A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.
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.
Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL 60637, USA.
David R
DR
Blair
Christopher S
CS
Lyttle
Jonathan M
JM
Mortensen
Charles F
CF
Bearden
Anders Boeck
AB
Jensen
Hossein
H
Khiabanian
Rachel
R
Melamed
Raul
R
Rabadan
Elmer V
EV
Bernstam
Søren
S
Brunak
Lars Juhl
LJ
Jensen
Dan
D
Nicolae
Nigam H
NH
Shah
Robert L
RL
Grossman
Nancy J
NJ
Cox
Kevin P
KP
White
Andrey
A
Rzhetsky
D004194:Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D055991:Health Records, Personal; D006801:Humans; D008957:Models, Genetic; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide