The Quantitative Genetics of Human Disease: 1 Foundations

TL;DR

This foundational paper introduces the core principles of quantitative genetics applied to human disease, emphasizing precise definitions, assumptions, and methods for estimation, serving as a basis for subsequent detailed studies.

Contribution

It provides a detailed, formal presentation of quantitative genetics concepts tailored for human disease research, clarifying common confusions and establishing a basis for future analyses.

Findings

Defines key quantitative genetics quantities in human disease context

Demonstrates methods for estimating genetic parameters

Clarifies distinctions between definitions and approximations

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. While practitioners in the field of human quantitative disease studies may find this work pedantic in detail, the principle 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.