Genotyping Array Design and Data Quality Control in the Million Veteran Program

Abstract

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with wholegenome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction

“…Informed consent is obtained from all participants to provide blood for genomic analysis and access to their full EHR data within the VA prior to and after enrollment. Imputed genetic information is available for up to 314,434 participants assigned to white-European ancestry using the HARE algorithm 57,58 . We used inpatient and outpatient ICD9/10 diagnostic and Current Procedural Terminology codes to identify subjects with clinical CAD either before enrollment going back to 2002 or after enrollment until mid-August 2018.…”

A review of UMAP in population genetics

“…Figure 4a and b visualize, respectively, the Genome Aggregation Database (gnomAD v3) from the Broad Institute [10] and Biobank Japan (BBJ) [11,12], each of which contains over 100, 000 individuals. When applied to ethnically diverse groups such as the UKB, BioMe [13], and the Million Veterans Program (MVP) [14], UMAP tends to highlight groups with different international migration and admixture histories. In relatively more homogeneous populations such as BBJ, it highlights clusters related to geographic features such as island populations.…”

Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Historical Cholesterol Exposure

“…DNA from peripheral blood collected at the time of enrolment was used to genotype participants with a custom array, enriched for known pathogenic variants, rare missense variants, indels, and loss-of-function variants. 9 These data were linked to EHR data, including International Classification of Disease (ICD) diagnosis and procedure codes, Current Procedural Terminology (CPT) codes, prescription data, and clinical laboratory measurements. A majority of EHR-based follow up for MVP participants is presently still captured prior to enrollment, given the VA adopted an EHR over 2 decades ago, and most veterans participating in MVP have received care at the VA over a similar period of time.…”

“…Sample collection, genotyping array, and quality control for MVP have been previously described. 9 Minimac version 4 was used for imputation with the 1000 Genomes phase 3 (version 5) reference haplotypes. 10 We assessed the LDLR, APOB, and PCSK9 loci for putative FH-causing variants.…”