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Fine-mapping

Introduction

Fine-mapping : Fine-mapping aims to identify the causal variant(s) within a locus for a disease, given the evidence of the significant association of the locus (or genomic region) in GWAS of a disease.

Fine-mapping using individual data is usually performed by fitting the multiple linear regression model:

\[y = Xb + e\]
  • \(b = (b_1, …, b_J)^T\) is a vector of genetic effects of variants.

Fine-mapping (using Bayesian methods) aims to estimate the PIP (posterior inclusion probability), which indicates the evidence for SNP j having a non-zero effect (namely, causal).

PIP(Posterior Inclusion Probability)

PIP is often calculated by the sum of the posterior probabilities over all models that include variant j as causal.

\[ PIP_j:=Pr(b_j\neq0|X,y) \]

Bayesian methods and Posterior probability

\[ Pr(M_m | O) = {{Pr(O | M_m) Pr(M_m)}\over{\sum_{i=1}^n{Pr( O | M_i) Pr(M_i)}}} \]

\(O\) : Observed data

\(M\) : Models (the configurations of causal variants in the context of fine-mapping).

\(Pr(M_m | O)\): Posterior Probability of Model m

\(Pr(O | M_m)\): Likelihood (the probability of observing your dataset given Model m is true.)

\(Pr(M_m)\): Prior distribution of Model m (the probability of Model m being true)

\({\sum_{i=1}^n{Pr( O | M_i) Pr(M_i)}}\): Evidence (the probability of observing your dataset), namely \(Pr(O)\)

Credible sets

A credible set refers to the minimum set of variants that contains all causal SNPs with probability \(α\). (Under the single-causal-variant-per-locus assumption, the credible set is calculated by ranking variants based on their posterior probabilities, and then summing these until the cumulative sum is \(>α\)). We usually report 95% credible sets (α=95%) for fine-mapping analysis.

Commonly used tools for fine-mapping

Methods assuming only one causal variant in the locus

  • ABF

Methods assuming multiple causal variants in the locus

  • SUSIE / SUSIE-RSS
  • CAVIAR, CAVIARBF, eCAVIAR
  • FINEMAP

Methods assuming a small number of larger causal effects with a large number of infinitesimal effects

  • SUSIE-inf
  • FINEMAP-inf

Methods for Cross-ancestry fine-mapping

  • SUSIEX

You can check here for more information.

In this tutorial, we will introduce SuSiE as an example. SuSiE stands for Sum of Single Effects” model.

The key idea behind SuSiE is :

\[b = \sum_{l=1}^L b_l \]

where each vector \(b_l = (b_{l1}, …, b_{lJ})^T\) is a so-called single effect vector (a vector with only one non-zero element). L is the upper bound of number of causal variants. And this model could be fitted using Iterative Bayesian Stepwise Selection (IBSS).

For fine-mapping with summary statistics using Susie (SuSiE-RSS), IBSS was modified (IBSS-ss) to take sufficient statistics (which can be computed from other combinations of summary statistics) as input. SuSie will then approximate the sufficient statistics to run fine-mapping.

Quote

For details of SuSiE and SuSiE-RSS, please check : Zou, Y., Carbonetto, P., Wang, G., & Stephens, M. (2022). Fine-mapping from summary data with the “Sum of Single Effects” model. PLoS Genetics, 18(7), e1010299. Link

File Preparation

  • Sumstats for the loci
  • SNP list for calculating LD matrix

Using python to check novel loci and extract the files.

import gwaslab as gl
import pandas as pd
import numpy as np

sumstats = gl.Sumstats("../06_Association_tests/1kgeas.B1.glm.firth",fmt="plink2")
...

sumstats.basic_check()
...

sumstats.get_lead()

Fri Jan 13 23:31:43 2023 Start to extract lead variants...
Fri Jan 13 23:31:43 2023  -Processing 1122285 variants...
Fri Jan 13 23:31:43 2023  -Significance threshold : 5e-08
Fri Jan 13 23:31:43 2023  -Sliding window size: 500  kb
Fri Jan 13 23:31:44 2023  -Found 59 significant variants in total...
Fri Jan 13 23:31:44 2023  -Identified 3 lead variants!
Fri Jan 13 23:31:44 2023 Finished extracting lead variants successfully!

SNPID CHR POS EA  NEA SE  Z P OR  N STATUS
110723  2:55574452:G:C  2 55574452  C G 0.160948  -5.98392  2.178320e-09  0.381707  503 9960099
424615  6:29919659:T:C  6 29919659  T C 0.155457  -5.89341  3.782970e-09  0.400048  503 9960099
635128  9:36660672:A:G  9 36660672  G A 0.160275  5.63422 1.758540e-08  2.467060  503 9960099
We will perform fine-mapping for the first significant loci whose lead variant is 2:55574452:G:C.

# filter in the variants in the this locus.

locus = sumstats.filter_value('CHR==2 & POS>55074452 & POS<56074452')
locus.fill_data(to_fill=["BETA"])
locus.harmonize(basic_check=False, ref_seq="/Users/he/mydata/Reference/Genome/human_g1k_v37.fasta")
locus.data.to_csv("sig_locus.tsv",sep="\t",index=None)
locus.data["SNPID"].to_csv("sig_locus.snplist",sep="\t",index=None,header=None)

check in terminal: 

head sig_locus.tsv
SNPID   CHR     POS     EA      NEA     BETA    SE      Z       P       OR      N       STATUS
2:54535206:C:T  2       54535206        T       C       0.30028978      0.142461        2.10786 0.0350429       1.35025 503     9960099
2:54536167:C:G  2       54536167        G       C       0.14885099      0.246871        0.602952        0.546541        1.1605  503     9960099
2:54539096:A:G  2       54539096        G       A       -0.0038474211   0.288489        -0.0133355      0.98936 0.99616 503     9960099
2:54540264:G:A  2       54540264        A       G       -0.1536723      0.165879        -0.926409       0.354234        0.857553        503     9960099
2:54540614:G:T  2       54540614        T       G       -0.1536723      0.165879        -0.926409       0.354234        0.857553        503     9960099
2:54540621:A:G  2       54540621        G       A       -0.1536723      0.165879        -0.926409       0.354234        0.857553        503     9960099
2:54540970:T:C  2       54540970        C       T       -0.049506452    0.149053        -0.332144       0.739781        0.951699        503     9960099
2:54544229:T:C  2       54544229        C       T       -0.14338203     0.151172        -0.948468       0.342891        0.866423        503     9960099
2:54545593:T:C  2       54545593        C       T       -0.1536723      0.165879        -0.926409       0.354234        0.857553        503     9960099

head  sig_locus.snplist
2:54535206:C:T
2:54536167:C:G
2:54539096:A:G
2:54540264:G:A
2:54540614:G:T
2:54540621:A:G
2:54540970:T:C
2:54544229:T:C
2:54545593:T:C
2:54546032:C:G

LD Matrix Calculation

Example

#!/bin/bash

plinkFile="../01_Dataset/1KG.EAS.auto.snp.norm.nodup.split.maf005.thinp020"

# LD r matrix
plink \
  --bfile ${plinkFile} \
  --keep-allele-order \
  --r square \
  --extract sig_locus.snplist \
  --out sig_locus_mt

# LD r2 matrix
plink \
  --bfile ${plinkFile} \
  --keep-allele-order \
  --r2 square \
  --extract sig_locus.snplist \
  --out sig_locus_mt_r2
Take a look at the LD matrix (first 5 rows and columns)

head -5 sig_locus_mt.ld | cut -f 1-5
1       -0.145634       0.252616        -0.0876317      -0.0876317
-0.145634       1       -0.0916734      -0.159635       -0.159635
0.252616        -0.0916734      1       0.452333        0.452333
-0.0876317      -0.159635       0.452333        1       1
-0.0876317      -0.159635       0.452333        1       1

head -5 sig_locus_mt_r2.ld | cut -f 1-5
1       0.0212091       0.0638148       0.00767931      0.00767931
0.0212091       1       0.00840401      0.0254833       0.0254833
0.0638148       0.00840401      1       0.204605        0.204605
0.00767931      0.0254833       0.204605        1       1
0.00767931      0.0254833       0.204605        1       1
Heatmap of the LD matrix:

image

Fine-mapping with summary statistics using SusieR

Note

install.packages("susieR")

# Fine-mapping with summary statistics
fitted_rss2 = susie_rss(bhat = sumstats$betahat, shat = sumstats$sebetahat, R = R, n = n, L = 10)

R : a p x p LD r matrix. N : Sample size. bhat : Alternative summary data giving the estimated effects (a vector of length p). This, together with shat, may be provided instead of z. shat : Alternative summary data giving the standard errors of the estimated effects (a vector of length p). This, together with bhat, may be provided instead of z. L : Maximum number of non-zero effects in the susie regression model. (defaul : L = 10)

Quote

For deatils, please check SusieR tutorial - Fine-mapping with susieR using summary statistics

Use susieR in jupyter notebook (with Python):

Please check : https://github.com/Cloufield/GWASTutorial/blob/main/12_fine_mapping/finemapping_susie.ipynb

image

Reference

  • Wang, G., Sarkar, A., Carbonetto, P. & Stephens, M. (2020). A simple new approach to variable selection in regression, with application to genetic fine mapping. Journal of the Royal Statistical Society, Series B 82, 1273–1300. https://doi.org/10.1111/rssb.12388
  • Zou, Y., Carbonetto, P., Wang, G. & Stephens, M. (2021). Fine-mapping from summary data with the “Sum of Single Effects” model. bioRxiv https://doi.org/10.1101/2021.11.03.467167
  • Schaid, Daniel J., Wenan Chen, and Nicholas B. Larson. "From genome-wide associations to candidate causal variants by statistical fine-mapping." Nature Reviews Genetics 19.8 (2018): 491-504.
  • Purcell, Shaun, et al. "PLINK: a tool set for whole-genome association and population-based linkage analyses." The American journal of human genetics 81.3 (2007): 559-575.