population control cohorts

Details

• Alternative Title:
  Sci Transl Med
• Personal Author:
  Minikel, Eric Vallabh ; Vallabh, Sonia M. ; Lek, Monkol ; Estrada, Karol ; Samocha, Kaitlin E. ; Sathirapongsasuti, J. Fah ; McLean, Cory Y. ; Tung, Joyce Y. ; Yu, Linda P.C. ; Gambetti, Pierluigi ; Blevins, Janis ; Zhang, Shulin ; Cohen, Yvonne ; Chen, Wei ; Yamada, Masahito ; Hamaguchi, Tsuyoshi ; Sanjo, Nobuo ; Mizusawa, Hidehiro ; Nakamura, Yosikazu ; Kitamoto, Tetsuyuki ; Collins, Steven J. ; Boyd, Alison ; Will, Robert G. ; Knight, Richard ; Ponto, Claudia ; Zerr, Inga ; Kraus, Theo F.J. ; Eigenbrod, Sabina ; Giese, Armin ; Calero, Miguel ; de Pedro-Cuesta, Jesús ; Haïk, Stéphane ; Laplanche, Jean-Louis ; Bouaziz-Amar, Elodie ; Brandel, Jean-Philippe ; Capellari, Sabina ; Parchi, Piero ; Poleggi, Anna ; Ladogana, Anna ; O'Donnell-Luria, Anne H. ; Karczewski, Konrad J. ; Marshall, Jamie L. ; Boehnke, Michael ; Laakso, Markku ; Mohlke, Karen L. ; Kähler, Anna ; Chambert, Kimberly ; McCarroll, Steven ; Sullivan, Patrick F. ; Hultman, Christina M. ; Purcell, Shaun M. ; Sklar, Pamela ; van der Lee, Sven J. ; Rozemuller, Annemieke ; Jansen, Casper ; Hofman, Albert ; Kraaij, Robert ; van Rooij, Jeroen G.J. ; Ikram, M. Arfan ; Uitterlinden, André G. ; van Duijn, Cornelia M. ; Daly, Mark J. ; MacArthur, Daniel G.
• Corporate Authors:
  Exome Aggregation Consortium (ExAC)
• Description:
  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 <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.
• Subjects:
  Article Case-Control Studies Cohort Studies Genetic Predisposition To Disease Humans Mutation Penetrance Prion Diseases Prions Risk Factors
• Source:
  Sci Transl Med. 8(322):322ra9
• Pubmed ID:
  26791950
• Pubmed Central ID:
  PMC4774245
• Document Type:
  Journal Article
• Funding:
  R01 DK093757/DK/NIDDK NIH HHS/United States ; R01GM104371/GM/NIGMS NIH HHS/United States ; R01 MH095034/MH/NIMH NIH HHS/United States ; R01 DK072193/DK/NIDDK NIH HHS/United States ; Department of Health/United Kingdom ; UR8/CCU515004/PHS HHS/United States ; U01 DK062370/DK/NIDDK NIH 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
• Volume:
  8
• Issue:
  322
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:ae9322c0566fff8a19238cd59cf2dc22768673865dc423f135ae17850ffef897
• Download URL:
  https://stacks.cdc.gov/view/cdc/38327/cdc_38327_DS1.pdf
• File Type:
  [PDF - 778.75 KB ]