TY - JOUR
T1 - XA nondegenerate code of deleterious variants in mendelian loci contributes to complex disease risk
AU - Blair, David R.
AU - Lyttle, Christopher S.
AU - Mortensen, Jonathan M.
AU - Bearden, Charles F.
AU - Jensen, Anders Boeck
AU - Khiabanian, Hossein
AU - Melamed, Rachel
AU - Rabadan, Raul
AU - Bernstam, Elmer V.
AU - Brunak, Søren
AU - Jensen, Lars Juhl
AU - Nicolae, Dan
AU - Shah, Nigam H.
AU - Grossman, Robert L.
AU - Cox, Nancy J.
AU - White, Kevin P.
AU - Rzhetsky, Andrey
N1 - Funding Information:
We are grateful to Steven Bagley, Richard R. Hudson, Ivan Iossifov, Ravinesh Kumar, Simon Lovestone, Fabiola Rivas, Gregory Gibson, Jason Pitt, Rita Rzhetsky, Michael Wigler, and anonymous reviewers for helpful comments on earlier versions of the manuscript. GeneXplain, GmbH, provided help with annotation of Mendelian disorders. This work was supported by grants (1P50MH094267, NHLBI MAPGen U01HL108634-01, P50GM081892-01A1, and 2T32GM007281-39) from the National Institutes of Health and by a Lever Award from the Chicago Biomedical Consortium.
PY - 2013/9/26
Y1 - 2013/9/26
N2 - Summary Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.
AB - Summary Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.
UR - http://www.scopus.com/inward/record.url?scp=84884890589&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.08.030
DO - 10.1016/j.cell.2013.08.030
M3 - Article
C2 - 24074861
AN - SCOPUS:84884890589
SN - 0092-8674
VL - 155
SP - X70-80
JO - Cell
JF - Cell
IS - 1
ER -