SuSiEx

SuSiEx is a C++ based command line tool that performs cross-ancestry fine-mapping using GWAS summary statistics and LD reference panels. The method is built on the Sum of Single Effects (SuSiE) model:

Wang, G., Sarkar, A., Carbonetto, P. & Stephens, M. A simple new approach to variable selection in regression, with application to genetic fine mapping. J. R. Stat. Soc. Series B Stat. Methodol. 82, 1273–1300 (2020). https://doi.org/10.1111/rssb.12388

Citation

Our method has been published in Nature Genetics. If you use SuSiEx in a published analysis, please cite our article:

Yuan, K., Longchamps, R. J., Pardiñas, A. F., Yu, M., Chen, T.-T., Lin, S.-C., Chen, Y., Lam, M., Liu, R., Xia, Y., Guo, Z., Shi, W., Shen, C., Schizophrenia Workgroup of Psychiatric Genomics Consortium, Daly, M. J., Neale, B. M., Feng, Y.-C. A., Lin, Y.-F., Chen, C.-Y., O’Donovan, M. C., Ge, T. & Huang, H. Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases. Nat. Genet. 56, 1841–1850 (2024). https://doi.org/10.1038/s41588-024-01870-z

Getting Started

• Clone this repository using the following git command:

  git clone https://github.com/getian107/SuSiEx.git

  Alternatively, download the source files from the github website (https://github.com/getian107/SuSiEx).

• SuSiEx requires C++ compiler GCC (https://gcc.gnu.org/) and parallel programming library OpenMP (https://www.openmp.org/) installed.

• Compile SuSiEx using the following command:

  cd src

  make all

• Or try the static compiled version, which is available in the bin_static folder.

• Once the compling is done, the executable SuSiEx will be found in the bin folder. Type

  ../bin/SuSiEx --help or ../bin/SuSiEx -h

  will print a list of command-line options.

Using SuSiEx

SuSiEx \
  --sst_file=SUM_STATS_FILE \ 
  --n_gwas=GWAS_SAMPLE_SIZE \ 
  --ref_file=REF_FILE \ 
  --ld_file=LD_MATRIX_FILE \ 
  --out_dir=OUTPUT_DIR \ 
  --out_name=OUTPUT_FILENAME \ 
  --chr=CHR \ 
  --bp=BP \ 
  --chr_col=CHR_COL \ 
  --snp_col=SNP_COL \ 
  --bp_col=BP_COL \ 
  --a1_col=A1_COL \ 
  --a2_col=A2_COL \ 
  --eff_col=EFF_COL \ 
  --se_col=SE_COL \ 
  --pval_col=PVAL_COL \ 
  --plink=PLINK \ 
  [ --keep-ambig=KEEP_AMBIGUOUS_SNPS \ ]
  [ --maf=MAF_THRESHOLD \ ]
  [ --n_sig=NUMBER_OF_SIGNALS \ ]
  [ --level=LEVEL \ ]
  [ --min_purity=MINIMUM_PURITY \ ]
  [ --mult-step=MULT_STEP_FITTING \ ]
  [ --pval_thresh=MARGINAL_PVAL_THRESHOLD \ ]
  [ --max_iter=MAXIMUM_ITERATIONS \ ]
  [ --tol=TOLERANCE \ ]
  [ --threads=N_THREADS ]

• SUM_STATS_FILE (required): Full path and filename of the GWAS summary statistics for each population, separated by comma. Each file must contain a header line. The column corresponding to the effect size estimates must have a header of BETA or OR, indicating whether the effect estimates are regression coefficients or odds ratios.

• GWAS_SAMPLE_SIZE (required): Sample size of the GWAS for each population, in the order corresponding to the GWAS summary statistics files, separated by comma.

• REF_FILE (optional): Full path and filename prefix of the reference panel for each population in PLINK binary format (.bed/.bim/.fam), in the order corresponding to the GWAS summary statistics files, separated by comma. The format for SNP IDs (e.g., rs IDs or chr:bp:a1:a2) and version of genome build must be consistent across GWAS summary statistics files and reference panels. A curated 1000 Genomes phase 3 reference panle in PLINK format can be download from the MAGMA website: https://ctg.cncr.nl/software/magma.

• LD_MATRIX_FILE (required): Full path and filename prefix of the LD matrix to be computed from the reference panels for each population, in the order corresponding to the GWAS summary statistics files, separated by comma. If LD matrices with the specified filenames already exist in the specified directory, the calculation of LD will be skipped and existing LD files will be used directly. A script for precomputing LD matrices and allele frequency files is available in the utilities folder.

• OUTPUT_DIR (required): Full path of the output directory.

• OUTPUT_FILENAME (required): Prefix of the output files.

• CHR (required): Chromosome of the fine-mapping region.

• BP (required): The start and end base pair coordinate of the fine-mapping region, separated by comma.

• CHR_COL (required): The column number of the chromosome code in each GWAS summary statistics file, separated by comma.

• SNP_COL (required): The column number of the SNP IDs in each GWAS summary statistics file, separated by comma.

• BP_COL (required): The column number of the base pair coordinate in each GWAS summary statistics file, separated by comma.

• A1_COL (required): The column number of the A1 allele (effective allele) in each GWAS summary statistics file, separated by comma.

• A2_COL (required): The column number of the A2 allele (alternative allele) in each GWAS summary statistics file, separated by comma.

• EFF_COL (required): The column number of the effect size estimate (beta or odds ratio) in each GWAS summary statistics file, separated by comma. SuSiEx will automatically recognize columns labeled with a prefix of "beta" as beta and a prefix of "or" as odds ratio (case-insensitive).

• SE_COL (required): The column number of the standard error of the effect size estimate in each GWAS summary statistics file, separated by comma.

• PVAL_COL (required): The column number of the p-value in each GWAS summary statistics file, separated by comma.

• PLINK (optional): The full path and filename of PLINK if LD matrices do not exist and need to be calculated from the reference panels.

• KEEP_AMBIGUOUS_SNPS (optional): If False, all ambiguous SNPs (A/T and G/C SNPs) will be removed; if True, ambiguous SNPs whose A1 and A2 can be matched with the A1 and A2 in the reference panel via allele flip will be retained. Default is False.

• MAF_THRESHOLD (optional): Minor allele frequency (MAF) threshold applied to the reference panel. Default is 0.005.

• NUMBER_OF_SIGNALS (optional): Maximum number of causal signals in the SuSiEx model. Default is 5.

• LEVEL (optional): Coverage level of the credible set. Default is 95%.

• MINIMUM_PURITY (optional): Minimum purity of the credible set. Credible sets with purity below this specified value will be filtered out. Default is 0.5.

• MULT_STEP_FITTING (optional): Use the multi-step modeling fitting approach. The model is first fitted using 5 signals. If the algorithm doesn't converge, the maximum number of signals is progressively reduced from 5 to 1 until convergence. If 5 credible sets are identified, the maximum number of signals is increased to 10. If the algorithm doesn't converge with 10 signals, the maximum number of signals is then progressively reduced from 10 to 5 until convergence. Default is False.

• MARGINAL_PVAL_THRESHOLD (optional): Filtering threshold for the marginal p-value. Credible sets containing no marginal p-value below this specified value will be filtered out. Default is 1e-05.

• MAXIMUM_ITERATIONS (optional): Maximum number of iterations allowed for the model fitting algorithm. Default is 100.

• TOLERANCE (optional): Tolerance for the convergence of the variational algorithm. Default is 1e-04.

• N_THREADS (optional): Number of threads for computation. Default is 1.

Output

A .summary file, a .cs file and a .snp file will be written to the specified output directory.

If the varitional algorithm did not converge, "FAIL" will be written to both the .summary file and the .cs file. If no credible set was identified at the specified coverage level after purity and marginal p-value filtering, "NULL" will be written to both the .summary file and the .cs file.

Otherwise, the .summary file contains credible set level information, which has a header line of the fine-mapping region and the following columns:

• CS_ID: ID of the credible set.

• CS_LENGTH: Size (number of SNPs) of the credible set.

• CS_PURITY: Purity of the credible set.

• MAX_PIP_SNP: SNP in the credible set that had the largest posterior inclusion probability (PIP).

• BP: The base pair coordinate of the MAX_PIP_SNP.

• REF_ALLELE: The reference allele of the MAX_PIP_SNP in each population, separated by comma.

• ALT_ALLELE: The alternative allele of the MAX_PIP_SNP in each population, separated by comma.

• REF_FRQ: Frequency of the reference allele in each reference panel, separated by comma.

• BETA: Marginal per-allele effect size of the MAX_PIP_SNP with respect to the reference allele in each population, separated by comma.

• SE: The standard error of the marginal per-allele effect size of the MAX_PIP_SNP in each population, separated by comma.

• -LOG10P: -log10 of the marginal p-value of the MAX_PIP_SNP in each population, separated by comma.

• MAX_PIP: Maximum posterior inclusion probability (PIP) in the credible set.

• POST-HOC_PROB_POP${i}: Post hoc probability credible set manifest causal in population ${i}.

The .cs file contains information for all the SNPs included in credible sets and has the following columns:

• CS_ID: ID of the credible set.

• SNP: SNP identifier.

• BP: The base pair coordinate of the SNP.

• REF_ALLELE: The reference allele of the SNP in each population, separated by comma.

• ALT_ALLELE: The alternative allele of the SNP in each population, separated by comma.

• REF_FRQ: Frequency of the reference allele in each reference panel, separated by comma.

• BETA: Marginal per-allele effect size of the SNP with respect to the reference allele in each population, separated by comma.

• SE: The standard error of the marginal per-allele effect size of the SNP in each population, separated by comma.

• -LOG10P: -log10 of the marginal p-value of the SNP in each population, separated by comma.

• CS_PIP: Posterior inclusion probability (PIP) of the SNP.

• OVRL_PIP: Posterior inclusion probability (PIP) of the SNP in any of the credible set.

The .snp file contains information for all the SNPs that are used in the fine-mapping algorithm. These are the SNPs that are located in the specified fine-mapping region, available in the GWAS summary statistics and the reference panel for at least one population, and survived the minor allele frequency filtering. It has the following columns:

• BP: The base pair coordinate of the SNP.

• SNP: SNP identifier.

• PIP(CS${i}): The posterior inclusion probability (PIP) of the SNP in credible set ${i}.

• LogBF(CS${i},Pop${j}): The Logarithm of Bayes factor for credible set ${i}, population ${j}. If the variational algorithm successfully converges and credible sets remain after the purity and marginal p-value filtering, the output will include column(s) of Logarithm of Bayes Factor for each population and credible set.

Example

cd eamples
../bin/SuSiEx \
	--sst_file=EUR.sumstats.txt,AFR.sumstats.txt \
	--n_gwas=50000,50000 \
	--ref_file=EUR,AFR \
	--ld_file=EUR,AFR \
	--out_dir=./ \
	--out_name=SuSiEx.EUR.AFR.output.cs95 \
	--level=0.95 \
	--pval_thresh=1e-5 \
	--maf=0.005
	--chr=1 \
	--bp=7314654,8314677 \
	--snp_col=2,2 \
	--chr_col=1,1 \
	--bp_col=3,3 \
	--a1_col=4,4 \
	--a2_col=5,5 \
	--eff_col=6,6 \
	--se_col=7,7 \
	--pval_col=9,9 \
	--plink=../utilities/plink \
	--mult-step=True \
	--keep-ambig=True \
	--threads=16

Support

Please direct questions or bug reports to Kai Yuan (kyuan@broadinstitute.org) and Tian Ge (tge1@mgh.harvard.edu).