Association tests

Endpoint

We included ​​2,861​ endpoints in the analysis. Endpoints with less than 80 cases among the 260,405 samples were excluded, as well as endpoints labeled with an OMIT tag in the endpoint definition file.

Null models

For null model computation for each endpoint, we used age, sex, 10 PCs and genotyping batch as covariates. Each genotyping batch was included as a covariate for an endpoint if there were at least 10 cases and 10 controls in that batch to avoid convergence issues. One genotyping batch need be excluded from covariates to not have them saturated. We excluded Thermo Fisher batch 16 as it was not enriched for any particular endpoints.

For calculating the genetic relationship matrix, only variants imputed with an INFO score > 0.95 in all batches were used. Variants with > 3 % missing genotypes were excluded as well as variants with MAF < 1 %. The remaining variants were LD pruned with a 1Mb window and r2 threshold of 0.1. This resulted in a set of 59,037 well-imputed not rare variants for GRM calculation.

SAIGE options for the null computation:

• LOCO = false

• numMarkers = 30

• traceCVcutoff = 0.0025

• ratioCVcutoff = 0.001

Association tests

We ran association tests against each of the 2,861 endpoints with SAIGE for each variant with a minimum allele count of 5 from the imputation pipeline (SAIGE optionminMAC = 5). We filtered the results to include variants with an imputation INFO > 0.6.