}
path = system.file(package="xQTLbiolinks", "extdata", "hg19ToHg38.over.chain")
ch = rtracklayer::import.chain(path)
dataRanges <- GenomicRanges::GRanges(gwasDF$chr,
IRanges::IRanges(gwasDF$position, gwasDF$position),
strand= "*",
gwasDF[,.(rsid, maf, pValue, beta, se)]
)
dataRanges_hg38 <- unlist(rtracklayer::liftOver(dataRanges, ch))
# retain the SNPs located in chromosome 1:22
dataRanges_hg38 <- dataRanges_hg38[which(as.character(GenomeInfoDb::seqnames(dataRanges_hg38)) %in% paste0("chr", 1:22)),]
message("== ",length(dataRanges_hg38),"/",nrow(gwasDF)," (",round(length(dataRanges_hg38)/nrow(gwasDF)*100,2),"%)"," left.")
gwasDFnew <- cbind(data.table::data.table(rsid = dataRanges_hg38$rsid, maf=dataRanges_hg38$maf, pValue=dataRanges_hg38$pValue, beta=dataRanges_hg38$beta, se=dataRanges_hg38$se),
data.table::data.table(chr = as.character(GenomeInfoDb::seqnames(dataRanges_hg38)), position=as.data.table(IRanges::ranges(dataRanges_hg38))$start ))
gwasDF <- gwasDFnew[chr==P_chrom,.(rsid, chr, position, pValue, maf, beta, se)]
rm(dataRanges, dataRanges_hg38, gwasDFnew)
}
#
tissueSiteDetailId <- tissueSiteDetailGTExv8[tissueSiteDetail, on="tissueSiteDetail"]$tissueSiteDetailId
gwasEqtlInfo <- merge(gwasDF, eqtlInfo[,.(rsid, maf, pValue, position,beta, se)], by=c("rsid", "position"), suffixes = c(".gwas",".eqtl"))
gwasEqtlInfo <- gwasEqtlInfo[se.eqtl !=0 & se.gwas !=0, ]
if(nrow(gwasEqtlInfo)==0){
message("No shared variants between eQTL and GWAS, please check your input!.")
return(NULL)
}
message("== Start the colocalization analysis of gene [", traitGene,"]")
if(method=="coloc"){
message("== Using method: coloc")
# 防止 check_dataset 中 p = pnorm(-abs(d$beta/sqrt(d$varbeta))) * 2 出错
suppressWarnings(coloc_Out <- coloc::coloc.abf(dataset1 = list( pvalues = gwasEqtlInfo$pValue.gwas, type="quant", N=gwasSampleNum, snp=gwasEqtlInfo$rsid, MAF=gwasEqtlInfo$maf.gwas),
dataset2 = list( pvalues = gwasEqtlInfo$pValue.eqtl, type="quant", N=ifelse(is.na(sampleNum[tissueSiteDetailId, on="tissueSiteDetailId"]$sampleNum), 300, sampleNum[tissueSiteDetailId, on="tissueSiteDetailId"]$sampleNum), snp=gwasEqtlInfo$rsid, MAF= gwasEqtlInfo$maf.eqtl)))
coloc_Out_results <- as.data.table(coloc_Out$results)
# coloc_Out_results$gene <- traitGenes[i]
coloc_Out_summary <- as.data.table(t(as.data.frame(coloc_Out$summary)))
coloc_Out_summary$traitGene <- traitGene
coloc_Out_summary$candidate_snp <- coloc_Out_results[order(-SNP.PP.H4)][1,]$snp
coloc_Out_summary$SNP.PP.H4 <- coloc_Out_results[order(-SNP.PP.H4)][1,]$SNP.PP.H4
message("== Done")
print(coloc_Out_summary)
# coloc_Out_summary$pearsonCoor <- cor(-log(gwasEqtlInfo$pValue.gwas, 10),-log(gwasEqtlInfo$pValue.eqtl, 10), method = "pearson")
return(list(coloc_Out_summary=coloc_Out_summary, gwasEqtlInfo=gwasEqtlInfo))
}
}
#' @title Conduct colocalization analysis with customized QTL data
#'
#' @param gwasDF data.frame or data.table, required cols: rsid, chrom, position, pValue, maf, beta, se
#' @param qtlDF data.frame or data.table, required cols: rsid, chrom, position, pValue, maf, beta, se
#' @param mafThreshold Cutoff of maf to remove rare variants.
#' @param gwasSampleNum Sample number of GWAS dataset. Default:50000.
#' @param qtlSampleNum Sample number of QTL dataset. Default:10000.
#' @param method (character) options: "coloc"(default) or "hyprcoloc" (need a highe version).
#' @param bb.alg For `hyprcoloc`, branch and bound algorithm: TRUE, employ BB algorithm; FALSE, do not. Default: FALSE.
#'
#' @return A list
#' @export
#' @examples
#' \donttest{
#' url1 <- "http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/gwasDFsub_MMP7.txt"
#' url2 <- "http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/eqtl/MMP7_qtlDF.txt"
#' gwasDF <- data.table::fread(url1)
#' qtlDF <- data.table::fread(url2)
#' output <- xQTLanalyze_coloc_diy(gwasDF = gwasDF, qtlDF=qtlDF, method="coloc")
#' }
xQTLanalyze_coloc_diy <- function(gwasDF, qtlDF, mafThreshold=0.01, gwasSampleNum=50000, qtlSampleNum=10000, method="coloc", bb.alg=FALSE){
rsid <- chrom <- chr <- position <- se <- pValue <- snpId <- maf <- pos <- i <- variantId <- se.eqtl <- se.gwas <-SNP.PP.H4 <- beta.eqtl <- beta.gwas <- posterior_prob <- regional_prob <-candidate_snp <- posterior_explained_by_snp <- NULL
. <- NULL
if(method == "coloc" && !requireNamespace("coloc")){
stop("please install package \"coloc\" with install.packages(\"coloc\").")
}
# eqtl dataset:
names(qtlDF) <- c("rsid", "chrom", "position", "pValue", "maf", "beta", "se")
# chromosome:
P_chrom <- ifelse(stringr::str_detect(qtlDF[1, ]$chr, "chr"), qtlDF[1, ]$chr, paste0("chr", qtlDF[1, ]$chr))
eqtlInfo <- qtlDF[,.(rsid,chrom, maf=as.numeric(maf), beta=as.numeric(beta), se=as.numeric(se), pValue=as.numeric(pValue), position=as.numeric(position))]
eqtlInfo<- eqtlInfo[maf>mafThreshold & maf <1,]
# 去重：
eqtlInfo <- eqtlInfo[order(rsid, pValue)][!duplicated(rsid)]
if(nrow(eqtlInfo)==0){
message("Number of eQTL association is <1")
return(NULL)
}
message("Data processing...")
##################### gwas dataset:
gwasDF <- gwasDF[,1:7]
data.table::setDT(gwasDF)
names(gwasDF) <- c("rsid", "chr", "position", "pValue", "maf", "beta", "se")
# gwas subset:
gwasDF <- na.omit(gwasDF)
# chromosome revise：
if( !stringr::str_detect(gwasDF[1,]$chr, stringr::regex("^chr")) ){
gwasDF$chr <- paste0("chr", gwasDF$chr)
}
# convert variable class:
gwasDF[,c("position", "pValue", "maf", "beta", "se"):=.(as.numeric(position), as.numeric(pValue), as.numeric(maf), as.numeric(beta), as.numeric(se))]
# MAF filter:
gwasDF <- gwasDF[maf > mafThreshold & maf<1,]
# 去重：
gwasDF <- gwasDF[order(rsid, pValue)][!duplicated(rsid)]
# retain SNPs with rs id:
# gwasDF <- gwasDF[stringr::str_detect(rsid,stringr::regex("^rs")),]
message(nrow(gwasDF))
#
gwasEqtlInfo <- merge(gwasDF, eqtlInfo[,.(rsid, maf, pValue, position,beta, se)], by=c("rsid", "position"), suffixes = c(".gwas",".eqtl"))
gwasEqtlInfo <- gwasEqtlInfo[se.eqtl !=0 & se.gwas !=0, ]
if(nrow(gwasEqtlInfo)==0){
message("No shared variants between eQTL and GWAS, please check your input!.")
return(NULL)
}
message("== Start the colocalization analysis")
if(method=="coloc"){
message("== Using method: coloc")
# 防止 check_dataset 中 p = pnorm(-abs(d$beta/sqrt(d$varbeta))) * 2 出错
suppressWarnings(coloc_Out <- coloc::coloc.abf(dataset1 = list( pvalues = gwasEqtlInfo$pValue.gwas, type="quant", N=gwasSampleNum, snp=gwasEqtlInfo$rsid, MAF=gwasEqtlInfo$maf.gwas),
dataset2 = list( pvalues = gwasEqtlInfo$pValue.eqtl, type="quant", N=qtlSampleNum, snp=gwasEqtlInfo$rsid, MAF= gwasEqtlInfo$maf.eqtl)))
coloc_Out_results <- as.data.table(coloc_Out$results)
# coloc_Out_results$gene <- traitGenes[i]
coloc_Out_summary <- as.data.table(t(as.data.frame(coloc_Out$summary)))
coloc_Out_summary$candidate_snp <- coloc_Out_results[order(-SNP.PP.H4)][1,]$snp
coloc_Out_summary$SNP.PP.H4 <- coloc_Out_results[order(-SNP.PP.H4)][1,]$SNP.PP.H4
message("== Done")
print(coloc_Out_summary)
# coloc_Out_summary$pearsonCoor <- cor(-log(gwasEqtlInfo$pValue.gwas, 10),-log(gwasEqtlInfo$pValue.eqtl, 10), method = "pearson")
return(list(coloc_Out_summary=coloc_Out_summary, gwasEqtlInfo=gwasEqtlInfo))
}
if(method=="hyprcoloc"){
stop("Please install package hyprcoloc and update to the latest version (v1.6.3) ")
}
}
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Defines functions xQTLanalyze_getSentinelSnp
Documented in xQTLanalyze_getSentinelSnp
#' @title Detect sentinel SNPs for GWAS using summary statistics data
#' @description
#' Return sentinel snps whose pValue < 5e-8(default) and SNP-to-SNP distance > 1e6 bp.
#' @param gwasDF A data.frame or a data.table object. Five columns are required (arbitrary column names is supported):
#'
#' `Col 1`. "snps" (character), , using an rsID (e.g. "rs11966562").
#'
#' `Col 2`. "chromosome" (character), one of the chromosome from chr1-chr22.
#'
#' `Col 3`. "postion" (integer), genome position of snp.
#'
#' `Col 4`. "P-value" (numeric).
#'
#' `Col 5`. "MAF" (numeric). Allel frequency.
#'
#' `Col 6`. "beta" (numeric). effect size.
#'
#' `Col 7`. "se" (numeric). standard error.
#'
#' @param pValueThreshold Cutoff of gwas p-value. Default: 5e-8
#' @param centerRange SNP-to-SNP distance. Default:1e6
#' @param mafThreshold Cutoff of maf to remove rare variants.
#' @param genomeVersion Genome version of input file. "grch37" or "grch38" (default).
#' @param grch37To38 TRUE or FALSE, we recommend converting grch37 to grch38, or using a input file of grch38 directly. Package `rtracklayer` is required.
#' @import data.table
#' @import stringr
#' @importFrom GenomicRanges GRanges
#' @importFrom IRanges IRanges ranges
#' @importFrom GenomeInfoDb seqnames
#' @return A data.table object.
#' @export
#'
#' @examples
#' \donttest{
#' url<-"http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/GLGC.txt"
#' gwasDF <- data.table::fread(url)
#' gwasDF <- gwasDF[, .(rsid, chr, position, P, maf, beta, se)]
#' sentinelSnpDF <- xQTLanalyze_getSentinelSnp(gwasDF)
#' }
xQTLanalyze_getSentinelSnp <- function(gwasDF, pValueThreshold=5e-8, centerRange=1e6, mafThreshold = 0.01, genomeVersion="grch38", grch37To38 = FALSE){
position <- pValue <- maf <- rsid <- chr <- se <- NULL
.<-NULL
# Detect gene with sentinal SNP:
gwasDF <- gwasDF[,1:7]
data.table::setDT(gwasDF)
message("== Preparing GWAS dataset... ")
names(gwasDF) <- c("rsid", "chr", "position", "pValue", "maf", "beta", "se")
gwasDF <- na.omit(gwasDF)
# chromosome revise：
if( !str_detect(gwasDF[1,]$chr, regex("^chr")) ){
gwasDF$chr <- paste0("chr", gwasDF$chr)
}
# convert variable class:
gwasDF[,c("position", "pValue", "maf", "beta", "se")] <- gwasDF[,.(position=as.numeric(position), pValue=as.numeric(pValue), maf=as.numeric(maf), beta=as.numeric(beta), se=as.numeric(se))]
# MAF filter:
gwasDF <- gwasDF[maf > mafThreshold & maf<1,]
# 去重：
# gwasDF <- gwasDF[order(rsid, pValue)][!duplicated(rsid)]
# retain SNPs with rs id:
# gwasDF <- gwasDF[stringr::str_detect(rsid,stringr::regex("^rs")),]
####################### convert hg19 to hg38:
if(genomeVersion =="grch37" & grch37To38){
message("== Converting SNPs' coordinate to GRCH38... ")
if(suppressMessages(!requireNamespace("rtracklayer"))){
message("Package [rtracklayer] is not installed! please install [rtracklayer] with following: ")
message("---------")
message('\"if (!require("BiocManager", quietly = TRUE)); BiocManager::install("rtracklayer")\"')
message("---------")
}
path = system.file(package="xQTLbiolinks", "extdata", "hg19ToHg38.over.chain")
ch = rtracklayer::import.chain(path)
gwasRanges <- GenomicRanges::GRanges(gwasDF$chr,
IRanges::IRanges(gwasDF$position, gwasDF$position),
strand= "*",
gwasDF[,.(rsid, maf, pValue, beta, se)]
)
gwasRanges_hg38 <- unlist(rtracklayer::liftOver(gwasRanges, ch))
# retain the SNPs located in chromosome 1:22
gwasRanges_hg38 <- gwasRanges_hg38[which(as.character(GenomeInfoDb::seqnames(gwasRanges_hg38)) %in% paste0("chr", 1:22)),]
gwasDF <- cbind(data.table(rsid = gwasRanges_hg38$rsid, maf=gwasRanges_hg38$maf, pValue=gwasRanges_hg38$pValue, beta = gwasRanges_hg38$beta, se = gwasRanges_hg38$se),
data.table::data.table(chr = as.character(GenomeInfoDb::seqnames(gwasRanges_hg38)), position=as.data.table(IRanges::ranges(gwasRanges_hg38))$start ))
gwasDF <- gwasDF[,.(rsid, chr, position, pValue, maf, beta, se)]
message("== ",length(gwasRanges_hg38),"/",nrow(gwasDF)," left.")
rm(gwasRanges, gwasRanges_hg38)
}else if(genomeVersion =="grch38" & grch37To38){
stop("Only grch37 genome version can be converted to grch38!")
}else if(!genomeVersion %in% c("grch38", "grch37")){
stop("Paramater genomeVersion must be choosen from grch38 and grch37, default: grch38.")
}
####################### detect sentinel snp:
message("== Detecting sentinel SNPs... ")
# pValue filter:
gwasDFsub <- gwasDF[pValue<pValueThreshold, ]
gwasDFsub <- gwasDFsub[chr %in% paste0("chr", 1:22)]
chrAll <- unique(gwasDFsub$chr)
chrAll <- chrAll[order(as.numeric(str_remove(chrAll,"chr")))]
sentinelSnpDF <- data.table()
for(i in 1:length(chrAll)){
gwasDFsubChrom <- gwasDFsub[chr==chrAll[i],][order(pValue, position)]
tmp <- copy(gwasDFsubChrom)
sentinelSnps_count <- 0
while(nrow(tmp)>0){
sentinelSnps_count <- sentinelSnps_count+1
sentinelSnpDF <- rbind(sentinelSnpDF, tmp[1,])
startPos <- tmp[1,]$position-centerRange
endPos <- tmp[1,]$position+centerRange
tmp <- tmp[position<startPos | position>endPos][order(pValue, position)]
}
message(" In ",chrAll[i], ", ",sentinelSnps_count, " sentinel SNPs detected. ")
rm(tmp, sentinelSnps_count, startPos, endPos)
}
message("== Totally, [", nrow(sentinelSnpDF), "] sentinel SNPs located in [",length(unique(sentinelSnpDF$chr)) ,"] chromosomes have been detected!")
return(sentinelSnpDF)
}
#' @title Identify trait genes using sentinel SNPs generated from `xQTLanalyze_getSentinelSnp`
#' @param sentinelSnpDF A data.table. Better be the results from the function "xQTLanalyze_getSentinelSnp", seven columns are required, including "rsid", "chr", "position", "pValue", "maf", "beta" and "se".
#' @param detectRange A integer value. Trait genes that harbor sentinel SNPs located in the 1kb range upstream and downstream of gene. Default: 1e6 bp
#' @param tissueSiteDetail (character) details of tissues in GTEx can be listed using `tissueSiteDetailGTExv8` or `tissueSiteDetailGTExv7`
#' @param genomeVersion "grch38" or "grch37". Default: "grch38"
#' @param grch37To38 TRUE or FALSE, we recommend converting grch37 to grch38, or using a input file of grch38 directly. Package `rtracklayer` is required.
#' @param overlapWithEGene TRUE(default) of FALSE. take the intersection with eGenes, egene data.frame will be automatically download from GTEx, or can be provided by the parameter `egeneDF` specified the data.frame of one column of genecode ID. Default:TRUE
#' @param egeneDF A data.table object of one column of gencode ID. requiring overlapWithEGene is TRUE.
#' @import data.table
#' @import stringr
#' @importFrom GenomicRanges GRanges
#' @importFrom IRanges IRanges ranges
#' @importFrom GenomeInfoDb seqnames
#' @return A data.table object
#' @export
#'
#' @examples
#' \donttest{
#' # without a customized egene file,
#' URL1<-"https://gitee.com/stronghoney/exampleData/raw/master/gwas/GLGC_CG0052/sentinelSnpDF.txt"
#' sentinelSnpDF <- data.table::fread(URL1)
#' traitsAll <- xQTLanalyze_getTraits(sentinelSnpDF, detectRange=1e4,"Brain - Cerebellum",
#' genomeVersion="grch37", grch37To38=TRUE)
#' # with a egene file:
#' egeneFile <- "http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/egeneDF.txt"
#' egeneDF <- data.table::fread(egeneFile)
#' traitsAll <- xQTLanalyze_getTraits(sentinelSnpDF, detectRange=1e4,"Brain - Cerebellum",
#' genomeVersion="grch37", grch37To38=TRUE, egeneDF=egeneDF)
#' }
xQTLanalyze_getTraits <- function(sentinelSnpDF, detectRange=1e6, tissueSiteDetail="", genomeVersion="grch38", grch37To38=FALSE, overlapWithEGene=TRUE, egeneDF=NULL){
rsid <- maf <- strand <- pValue <- chr <- position <- chromosome <- NULL
. <-genes <- geneSymbol <- gencodeId <- geneType <- description<- NULL
data.table::setDT(sentinelSnpDF)
# if(overlapWithEGene){
# if( length(tissueSiteDetail)!=1 | tissueSiteDetail=="" | !(tissueSiteDetail %in% tissueSiteDetailGTExv8$tissueSiteDetail) ){
# stop("== \"tissueSiteDetail\" can not be null. Please choose the tissue from tissue list of tissueSiteDetailGTExv8")
# }
# }
# (未做) 由于下一步的 xQTLdownload_eqtlPost 函数只能 query 基于 hg38(v26) 的突变 1e6 bp附近的基因，所以如果输入的GWAS是 hg19 的突变坐标，需要进行转换为38，然后再进行下一步 eqtl sentinel snp filter.
# 由于从 EBI category 里获得的是 hg38(v26) 的信息，所以如果这一步是 hg19 的1e6范围内，则在 hg38里就会未必，所以需要这一步，如果是hg19，则对突变的坐标进行变换：
####################### convert hg19 to hg38:
if( genomeVersion =="grch37" & !grch37To38 & tissueSiteDetail!="" ){
stop("Because the genome version of eqtl associations only support GRCH38, sentinel SNP should be converted to GRCH38 before colocalization analysis if GRCH37 is provided.")
genecodeVersion = "v19"
datasetId="gtex_v7"
}else if(genomeVersion =="grch37" & !grch37To38 & tissueSiteDetail==""){
genecodeVersion = "v19"
datasetId="gtex_v7"
}else if( genomeVersion =="grch37" & grch37To38){
genecodeVersion = "v26"
datasetId="gtex_v8"
message("== Converting SNPs' coordinate to GRCH38... ")
if(suppressMessages(!requireNamespace("rtracklayer"))){
message("Package [rtracklayer] is not installed! please install [rtracklayer] with following: ")
message("---------")
message('\"if (!require("BiocManager", quietly = TRUE)); BiocManager::install("rtracklayer")\"')
message("---------")
}
path = system.file(package="xQTLbiolinks", "extdata", "hg19ToHg38.over.chain")
ch = rtracklayer::import.chain(path)
dataRanges <- GenomicRanges::GRanges(sentinelSnpDF$chr,
IRanges::IRanges(sentinelSnpDF$position, sentinelSnpDF$position),
strand= "*",
sentinelSnpDF[,.(rsid, maf, pValue)]
)
dataRanges_hg38 <- unlist(rtracklayer::liftOver(dataRanges, ch))
# retain the SNPs located in chromosome 1:22
dataRanges_hg38 <- dataRanges_hg38[which(as.character(GenomeInfoDb::seqnames(dataRanges_hg38)) %in% paste0("chr", 1:22)),]
message("== ",length(dataRanges_hg38),"/",nrow(sentinelSnpDF)," left.")
sentinelSnpDF <- cbind(data.table(rsid = dataRanges_hg38$rsid, maf=dataRanges_hg38$maf, pValue=dataRanges_hg38$pValue),
data.table::data.table(chr = as.character(GenomeInfoDb::seqnames(dataRanges_hg38)), position=as.data.table(IRanges::ranges(dataRanges_hg38))$start ))
sentinelSnpDF <- sentinelSnpDF[,.(rsid, chr, position, pValue, maf)]
rm(dataRanges, dataRanges_hg38)
}else if( genomeVersion =="grch38" & !grch37To38){
genecodeVersion = "v26"
datasetId="gtex_v8"
}else if( genomeVersion =="grch38" & grch37To38 ){
genecodeVersion = "v26"
datasetId="gtex_v8"
message("Genome version of grch38 is used!")
}else if(!genomeVersion %in% c("grch38", "grch37")){
stop("Paramater genomeVersion must be choosen from grch38 and grch37, default: grch38.")
}
###################### tissueSiteDetail="Brain - Cortex", maf_threshold=0.01
geneInfo <- extractGeneInfo(gencodeGeneInfoAllGranges, genomeVersion = genecodeVersion)
chrAll <- unique(sentinelSnpDF$chr)
chrAll <- chrAll[order(as.numeric(str_remove(chrAll,"chr")))]
########################## # 确保这些 SNPs 在 GTEx 里是有的， rsid 和 位置信息都一致才保留：
# message("== Validating variant in GTEx....")
# sentinelSnpDFNew <- data.table()
# for(i in 1:length(chrAll)){
# sentinelSnpChromRaw <- sentinelSnpDF[chr==chrAll[i],]
# snpTMP <- suppressMessages(xQTLquery_varPos(chrom = ifelse(datasetId=="gtex_v8", chrAll[i], str_remove(chrAll[i], "chr")), pos = sentinelSnpChromRaw$position, datasetId = datasetId))
# if( !exists("snpTMP") || is.null(snpTMP) ){
# stop("== Fail to fecth variant information, please check your network.")
# }
# # 使用 position 和 rsid 进行merge:， 因为 rsid 有可能有版本差异，而position可能有由于 liftover 转换产生差异。
# sentinelSnpChrom <- merge(sentinelSnpChromRaw, unique(snpTMP[,.(position=pos,rsid = snpId)]), by=c("rsid", "position"))
# if(nrow(sentinelSnpChrom)>0){
# sentinelSnpDFNew <- rbind(sentinelSnpDFNew, sentinelSnpChrom)
# }else{
# next()
# }
# message(" ", chrAll[i], ", ", nrow(sentinelSnpChrom),"/", nrow(sentinelSnpChromRaw) ," SNPs retained.")
# rm(sentinelSnpChromRaw, sentinelSnpChrom, snpTMP)
# }
# if(nrow(sentinelSnpDFNew)==0){
# stop("There is no shared variants found in your gwas dataset.")
# }else{
# message("== Totally, ",nrow(sentinelSnpDFNew), "/",nrow(sentinelSnpDF), " sentinel SNPs retained.")
# }
sentinelSnpDFNew <- copy(sentinelSnpDF)
######################## 1
message("== Detecting the trait genes of sentinel snps... ")
traitsAll <- data.table()
for(i in 1:length(chrAll)){
geneInfoChrom <- geneInfo[chromosome == chrAll[i]]
sentinelSnpChrom <- sentinelSnpDFNew[chr==chrAll[i],]
Traits <- rbindlist(lapply(1:nrow(geneInfoChrom), function(x){
tmp<-geneInfoChrom[x,];
startPos <- tmp$start - detectRange; endPos <- tmp$end + detectRange;
traits <- sentinelSnpChrom[position>=startPos & position<=endPos ];
traits$gencodeId <- tmp$gencodeId
return(traits)
}))
traitsAll <- rbind(traitsAll, Traits)
message(i," - ", chrAll[i]," - [",nrow(Traits),"] gene-SNP pairs of [",length(unique(Traits$gencodeId)),"] genes and [",length(unique(Traits$rsid)),"] SNPs." )
rm(sentinelSnpChrom, geneInfoChrom, Traits)
}
message("== Fetching [", length(unique(traitsAll$gencodeId)),"] genes' information from the GTEx...")
# geneAnnot <- xQTLquery_gene(unique(traitsAll$gencodeId), geneType = "gencodeId")
# if( datasetId=="gtex_v7" ){
# geneAnnot$chromosome <- paste0("chr",geneAnnot$chromosome)
# }
# if( exists("geneAnnot") && !is.null(geneAnnot) && nrow(geneAnnot)>0 ){
# traitsAll <- merge(geneAnnot[,.(genes, geneSymbol,gencodeId, geneType, description, chromosome, start,end ,strand)],traitsAll, by.x="genes",by.y="gencodeId", all.x=TRUE)[,-c("genes")]
# traitsAll <- traitsAll[,.( chromosome, geneStart=start, geneEnd=end, geneStrand=strand, geneSymbol, gencodeId, rsid, position, pValue, maf )][order(as.numeric(str_remove(chromosome, "chr")), pValue, position)]
# message("== Totally, [",nrow(traitsAll), "] associations between [",length(unique(traitsAll$gencodeId)),"] traits genes and [",length(unique(traitsAll$rsid)),"] SNPs are detected." )
# }
# Get the overlap with the eGgenes:
if(overlapWithEGene & is.null(egeneDF)){
egeneDF <- xQTLdownload_egene(tissueSiteDetail = tissueSiteDetail) #11240
traitsAll <- traitsAll[gencodeId %in% egeneDF$gencodeId | gencodeId %in% unlist(lapply(egeneDF$gencodeId, function(x){ str_split(x, fixed("."))[[1]][1] }))]
message("== After taking the intersection with egenes, [",nrow(traitsAll), "] associations between [",length(unique(traitsAll$gencodeId)),"] traits genes and [",length(unique(traitsAll$rsid)),"] SNPs are detected." )
}else if(overlapWithEGene & !(is.null(egeneDF))){
egeneDF <- egeneDF[,1]
names(egeneDF) <- "gencodeId"
traitsAll <- traitsAll[gencodeId %in% egeneDF$gencodeId | gencodeId %in% unlist(lapply(egeneDF$gencodeId, function(x){ str_split(x, fixed("."))[[1]][1] }))]
message("== ",nrow(egeneDF), " eGenes are provided...")
message(" After taking the intersection with egenes, [",nrow(traitsAll), "] associations between [",length(unique(traitsAll$gencodeId)),"] traits genes and [",length(unique(traitsAll$rsid)),"] SNPs are detected." )
}
return(traitsAll)
}
#' @title Conduct colocalization analysis with trait genes generated from `xQTLanalyze_getTraits`
#' @param gwasDF A data.frame or data.table objectof gwas.
#'
#' @param traitGene A gene symbol or a gencode id (versioned).
#' @param geneType (character) options: "auto","geneSymbol" or "gencodeId". Default: "auto".
#' @param genomeVersion "grch38" (default) or "grch37". Note: grch37 will be converted to grch38 automatically.
#' @param tissueSiteDetail (character) details of tissues in GTEx can be listed using `tissueSiteDetailGTExv8` or `tissueSiteDetailGTExv7`
#' @param study (character) name of studies can be listed using "ebi_study_tissues"
#' @param mafThreshold Cutoff of maf to remove rare variants.
#' @param population Supported population is consistent with the LDlink, which can be listed using function "LDlinkR::list_pop()"
#' @param gwasSampleNum Sample number of GWAS dataset. Default:50000.
#' @param token LDlink provided user token, default = NULL, register for token at https://ldlink.nci.nih.gov/?tab=apiaccess
#' @param method (character) options: "coloc"(default) or "hyprcoloc" (must be updated to the latest version from the github to use hyprcoloc ). Package `coloc` or `hyprcoloc` is required.
#' @param bb.alg For `hyprcoloc`, branch and bound algorithm: TRUE, employ BB algorithm; FALSE, do not. Default: FALSE.
#'
#' @return A list of coloc result and details.
#' @export
#'
#' @examples
#' \donttest{
#' url1 <- "http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/gwasDFsub_MMP7.txt"
#' gwasDF <- data.table::fread(url1)
#' output <- xQTLanalyze_coloc(gwasDF = gwasDF, traitGene= "MMP7", tissueSiteDetail="Prostate")
#' }
xQTLanalyze_coloc <- function(gwasDF, traitGene, geneType="auto", genomeVersion="grch38", tissueSiteDetail="", study="gtex_v8", mafThreshold=0.01, population="EUR", gwasSampleNum=50000, method="coloc", token="9246d2db7917", bb.alg=FALSE){
rsid <- chr <- position <- se <- pValue <- snpId <- maf <- pos <- i <- variantId <- se.eqtl <- se.gwas <-SNP.PP.H4 <- beta.eqtl <- beta.gwas <- posterior_prob <- regional_prob <-candidate_snp <- posterior_explained_by_snp <- NULL
qtl_group <- NULL
. <- NULL
# tissueSiteDetail="Brain - Cortex"
# geneType="geneSymbol"
# genomeVersion="grch37"
# gwasSampleNum=50000
# mafThreshold=0.01
# https://stackoverflow.com/questions/66849936/make-cran-r-package-suggest-github-r-package
population <- ""
token <- ""
if(method == "coloc" && !requireNamespace("coloc")){
stop("please install package \"coloc\" with install.packages(\"coloc\").")
}
# Automatically determine the type of variable:
if(geneType=="auto"){
if( all(unlist(lapply(traitGene, function(g){ stringr::str_detect(g, "^ENSG") }))) ){
geneType <- "gencodeId"
}else{
geneType <- "geneSymbol"
}
}
# eqtl dataset:
eqtlInfo <- xQTLdownload_eqtlAllAsso(traitGene, geneType = geneType, tissueLabel=tissueSiteDetail, study=study, withB37VariantId = FALSE)
if( !exists("eqtlInfo") || is.null(eqtlInfo)){
message(i," | gene", traitGene, "has no eqtl associations, next!")
message(" = None eQTL associations obtained of gene [",traitGene,"], please change the gene name or ENSEMBLE ID.")
return(NULL)
}
# 如果有有多个 qtl_group, 只保留第一个。
eqtlInfo <- eqtlInfo[ qtl_group ==eqtlInfo[1,]$qtl_group,]
eqtlInfo[,position:=.(pos)]
# chromosome:
P_chrom <- paste0("chr",eqtlInfo[1,]$chrom)
eqtlInfo<- eqtlInfo[maf>mafThreshold & maf <1,]
# 去重：
eqtlInfo <- eqtlInfo[order(snpId, pValue)][!duplicated(snpId)]
# subset:
eqtlInfo <- na.omit( eqtlInfo[,.(rsid=snpId, maf=as.numeric(maf), beta, se, pValue=as.numeric(pValue), position=as.numeric(position))] )
if(nrow(eqtlInfo)==0){
message("Number of eQTL association is <1")
return(NULL)
}
message("Data processing...")
##################### gwas dataset:
gwasDF <- gwasDF[,1:7]
data.table::setDT(gwasDF)
names(gwasDF) <- c("rsid", "chr", "position", "pValue", "maf", "beta", "se")
# gwas subset:
gwasDF <- na.omit(gwasDF)
p_chrom_tmp <- ifelse(stringr::str_detect(gwasDF[1,]$chr, "chr"),P_chrom, stringr::str_remove(P_chrom, "chr"))
gwasDF <- gwasDF[chr==p_chrom_tmp,]
# convert variable class:
gwasDF[,c("position", "pValue", "maf", "beta", "se"):=.(as.numeric(position), as.numeric(pValue), as.numeric(maf), as.numeric(beta), as.numeric(se))]
# MAF filter:
gwasDF <- gwasDF[maf > mafThreshold & maf<1,]
# 去重：
gwasDF <- gwasDF[order(rsid, pValue)][!duplicated(rsid)]
# retain SNPs with rs id:
gwasDF <- gwasDF[stringr::str_detect(rsid,stringr::regex("^rs")),]
# chromosome revise：
if( !str_detect(gwasDF[1,]$chr, stringr::regex("^chr")) ){
gwasDF$chr <- paste0("chr", gwasDF$chr)
}
##### convert to grch38:
if(genomeVersion == "grch37"){
message("== Converting GWAS coordinate to GRCH38... ")
if(suppressMessages(!requireNamespace("rtracklayer"))){
message("Package [rtracklayer] is not installed! please install [rtracklayer] with following: ")
message("---------")
message('\"if (!require("BiocManager", quietly = TRUE)); BiocManager::install("rtracklayer")\"')
message("---------")
}
path = system.file(package="xQTLbiolinks", "extdata", "hg19ToHg38.over.chain")
ch = rtracklayer::import.chain(path)
dataRanges <- GenomicRanges::GRanges(gwasDF$chr,
IRanges::IRanges(gwasDF$position, gwasDF$position),
strand= "*",
gwasDF[,.(rsid, maf, pValue, beta, se)]
)
dataRanges_hg38 <- unlist(rtracklayer::liftOver(dataRanges, ch))
# retain the SNPs located in chromosome 1:22
dataRanges_hg38 <- dataRanges_hg38[which(as.character(GenomeInfoDb::seqnames(dataRanges_hg38)) %in% paste0("chr", 1:22)),]
message("== ",length(dataRanges_hg38),"/",nrow(gwasDF)," (",round(length(dataRanges_hg38)/nrow(gwasDF)*100,2),"%)"," left.")
gwasDFnew <- cbind(data.table::data.table(rsid = dataRanges_hg38$rsid, maf=dataRanges_hg38$maf, pValue=dataRanges_hg38$pValue, beta=dataRanges_hg38$beta, se=dataRanges_hg38$se),
data.table::data.table(chr = as.character(GenomeInfoDb::seqnames(dataRanges_hg38)), position=as.data.table(IRanges::ranges(dataRanges_hg38))$start ))
gwasDF <- gwasDFnew[chr==P_chrom,.(rsid, chr, position, pValue, maf, beta, se)]
rm(dataRanges, dataRanges_hg38, gwasDFnew)
}
#
tissueSiteDetailId <- tissueSiteDetailGTExv8[tissueSiteDetail, on="tissueSiteDetail"]$tissueSiteDetailId
gwasEqtlInfo <- merge(gwasDF, eqtlInfo[,.(rsid, maf, pValue, position,beta, se)], by=c("rsid", "position"), suffixes = c(".gwas",".eqtl"))
gwasEqtlInfo <- gwasEqtlInfo[se.eqtl !=0 & se.gwas !=0, ]
if(nrow(gwasEqtlInfo)==0){
message("No shared variants between eQTL and GWAS, please check your input!.")
return(NULL)
}
message("== Start the colocalization analysis of gene [", traitGene,"]")
if(method=="coloc"){
message("== Using method: coloc")
# 防止 check_dataset 中 p = pnorm(-abs(d$beta/sqrt(d$varbeta))) * 2 出错
suppressWarnings(coloc_Out <- coloc::coloc.abf(dataset1 = list( pvalues = gwasEqtlInfo$pValue.gwas, type="quant", N=gwasSampleNum, snp=gwasEqtlInfo$rsid, MAF=gwasEqtlInfo$maf.gwas),
dataset2 = list( pvalues = gwasEqtlInfo$pValue.eqtl, type="quant", N=ifelse(is.na(sampleNum[tissueSiteDetailId, on="tissueSiteDetailId"]$sampleNum), 300, sampleNum[tissueSiteDetailId, on="tissueSiteDetailId"]$sampleNum), snp=gwasEqtlInfo$rsid, MAF= gwasEqtlInfo$maf.eqtl)))
coloc_Out_results <- as.data.table(coloc_Out$results)
# coloc_Out_results$gene <- traitGenes[i]
coloc_Out_summary <- as.data.table(t(as.data.frame(coloc_Out$summary)))
coloc_Out_summary$traitGene <- traitGene
coloc_Out_summary$candidate_snp <- coloc_Out_results[order(-SNP.PP.H4)][1,]$snp
coloc_Out_summary$SNP.PP.H4 <- coloc_Out_results[order(-SNP.PP.H4)][1,]$SNP.PP.H4
message("== Done")
print(coloc_Out_summary)
# coloc_Out_summary$pearsonCoor <- cor(-log(gwasEqtlInfo$pValue.gwas, 10),-log(gwasEqtlInfo$pValue.eqtl, 10), method = "pearson")
return(list(coloc_Out_summary=coloc_Out_summary, gwasEqtlInfo=gwasEqtlInfo))
}
}
#' @title Conduct colocalization analysis with customized QTL data
#'
#' @param gwasDF data.frame or data.table, required cols: rsid, chrom, position, pValue, maf, beta, se
#' @param qtlDF data.frame or data.table, required cols: rsid, chrom, position, pValue, maf, beta, se
#' @param mafThreshold Cutoff of maf to remove rare variants.
#' @param gwasSampleNum Sample number of GWAS dataset. Default:50000.
#' @param qtlSampleNum Sample number of QTL dataset. Default:10000.
#' @param method (character) options: "coloc"(default) or "hyprcoloc" (need a highe version).
#' @param bb.alg For `hyprcoloc`, branch and bound algorithm: TRUE, employ BB algorithm; FALSE, do not. Default: FALSE.
#'
#' @return A list
#' @export
#' @examples
#' \donttest{
#' url1 <- "http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/gwasDFsub_MMP7.txt"
#' url2 <- "http://bioinfo.szbl.ac.cn/xQTL_biolinks/xqtl_data/eqtl/MMP7_qtlDF.txt"
#' gwasDF <- data.table::fread(url1)
#' qtlDF <- data.table::fread(url2)
#' output <- xQTLanalyze_coloc_diy(gwasDF = gwasDF, qtlDF=qtlDF, method="coloc")
#' }
xQTLanalyze_coloc_diy <- function(gwasDF, qtlDF, mafThreshold=0.01, gwasSampleNum=50000, qtlSampleNum=10000, method="coloc", bb.alg=FALSE){
rsid <- chrom <- chr <- position <- se <- pValue <- snpId <- maf <- pos <- i <- variantId <- se.eqtl <- se.gwas <-SNP.PP.H4 <- beta.eqtl <- beta.gwas <- posterior_prob <- regional_prob <-candidate_snp <- posterior_explained_by_snp <- NULL
. <- NULL
if(method == "coloc" && !requireNamespace("coloc")){
stop("please install package \"coloc\" with install.packages(\"coloc\").")
}
# eqtl dataset:
names(qtlDF) <- c("rsid", "chrom", "position", "pValue", "maf", "beta", "se")
# chromosome:
P_chrom <- ifelse(stringr::str_detect(qtlDF[1, ]$chr, "chr"), qtlDF[1, ]$chr, paste0("chr", qtlDF[1, ]$chr))
eqtlInfo <- qtlDF[,.(rsid,chrom, maf=as.numeric(maf), beta=as.numeric(beta), se=as.numeric(se), pValue=as.numeric(pValue), position=as.numeric(position))]
eqtlInfo<- eqtlInfo[maf>mafThreshold & maf <1,]
# 去重：
eqtlInfo <- eqtlInfo[order(rsid, pValue)][!duplicated(rsid)]
if(nrow(eqtlInfo)==0){
message("Number of eQTL association is <1")
return(NULL)
}
message("Data processing...")
##################### gwas dataset:
gwasDF <- gwasDF[,1:7]
data.table::setDT(gwasDF)
names(gwasDF) <- c("rsid", "chr", "position", "pValue", "maf", "beta", "se")
# gwas subset:
gwasDF <- na.omit(gwasDF)
# chromosome revise：
if( !stringr::str_detect(gwasDF[1,]$chr, stringr::regex("^chr")) ){
gwasDF$chr <- paste0("chr", gwasDF$chr)
}
# convert variable class:
gwasDF[,c("position", "pValue", "maf", "beta", "se"):=.(as.numeric(position), as.numeric(pValue), as.numeric(maf), as.numeric(beta), as.numeric(se))]
# MAF filter:
gwasDF <- gwasDF[maf > mafThreshold & maf<1,]
# 去重：
gwasDF <- gwasDF[order(rsid, pValue)][!duplicated(rsid)]
# retain SNPs with rs id:
# gwasDF <- gwasDF[stringr::str_detect(rsid,stringr::regex("^rs")),]
message(nrow(gwasDF))
#
gwasEqtlInfo <- merge(gwasDF, eqtlInfo[,.(rsid, maf, pValue, position,beta, se)], by=c("rsid", "position"), suffixes = c(".gwas",".eqtl"))
gwasEqtlInfo <- gwasEqtlInfo[se.eqtl !=0 & se.gwas !=0, ]
if(nrow(gwasEqtlInfo)==0){
message("No shared variants between eQTL and GWAS, please check your input!.")
return(NULL)
}
message("== Start the colocalization analysis")
if(method=="coloc"){
message("== Using method: coloc")
# 防止 check_dataset 中 p = pnorm(-abs(d$beta/sqrt(d$varbeta))) * 2 出错
suppressWarnings(coloc_Out <- coloc::coloc.abf(dataset1 = list( pvalues = gwasEqtlInfo$pValue.gwas, type="quant", N=gwasSampleNum, snp=gwasEqtlInfo$rsid, MAF=gwasEqtlInfo$maf.gwas),
dataset2 = list( pvalues = gwasEqtlInfo$pValue.eqtl, type="quant", N=qtlSampleNum, snp=gwasEqtlInfo$rsid, MAF= gwasEqtlInfo$maf.eqtl)))
coloc_Out_results <- as.data.table(coloc_Out$results)
# coloc_Out_results$gene <- traitGenes[i]
coloc_Out_summary <- as.data.table(t(as.data.frame(coloc_Out$summary)))
coloc_Out_summary$candidate_snp <- coloc_Out_results[order(-SNP.PP.H4)][1,]$snp
coloc_Out_summary$SNP.PP.H4 <- coloc_Out_results[order(-SNP.PP.H4)][1,]$SNP.PP.H4
message("== Done")
print(coloc_Out_summary)
# coloc_Out_summary$pearsonCoor <- cor(-log(gwasEqtlInfo$pValue.gwas, 10),-log(gwasEqtlInfo$pValue.eqtl, 10), method = "pearson")
return(list(coloc_Out_summary=coloc_Out_summary, gwasEqtlInfo=gwasEqtlInfo))
}
if(method=="hyprcoloc"){
stop("Please install package hyprcoloc and update to the latest version (v1.6.3) ")
}
}
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