Hello devels/users,

I'm interested in using GENESIS package for admixMapMM function to perform local ancestry association on data on a three-way admixed population. I've inferred local ancestry using RfmixV1. I know location of each SNP, name and per ancestry dosage (0,1,2) information per person. I've two doubts in pipeline I'm learning from (links at end ).

1) Doubt 1

genoDataList <- list()
for (anc in c("eur", "afr", "amer")){
  gdsr <- GdsGenotypeReader(gds, genotypeVar=paste0("dosage_", anc))
  genoDataList[[anc]] <- GenotypeData(gdsr, scanAnnot=scanAnnot)
}

Over here - I think (maybe I'm wrong) the code wants to extract dosage per ancestry. However, when I look at genoDataList$afr, for example, the .gds data contain eur, as well as amer dosage. Detailed code below:

 gds.afr <- GdsGenotypeReader(gds, genotypeVar="dosage_afr")
 gds.afr
File: /tmp/Rtmpt27CXN/file74522ce3bdf6 (66.9M)
+    [  ] *
|--+ sample.id   { Int32,factor 173 ZIP(40.9%), 283B } *
|--+ snp.id   { Int32 20000 ZIP(34.6%), 27.1K }
|--+ snp.position   { Int32 20000 ZIP(34.6%), 27.1K }
|--+ snp.chromosome   { Int32 20000 ZIP(0.13%), 103B }
|--+ genotype   { Bit2 20000x173, 844.7K } *
|--+ dosage_eur   { Int32 173x20000, 13.2M }
|--+ dosage_afr   { Float64 173x20000, 26.4M }
\--+ dosage_amer   { Float64 173x20000, 26.4M }

2) Doubt 2

Information per marker I've is inferred using data (position and chromsome) from imputation(SHAPEIT2-IMPUTE2) which were transformed for RFmixv1 tool input data using reference panels to infer ancestry haplotypes. I don't have genotype (0,1,2) information per SNP per person. However, I have SNP IMPUTE2 dosage information from each SNP, per person for which I've inferred local ancestry. More on IMPUTE2 dosage in doubt 2.c.

The data structure employed in analysis, as shown in above example code has genotype variable. I'd like to know following things:

2.a - Is genotype information used in joint association analysis?

2.b If the genotype information isn't used then how do I create dummy genotype for each person per marker?

2.c If genotype information is used, then, how do I proceed? I can convert imputed data into plink file and proceed, but that's approximated based on posterior probabilities from IMPUTE2 files. The dosage information from IMPUTE2 range from 0-2, a quantitative value, and not the ancestry dosage(0,1,2).

2.d If genotype information is used in association analysis, do you think IMPUTE2 dosage information could be used to perform a joint analysis?

"https://www.biostat.washington.edu/sites/default/files/modules/2017SISG1211admixture_mapping.pdf" https://rdrr.io/bioc/GENESIS/man/admixMapMM.html

R tools and version info:

[1] GENESIS_2.8.1       gdsfmt_1.14.1       GWASTools_1.24.1
[4] Biobase_2.38.0      BiocGenerics_0.24.0
R version 3.4.2 (2017-09-28)
Platform: x86_64-pc-linux-gnu (64-bit)
Running under: Debian GNU/Linux 9 (stretch)

The admixMapMM function is deprecated, and has been replaced by the admixMap function in current versions of GENESIS. However, I think your questions apply equally to the old and new versions.

1. The show method for a GdsGenotypeReader object displays all the information in the GDS file, regardless of which node is chosen to read genotypes from. When you call the getGenotype method on genoDataList$afr, it will read from the dosage_afr node.

2. The admixMapMM and admixMap functions will only use data from the nodes you specify with the genotypeVar argument when you create the GdsGenotypeReader object, as in the example. It looks like you have stored RFMix local ancestry dosages in the "dosageafr", "dosageeur", and "dosage_amer" nodes, which is exactly what the function expects. It will perform a joint test across as many ancestries as you provide in the genoDataList object, which should perhaps be two instead of three, if you only have three ancestries in total. Quoting one of my GENESIS co-authors: "The reason for this is that the sum of all local ancestries at a particular locus must add up to 2, so if there are K ancestry groups, then only K-1 genotypes can be included since one local ancestry count can be written as a linear combination of all of the other local ancestry counts, resulting in collinearity and a matrix that won't be invertible."

The IMPUTE2 genotype dosage should not be used in the admixMap function, but can be used to test for association using assocTestSingle in current versions of GENESIS (or assocTestMM in the version you are using, but please be aware that we can no longer provide support for that version).