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+---
+layout: default
+title: Estimate effect sizes and heritability for rare variants  
+nav_order: 9
+description: "RareEffect is a novel method to estimate the variant-level effect size (beta) and region-level (gene-level) heritability for rare variants"
+has_children: false
+has_toc: true
+---
+
+# RareEffect
+
+RareEffect is a novel method to estimate the variant-level effect size (beta) and region-level (gene-level) heritability for rare variants.
+RareEffect is integrated into SAIGE and is available in SAIGE version 1.3.x or higher.
+
+## Procedure
+
+1. First, run SAIGE step 1. The output file from SAIGE step 1 (`.rda` file) will be used as the input for RareEffect.
+2. The inputs for RareEffect are as follows:
+
+  * Genotype file (plink bed/bim/fam)
+  * Group file (same format as the group file for SAIGE-GENE+)
+  * SAIGE step 1 output rda file
+
+3. Execute the main function of RareEffect. An example command is provided below.
+
+```
+Rscript run_RareEffect.R \
+    --rdaFile=$PATH_TO_RDA_FILE \
+    --chrom=$CHR \
+    --geneName=$GENE_NAME \
+    --groupFile=$PATH_TO_GROUP_FILE \
+    --traitType=binary \
+    --bedFile=$PATH_TO_BED_FILE \
+    --bimFile=$PATH_TO_BIM_FILE \
+    --famFile=$PATH_TO_FAM_FILE \
+    --macThreshold=10 \
+    --collapseLoF=FALSE \
+    --outputPrefix=$PATH_TO_OUTPUT_FILE
+```
+
+  * rdaFile: SAIGE step 1 output file
+  * chrom: chromosome number (eg. 11)
+  * geneName: name of gene to analyze (eg. APOC3)
+  * groupFile: group file containing variant list and functional annotations.
+  * traitType: type of trait to be analyzed, `binary` or `quantitative`
+  * bedFile, bimFile, famFile: genotype file
+  * macThreshold: minor allele count threshold for ultra-rare variant collapsing
+  * collapseLoF: if true, RareEffect collapses all LoF variants into one super-variant like Burden test (regardless of their MAC)
+  * outputPrefix: path to output
+
+4. RareEffect generates two output files: variant-level effect size and region-level heritability.
+
+  * Variant-level effect size
+
+```
+variant          effect              PEV
+11:116830637:C:T 0.304491201231766   0.00727297925199994
+11:116830638:G:A 0.325660176157425   0.000662034527515423
+11:116830638:G:T 0.21230324192781    0.0645359637154959
+11:116830897:G:T 0.310004879463224   0.060623563613811
+lof_UR           0.261071923418984   0.0869925579756295
+11:116830533:G:A -0.0631819446554343 0.0235133013294374
+11:116830620:C:T -0.0130476721146154 0.0539691054813582
+11:116830787:G:A 0.0448881905903484  0.0317167120002997
+11:116830833:C:A 0.310894962948392   0.0570479313033626
+```
+
+  * Region-level heritability
+
+```
+LoF                 mis                 syn                  all
+0.00326766343863732 0.00028977664861778 3.21446473889367e-05 0.00358958473464404
+```
+
+5. Using the variant-level effect size from RareEffect, you can calculate the polygenic score in another cohort.
+
+```
+Rscript calculate_RareEffect_PRS.R \
+    --effectFile $PATH_TO_EFFECT_SIZE_FILE \
+    --bedFile $PATH_TO_BED_FILE \
+    --bimFile $PATH_TO_BIM_FILE \
+    --famFile $PATH_TO_FAM_FILE \
+    --groupFile $PATH_TO_GROUP_FILE \
+    --geneName $GENE_NAME \
+    --variantListFile $PATH_TO_VARIANT_LIST_FILE \
+    --outputPrefix $PATH_TO_OUTPUT_FILE
+```
+
+  * effectFile: variant-level effect size output from RareEffect main function
+  * variantListFile: list of common and rare, but non-ultra-rare variants. These variants will not be used for ultra-rare variant scoring.
+
+  * Individual RareEffect PRS
+```
+IID     PRS
+1000019 0
+1000022 0
+1000035 0
+1000046 0
+1000054 0
+1000063 0
+1000078 0.48012911
+1000081 0
+1000090 0
+1000105 0
+```
+
+## Example output
+
+We estimated variant-level effect size and gene-level heritability for genome-wide significant genes (or top 10 genes) using 393,247 White British individuals in UKB WES data.
+The example output files can be downloaded at:
+  * Variant-level effect size: https://storage.googleapis.com/leelabsg/RareEffect/RareEffect_effect_size.zip
+  * Gene-level signed heritability: https://storage.googleapis.com/leelabsg/RareEffect/RareEffect_h2.zip