LoF variant burden

Gene-based burden test results of loss of function variants (LoFs).

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

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.