The quantitative genetics of human disease: 1. Foundations
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Published:2023-12-07
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Volume:
Page:1-49
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ISSN:
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Container-title:Human Population Genetics and Genomics
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language:en
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Short-container-title:Hum Popul Genet Genom
Author:
Cutler David J.1, Jodiery Kiana2, Bass Andrew J.3, Epstein Michael P.1
Affiliation:
1. Department of Human Genetics, Emory University, Atlanta, Georgia, USA 2. Center of Computational and Quantitative Genetics, Emory University, Atlanta, Georgia, USA 3. Department of Human Genetics, Emory University, Atlanta, Georgia
Abstract
In this the first of an anticipated four paper series, fundamental results of
quantitative genetics are presented from a first principles approach. While
none of these results are in any sense new, they are presented in extended
detail to precisely distinguish between definition and assumption, with a
further emphasis on distinguishing quantities from their usual
approximations. Terminology frequently encountered in the field of human
genetic disease studies will be defined in terms of their quantitive genetics
form. Methods for estimation of both quantitative genetics and the related
human genetics quantities will be demonstrated. The principal target
audience for this work is trainees reasonably familiar with population
genetics theory, but with less experience in its application to human disease
studies. We introduce much of this formalism because in later papers in this
series, we demonstrate that common areas of confusion in human disease
studies can be resolved be appealing directly to these formal definitions. The
second paper in this series will discuss polygenic risk scores. The third paper
will concern the question of “missing” heritability and the role interactions
may play. The fourth paper will discuss sexually dimorphic disease and the
potential role of the X chromosome.
Background: With over a hundred years of history, most fundamental
results in quantitative genetics are well known to most population genetics
students, yet there is often considerable confusion concerning precise
definitions and assumptions, particularly when interactions may exist. The
connections between quantitative genetics and human disease genetics can
be obscure to many.
Methods: Fundamental quantitative genetics quantities are derived as
conditional expectations of phenotype. Genetic, environmental, additive,
dominance and interaction effects and their associated variances are defined,
with key results explicitly derived. The effects of linkage disequilibrium and
methods to account for it are examined. Methods to estimate and interpret
heritability are discussed.
Results: Application of quantitative genetics quantities are extended to
binary traits with special emphasis on translation between commonly
estimated human disease genetics quantities and their corresponding
quantitative genetics representations.
Conclusions: The distinction between modeling definitions and assumptions
is made clear. Methods to unite human disease genetics and quantitative
genetics are elucidated. Methods to account for linkage disequilibrium and
other forms of interaction are described.
Funder
National Institutes of Health
Publisher
Pivot Science Publications Corporation
Subject
General Medicine,General Earth and Planetary Sciences,General Environmental Science,General Medicine,Ocean Engineering,General Medicine,General Medicine,General Medicine,General Medicine,General Earth and Planetary Sciences,General Environmental Science,General Medicine
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