RAREMETALWORKER

Rare-Metal-Worker is a software for generating summary level statistics for meta analyses using Rare-Metals. It handles both related individuals and unrelated individuals.

Change Log

• Version 0.1 is released on 11/13/2012.
• Modified Rare-Metal-Worker to let it output LD matrix by a sliding window. (11/14/2012)

Key Features

Rare-Metal-Worker has the following features:

• Takes genotypes from either Merlin format PED file or VCF file.
• Generates summary level statistics for both related and unrelated individuals.
• Generates variants LD matrix by a sliding window of preferred size.
• Handles related individuals using a kinship matrix derived from the pedigree or from genotype data.
• Has the option of fitting shared environment.
• Can handle variants on Chromosome X.

Software Specifications

Input Files

Rare-Metal-Worker needs the following files as input: PED and DAT file in Merlin format, AND/OR a VCF file. When genotypes are stored in PED and DAT file, VCF file is not needed. However, even if genotypes are saved in a VCF file, PED and DAT files are still needed for carrying covariate and trait information.

PED and DAT Files

• When PED file has genotypes saved, there is no need of VCF file as input.
• Rare-Metal-Worker takes PED and DAT file in Merlin format. Please refer to the following link for specifications.

 http://www.sph.umich.edu/csg/abecasis/merlin/tour/input_files.html

• DAT file must have variant names in the following format "M chr:pos". Here is an example of variant name format in DAT file:

 M 1:123456
 M 1:234567
 M 2:111111
 M 2:222222
 M X:12345
 M X:111111

• Markers in PED and DAT file must be sorted by chromosome and position.

VCF File

• Another option is to use VCF as input. Please refer to the following link for VCF file specification:

  http://www.1000genomes.org/wiki/Analysis/Variant%20Call%20Format/vcf-variant-call-format-version-41  

• VCF file should be compressed by bgzip and indexed by tabix, using the following command:

 bgzip input.vcf     ## this command will produce input.vcf.gz
 tabix -pvcf -f input.vcf.gz  ## this command will produce input.vcf.gz.tbi

Covariates & Traits

• Covariate and trait values are saved in PED file. Covariate and trait descriptions are saved in DAT file.
• It follows Merlin input format as in the above link.

Software Options

The following options are currently available in Rare-Metal-Worker:

   Options:
      Input Files : --ped [Exomechip.pheno.ped], --dat [Exomechip.pheno.dat],
                    --vcf []
     Output Files : --prefix [], --LDwindow [1000000]
       VC Options : --vcShared, --vcX, --useCovariates [ON]
    Trait Options : --makeResiduals, --inverseNormal [ON], --traitName []
   Kinship Source : --kinPedigree [ON], --kinGeno, --kinFile [], --kinSave
  Kinship Options : --kinMaf [0.05], --kinMiss [0.05]
     Chromosome X : --xLabel [X], --xStart [2699520], --xEnd [154931044]

The usage of these options are explained one-by-one using examples in the following:

Input Files

• When genotypes are saved in VCF file, PED and DAT files are also necessary for containing pedigree structure, covariate and trait information. An example is in the following:

 --ped input.ped --dat input.dat --vcf input.vcf.gz

• When genotypes are saved in PED file, VCF file is not needed. An example is in the following:

 --ped input.ped --dat input.dat

Output Files

--prefix is optional.

• If --prefix is not specified, the output file names will be:

 traitname.singlevar.score.txt
 traitname.singlevar.cov.txt

• If --prefix prefix is specified, then the output file names are:

 prefix.traitname.singlevar.score.txt
 prefix.traitname.singlevar.cov.txt

VC Options

• When --vcShared and --vcX are specified, Rare-Metal-Worker know that you want to fit shared environment and/or chromosome X variance component together with genetic component and non-shared environment.
• When --useCovariates is specified, Rare-Metal-Worker understands covariates should be read from PED file. Covariates are fit as fixed effects.

Trait Options

• --makeResiduals is created to be used with --useCovariates together to generate residuals from linear regressions ignoring variance components first and then variance components will be estimated from those residuals. If --inverseNormal options is also used, then the residuals from linear regression will be inverse normalized before fitting variance component model.
  • An example to use residuals after adjusting covariates, inverse normalize the residuals and then fit variance component model is in the following:

  --useCovariates --makeResiduals --inverseNormal

• • An example to fit fixed effects together with variance components is in the following:

  --useCovariates --inverseNormal 

• If --inverseNormal is used WITHOUT --makeResiduals, then trait values are inverse normalized before any model fitting.
• --traitName is created for the situation when you have many traits saved in your PED and DAT file, but you are interested in one or a few of them. It can read a file ending with .txt with each trait of interest in a separate line, or trait names separated with "/". An example to handle one trait or multiple traits is in the following:

  --traitName LDL
  --traitName LDL/HDL/TG
  --traitName traitsOfInterest.txt

Kinship Source

• --kinPed allows Rare-Metal-Worker to generate kinship matrix from pedigree, when pedigree information is available. This option is on by default.
• --kinGeno informs Rare-Metal-Worker to generate kinship matrix from all available variants that pass the criteria, specified in --kinMaf and --kinMiss options. The default will take variants with MAF>0.05 and genotype missing rate <0.05.
• --kinFile let Rare-Metal-Worker read in a kinship matrix from a file. However, the kinship matrix has to be generated using Rare-Metal-Worker previously.
• --kinSave allows you to save the kinship.

Chromosome X

• --xStart and --xEnd specifies the start and end of non-pseudo-autosomal regions on chromosome X. These options should be specified when --fitX is used.

Other Options

• --LDwindow specifies the size of the window to calculate variants LD matrix. The default is 1MB.

Handling Unrelated Individuals

• To let Rare-Metal-Worker handle unrelated individuals, we just have to code the individuals as unrelated in PED file, or each individual belongs to a unique family. Then Rare-Metal-Worker will take care of the rest.
• However, when --kinGenotype is also used, Rare-Metal-Worker will consider them as related and generate kinship matrix from genotypes.
• An example is shown as following (header is for illustration purpose, not in real PED file):

  famid pid fid mid sex age trait
  1     1.1   0   0   1  10  -0.3
  2     2.1   0   0   1  56  0.0
  3     3.1   0   0   2  31  0.4
  4     4.1   0   0   2  23  0.008
  5     5.1   0   0   2  34  2.35

Examples

Related individuals

• When you have genotype stored in ped file and dat file, and want to use pedigree kinship:

 /bin/Rare-Metal-Worker --ped yourInput.ped --dat yourInput.dat --traitName LDL

• When you have genotype stored in ped file and dat file, and want to use kinship generated from genotypes:

 /bin/Rare-Metal-Worker --ped yourInput.ped --dat yourInput.dat --kinGeno --kinSave --traitName LDL (--kinSave allows you to save kinship matrix for future use.)

• When you have genotype stored in vcf file and want to use pedigree kinship:

 /bin/Rare-Metal-Worker --ped yourInput.ped --dat yourInput.dat --vcf yourInput.vcf.gz

• When you have genotype stored in vcf file and want to use kinship generated from genotype:

 /bin/Rare-Metal-Worker --ped yourInput.ped --dat yourInput.dat --vcf yourInput.vcf.gz --kinGeno --kinSave (--kinSave allows you to save kinship matrix for future use.)

Unrelated individuals

• Command are the same as in above example, except each individual has to have a distinct family ID in ped file.