> For the complete documentation index, see [llms.txt](https://finngen.gitbook.io/documentation/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://finngen.gitbook.io/documentation/methods/lof-variant-burden.md).

# LoF variant burden

## Variant Selection

Loss of function (LoF) variants were generated from vcf files with VEP (<https://github.com/Ensembl/ensembl-vep>). LoF variants are defined as having one of the following consequences:

* frameshift\_variant
* splice\_donor\_variant
* stop\_gained
* splice\_acceptor\_variant

&#x20;Also, a max\_maf (0.01) and minimum info score (0.8) filters are applied.\
\
This leaves 4,793 genes on autosomal chromosomes that can be used for the association tests.

## Endpoints

We used all 2,752 passing core binary phenotypes in the analyses with the exception of PD\_DEMENTIA\_EXMORE which failed to converge during the association test.

## Association tests

The null models from core additive GWAS runs were used. Tests are performed with regenie --step2 in burden mode using a max mask (i.e. using the maximum number of ALT alleles across sites). Only autosomal chromosomes (1-22) were used in the analysis.