Genotyping and Imputation of Genetic Variants

DNA extracted from participants’ blood was genotyped using a customized Affymetrix Axiom® biobank array, the MVP 1.0 Genotyping Array. The array was enriched for both common and rare genetic variants of clinical significance in different ethnic backgrounds. Quality-control procedures used to assign ancestry, remove low-quality samples and variants, and perform genotype imputation were previously described^{47 (link)}. We excluded: duplicate samples, samples with more heterozygosity than expected, an excess (>2.5%) of missing genotype calls, or discordance between genetically inferred sex and phenotypic gender^{47 (link)}. In addition, one individual from each pair of related individuals (more than second degree relatedness as measured by the KING software)^{48 (link)} were removed. Prior to imputation, variants that were poorly called (genotype missingness > 5%) or that deviated from their expected allele frequency observed in the 1000 Genomes reference data were excluded. After pre-phasing using EAGLE v2.4^{49 (link)}, we then imputed to the 1000 Genomes phase 3 version 5 reference panel (1000 G) using Minimac4^{50 (link)}. Genotyped SNPs after quality control were interpolated into the imputation file. Imputed variants with poor imputation quality (r² < 0.3) were excluded from further analyses.