How rare and common risk variation jointly affect liability for autism spectrum disorder.
Lambertus Klei, Lora Lee McClain, Behrang Mahjani and 13 others
PMID 34615521WHAT IT FOUND
ASD subjects carried more common genetic risk than controls.
Rare damaging variants did not replace common risk. Carriers averaged between non-carriers and controls, which fits a combined genetic risk model.
Key findings
01ASD subjects had higher common genetic risk scores than unaffected subjects, whether or not they carried rare damaging variants.
02Among ASD subjects, rare variant carriers had lower common risk scores than non-carriers.
03The average combined risk score in rare variant carriers was close to the midpoint between ASD subjects and unaffected subjects, which suggests rare and common genetic risk combine.
STILL TO COME
How it was doneWhat they found
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What it does not show
The study used only European descent samples, so the results may not apply to other ancestry groups. Some people counted as non-carriers may actually carry rare damaging variants because not all autism subjects were fully characterized for rare variants. Some controls were assumed unaffected, but they may have been affected. The number of rare variant carriers was small, so the additive pattern is only a coarse finding. The genetic scores are research tools, not clinical diagnostic tests. The training and testing method could overfit the data, so the authors corrected the significance tests.
Declared interests
The work was supported by the National Institute of Mental Health, the Simons Foundation, and the Beatrice and Samuel A. Seaver Foundation.
The easy way to misread this
Do not read the rare variant carrier pattern as proof that a rare variant alone explains autism. The carriers still had common genetic risk, and the authors say the evidence is far from conclusive.