Allele definition

How to obtain PGx allele definitions from literature

PGx alleles are collected and distributed through various channels

• PGx alleles on JSON-LD format from the PharmGKB API
• PGx alleles on Excel-style formats, also accessible through the PharmGKB API
• PGx alleles as VCF files from PharmVar

PGx allele definitions are given in either GRCh37 or GRCh38 reference coordinates. The process of changing from GRCh37 to GRCh38 for PharmGKB seems to be only partially completed (at least in the JSON-LD data). The allele definitions from the three sources are not always one-to-one, and some background knowledge about why this is, is required

How to define PGx alleles for next generation sequencing

PGx alleles are defined as collections of one or more SNPs, INDELs or structural variants. When a patient is sequenced by next generation sequencing (NGS) we may typically observe more variants than those which are included in any individual PGx allele definitions.

The 16 possible haplotypes for a four loci, decomposed variant calling

This means that

• Patients may have a large, ambiguous number of matching PGx alleles
• Patients may have additional variants that may modify the effect of a known PGx allele

We illustrate some of the problems that we encountered when trying to match patient haplotypes to the PGx allele definitions, by a four loci PGx gene

The SNP array method

PGx alleles defined as collections of variants, with no requirement on loci that are not part of the definition, will assign the same PGx allele to several different haplotypes

This definition only requires matches for variants explicitly included in PGx allele definitions.

This means that

• Several PGx alleles may match the patient
• But the presence of additional variants will have no effect on reported PGx alleles

The PharmCAT method

This definition requires matches also for variants not explicitly included in PGx allele definitions.

PGx alleles defined as complete haplotypes classifies the patient uniquely

This means that

• Only one PGx allele can exist simultaneously for the same patient
• But whenever we have additional variants, no PGx alleles will be reported

(Note that in practice PharmCAT lets the user decide which allele definitions to use in their NamedAlleleMatcher)

Which definition should we stick to?

Method	Advantages	Disadvantages
SNP array method	Compatible with previous SNP array methods. Assigns PGx alleles to the maximum number of patients	Multiple PGx alleles are possible
PharmCAT method	One PGx allele per patient	Less compatible with previous SNP array methods. Some patients are no longer assigned to a known PGx allele