A nondegenerate code of deleterious variants in mendelian Loci contributes to complex disease risk

David R Blair; Christopher S Lyttle; Jonathan M Mortensen; Charles F Bearden; Anders Boeck Jensen; Hossein Khiabanian; Rachel Melamed; Raul Rabadan; Elmer V Bernstam; Søren Brunak; Lars Juhl Jensen; Dan Nicolae; Nigam H Shah; Robert L Grossman; Nancy J Cox; Kevin P White; Andrey Rzhetsky

doi:10.1016/j.cell.2013.08.030

A nondegenerate code of deleterious variants in mendelian Loci contributes to complex disease risk

David R Blair, Christopher S Lyttle, Jonathan M Mortensen, Charles F Bearden, Anders Boeck Jensen, Hossein Khiabanian, Rachel Melamed, Raul Rabadan, Elmer V Bernstam, Søren Brunak, Lars Juhl Jensen, Dan Nicolae, Nigam H Shah, Robert L Grossman, Nancy J Cox, Kevin P White, Andrey Rzhetsky

128 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Cell
Volume	155
Issue number	1
Pages (from-to)	70-80
Number of pages	11
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2013.08.030
Publication status	Published - 26 Sept 2013

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Blair, D. R., Lyttle, C. S., Mortensen, J. M., Bearden, C. F., Jensen, A. B., Khiabanian, H., Melamed, R., Rabadan, R., Bernstam, E. V., Brunak, S., Jensen, L. J., Nicolae, D., Shah, N. H., Grossman, R. L., Cox, N. J., White, K. P., & Rzhetsky, A. (2013). A nondegenerate code of deleterious variants in mendelian Loci contributes to complex disease risk. Cell, 155(1), 70-80. https://doi.org/10.1016/j.cell.2013.08.030

Blair, DR, Lyttle, CS, Mortensen, JM, Bearden, CF, Jensen, AB, Khiabanian, H, Melamed, R, Rabadan, R, Bernstam, EV, Brunak, S , Jensen, LJ, Nicolae, D, Shah, NH, Grossman, RL, Cox, NJ, White, KP & Rzhetsky, A 2013, 'A nondegenerate code of deleterious variants in mendelian Loci contributes to complex disease risk', Cell, vol. 155, no. 1, pp. 70-80. https://doi.org/10.1016/j.cell.2013.08.030

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title = "A nondegenerate code of deleterious variants in mendelian Loci contributes to complex disease risk",

abstract = "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.",

author = "Blair, {David R} and Lyttle, {Christopher S} and Mortensen, {Jonathan M} and Bearden, {Charles F} and Jensen, {Anders Boeck} and Hossein Khiabanian and Rachel Melamed and Raul Rabadan and Bernstam, {Elmer V} and S{\o}ren Brunak and Jensen, {Lars Juhl} and Dan Nicolae and Shah, {Nigam H} and Grossman, {Robert L} and Cox, {Nancy J} and White, {Kevin P} and Andrey Rzhetsky",

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T1 - A 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

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.

U2 - 10.1016/j.cell.2013.08.030

DO - 10.1016/j.cell.2013.08.030

M3 - Journal article

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SN - 0092-8674

VL - 155

SP - 70

EP - 80

JO - Cell

JF - Cell

IS - 1

ER -

A nondegenerate code of deleterious variants in mendelian Loci contributes to complex disease risk

Abstract

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