Why do some individuals defy their polygenic score?

A polygenic score, built from common variants

Each common variant may add a small up or down effect; together they sum to one score.

Illustrative simulation — synthetic data, not real measurements.

Common DNAYour genome carries millions of common variants — small DNA differences shared across people.

Small effectsEach one may nudge a trait a little — some up, some down. Alone, the effect is tiny.

Polygenic scoreSum thousands of them and you get a polygenic score — a single prediction for the trait, the forecast you'll see next.

A population, sorted by genetic prediction

Each dot is a person, placed by polygenic score (across) and observed trait (up).

Illustrative simulation — synthetic data, not real measurements.


	Misaligned	Aligned
Variant observed	—	—
Not observed	—	—

Enrichment odds ratio

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Your turnDrag to set the gene's burden effect and how often it is observed.

Rare-variant burden effect+0.0 SD

Burden frequency0.50%

The populationEach dot is a person. We have lined everyone up by their polygenic score — the prediction baked into common DNA — against the trait they actually have.

AlignedFor most people the forecast holds. Their observed values match the expected values predicted by their common-variant polygenic score, hugging the diagonal. We call them aligned.

MisalignedBut look at the edges. Some sit far above or below the line — observing much more, or much less, of the trait than their score predicted.

The causeWhat can pull them out? A burden of rare, damaging variants in a single gene, counted together. The gold-ringed people harbour these rare variants; watch them climb into the extremes — and the enrichment odds rise.

Your turnThe controls are live — explore how rare-variant burden reshapes the tails.

Part two · Disease, and the liability threshold

Crossing the line

For a disease, the same idea runs through a threshold. Risks add up to a hidden “liability”; cross the line and you are diagnosed.

Liability versus polygenic risk

Above the line: diagnosed cases. Below: controls. Gold marks where rare-variant burden nudged someone.

Illustrative simulation — synthetic data, not real measurements.

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Your turnSlide from protective to pathogenic; set frequency and prevalence.

Rare-variant burden effectnone

Burden frequency0.50%

Disease prevalence6%

LiabilityGenetic and other risks sum into a hidden liability. We plot it against polygenic risk — risk rising as you move right.

The thresholdAbove a threshold you are diagnosed — a case. Below it, a control.

PathogenicA pathogenic burden lifts liability, carrying low-risk people over the line. Cases with it cluster at low PRS — the red arrow marks the shift.

ProtectiveA protective burden does the reverse — holding high-risk people under the line, so controls with it cluster at high PRS. The arrow flips direction.

Your turnThe controls are live — slide from protective to pathogenic and watch the arrow.

The gap between prediction and reality is where rare, large-effect variants can hide. Find those people — and you have a way to find those genes.

Read the paper

How to cite

Baya NA, Lassen FH, Hill B, Venkatesh SS, Currant H, Lindgren CM, Palmer DS. Individuals who deviate from polygenic expectation are enriched for damaging variants in genes linked to rare disease. Am J Hum Genet. Published online June 22, 2026. doi: https://doi.org/10.1016/j.ajhg.2026.05.013