Polygenic scores

Effect sizes per variant come from a genome-wide association study, that is a weight describing how strongly a risk allele shifts the value. The score multiplies, for each variant, the number of effect alleles carried by its weight and sums all contributions. The PGS Catalog provides these weight lists in a standardised, citable format so a computation stays reproducible and traceable. Each model carries a stable identifier such as PGS000004 that records the source study, effect type, and genome build.

Genome does not use an external score engine; it applies the PGS Catalog weight file directly through its own matching pass. It reads the score file line by line, recognises the columns for rsID, effect allele, and effect weight including the harmonised hm_ columns, and looks up each variant in the sample's genotypes. Per variant it counts the dosage of the effect allele, that is 0, 1, or 2 copies, multiplies it by the weight, and adds the contribution to a running sum; markers flagged as recessive count only at two copies. Before summing, Genome checks at the first shared rsID that the score and SNP files match the same reference genome, and aborts on a divergent position or chromosome. Optional HLA alleles in a model are resolved against an HLA*LA bestguess.txt instead of being estimated from SNP dosages.

A weighted sum depends on which model markers can actually be evaluated in the sample. Genome therefore reports marker coverage and records the PGS identifier and source. Missing markers do not contribute to the calculated sum; depending on their weights, this can shift the score up or down and limit comparability. This matters for short-read WGS when a model includes markers that are absent from the calling pipeline or not covered adequately.

A high score means elevated average risk in the reference population, not certainty for an individual. For populations underrepresented in the source studies, scores are often poorly calibrated, because allele frequencies and linkage patterns differ between ancestry groups; the same score can then land in the wrong part of the distribution. Genome reports only the raw weighted sum together with coverage and does not place it on a percentile or risk scale, since that would require a matching reference distribution. PGS thus remains a research quantity, not a clinical test.