Quantifying prion disease penetrance using large population control cohorts.
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| Abstract | More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from |
| Year of Publication | 2016
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| Journal | Sci Transl Med
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| Volume | 8
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| Issue | 322
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| Pages | 322ra9
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| Date Published | 2016 Jan 20
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| ISSN | 1946-6242
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| URL | |
| DOI | 10.1126/scitranslmed.aad5169
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| PubMed ID | 26791950
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| PubMed Central ID | PMC4774245
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| Grant list | R01GM104371 / GM / NIGMS NIH HHS / United States
R01 MH095034 / MH / NIMH NIH HHS / United States
Department of Health / United Kingdom
UR8/CCU515004 / PHS HHS / United States
U54 DK105566 / DK / NIDDK NIH HHS / United States
U54DK105566 / DK / NIDDK NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
UR8 CI515004 / CI / NCPDCID CDC HHS / United States
R01 GM104371 / GM / NIGMS NIH HHS / United States
F32 GM115208 / GM / NIGMS NIH HHS / United States
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