Association tests

Endpoint

We included ​​3,095​ endpoints in the analysis. Endpoints with less than 80 cases or less than 1,000 controls among the 309,154 samples were excluded, as well as endpoints labeled with an OMIT tag in the endpoint definition file.

Null models

For regenie step 1 LOCO prediction computation for each endpoint, we used age, sex, 10 PCs, Finngen 1 or 2 chip or legacy genotyping batch as covariates.

The null model didn’t initially converge for three phenotypes: L12_ALOPECANDRO, DRY_AMD and N14_ENDOMETRIOSIS_FALLOPIAN_TUBE. For the first two, we excluded legacy batches with less than 10 cases from covariates and for N14_ENDOMETRIOSIS_FALLOPIAN_TUBE, we excluded all legacy batches from covariates, and the nulls converged successfully.

For calculating genetic relatedness in regenie step 1, we included variants 1) imputed with an INFO score > 0.95 in all batches and 2) > 97 % non-missing genotypes and 3) MAF > 1 %. The remaining variants were LD pruned with a 1Mb window and r2 threshold of 0.1. This resulted in a set of 55,139 well-imputed not rare variants for relatedness calculation.

We used a genotype block size of 1,000 in regenie step 1.

Association tests

We ran association tests with regenie for each of the 3,095 endpoints for each variant with a minimum allele count of 5 among each phenotype’s cases and controls. We used the approximate Firth test for variants with an initial p-value of less than 0.01 and computed the standard error based on effect size and likelihood ratio test p-value (regenie options --firth --approx --pThresh 0.01 --firth-se).