Finemapping - how to define a locus?

Question

[nhaus]

I am currently trying to fine-map the significant SNPs that I have identified from my GWAS study.

I read some reviews and decided that I want to use PolyFun (in combination with Susie) to do the job. There, like with any other fine-mapping tool, we operate over each locus of interest individually. The problem is, that I have a hard time understanding how to define the locus, i.e. the start and stop position.

Imagine I have the following SNPs that I want to finemap for chromosome 12:

#CHROM      POS         ID REF ALT A1 TEST OBS_CT     BETA       SE  T_STAT
1:     12 23999769 rs78624193   T   G  G  ADD     92 0.982637 0.198682 4.94578
2:     12 24008435 rs11047132   T   G  G  ADD     92 1.095340 0.212070 5.16500
3:     12 24016182 rs10505909   T   C  C  ADD     92 1.095390 0.212063 5.16540
4:     12 24023714 rs11047141   T   C  C  ADD     92 1.095140 0.212019 5.16530
5:     12 24047496 rs12425715   G   C  C  ADD     92 1.266160 0.252284 5.01879
             P
1: 4.18463e-06
2: 1.75800e-06
3: 1.75519e-06
4: 1.75589e-06
5: 3.14072e-06

How do I determine the appropriate locus? Is it just something like 1MB downstream of SNP1 and 1MB upstream of SNP5?

Any help is much appreciated!

Answer 1

[zx8754]

We defined the region (locus) using 1000 genomes data, either 500KB from index SNPs or in R2 > 0.3, whichever gives wider region.

• Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants (2018)

  Region boundaries for dense genotyping were defined as the greater of ±500 kb from the index SNPs or the maximum distance of any variant with r2 > 0.3 to the index SNP in 1KG (phase 1 version 3, March 2012 release)

Note: for our new publication (in progress) we decided to use 800kb.

Answer 2

[1311703846]

I agree with zx8754, usually flanking 500Kb is a good choice. Additionally, larger windows size could result precision output, so you can using loci larger than 1 MB.