Comparing low-pass sequencing and genotyping for trait mapping in pharmacogenetics

Area of Science:

• Genomics
• Pharmacogenetics
• Bioinformatics

Background:

• Low-pass sequencing is a cost-effective method for identifying genetic variants influencing multifactorial traits.
• Genotyping arrays are standard for pharmacogenetic (PGx) studies, which often involve smaller sample sizes but larger effect sizes.

Purpose of the Study:

• To compare low-pass sequencing with array-based genotyping for pharmacogenetics (PGx) applications.
• To evaluate the performance of low-pass sequencing at various coverages (0.4x-1x) for genotype imputation and pharmacogenetic variant identification.

Main Methods:

• Sequenced 79 individuals at 1x genome coverage and genotyped them using the Affymetrix Axiom Biobank Precision Medicine Research Array (PMRA).
• Down-sampled sequencing data to 0.8x, 0.6x, and 0.4x coverage for genotype imputation.
• Imputed human leukocyte antigen (HLA) genotypes from both sequencing and array data.
• Compared overall concordance, concordance at pharmacogenetics-related single nucleotide polymorphisms (SNPs), HLA genotype concordance, and imputation r².

Main Results:

• Overall concordance between low-pass sequencing (0.4x-1x) and arrays ranged from 98.2% to 99.2%.
• Imputation accuracy (r²) at common SNPs was comparable between 0.4x sequencing (0.90) and arrays (0.90), and higher for 1x sequencing (0.96).
• Pharmacogenetic variant concordance mirrored overall concordance.
• Imputed human leukocyte antigen (HLA) genotype concordance was also assessed.

Conclusions:

• Low-pass sequencing above 0.4x coverage demonstrates higher power for pharmacogenetics association studies compared to the PMRA.
• Low-pass sequencing is a competitive alternative to genotyping arrays for trait mapping in pharmacogenetics.