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Genetic Architecture of Complex Traits and Disease Risk Predictors

Soke Yuen Yong, Timothy G. Raben, Louis Lello, Stephen D.H. Hsu
doi: https://doi.org/10.1101/2020.02.12.946608
Soke Yuen Yong
1Department of Physics and Astronomy, Michigan State University
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  • For correspondence: yongsoke@msu.edu
Timothy G. Raben
1Department of Physics and Astronomy, Michigan State University
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Louis Lello
1Department of Physics and Astronomy, Michigan State University
2Genomic Prediction, North Brunswick, NJ
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Stephen D.H. Hsu
1Department of Physics and Astronomy, Michigan State University
2Genomic Prediction, North Brunswick, NJ
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Abstract

Genomic prediction of complex human traits (e.g., height, cognitive ability, bone density) and disease risks (e.g., breast cancer, diabetes, heart disease, atrial fibrillation) has advanced considerably in recent years. Predictors have been constructed using penalized algorithms that favor sparsity: i.e., which use as few genetic variants as possible. We analyze the specific genetic variants (SNPs) utilized in these predictors, which can vary from dozens to as many as thirty thousand. We find that the fraction of SNPs in or near genic regions varies widely by phenotype. For the majority of disease conditions studied, a large amount of the variance is accounted for by SNPs outside of coding regions. The state of these SNPs cannot be determined from exome-sequencing data. This suggests that exome data alone will miss much of the heritability for these traits – i.e., existing PRS cannot be computed from exome data alone. We also study the fraction of SNPs and of variance that is in common between pairs of predictors. The DNA regions used in disease risk predictors so far constructed seem to be largely disjoint (with a few interesting exceptions), suggesting that individual genetic disease risks are largely uncorrelated. It seems possible in theory for an individual to be a low-risk outlier in all conditions simultaneously.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 13, 2020.
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Genetic Architecture of Complex Traits and Disease Risk Predictors
Soke Yuen Yong, Timothy G. Raben, Louis Lello, Stephen D.H. Hsu
bioRxiv 2020.02.12.946608; doi: https://doi.org/10.1101/2020.02.12.946608
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Genetic Architecture of Complex Traits and Disease Risk Predictors
Soke Yuen Yong, Timothy G. Raben, Louis Lello, Stephen D.H. Hsu
bioRxiv 2020.02.12.946608; doi: https://doi.org/10.1101/2020.02.12.946608

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