Open problems in human trait genetics

Nadav Brandes; Omer Weissbrod; Michal Linial

doi:10.1186/s13059-022-02697-9

Open problems in human trait genetics

Genome Biol. 2022 Jun 20;23(1):131. doi: 10.1186/s13059-022-02697-9.

Authors

Nadav Brandes¹, Omer Weissbrod², Michal Linial³

Affiliations

¹ School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel. nadav.brandes@mail.huji.ac.il.
² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³ Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Abstract

Genetic studies of human traits have revolutionized our understanding of the variation between individuals, and yet, the genetics of most traits is still poorly understood. In this review, we highlight the major open problems that need to be solved, and by discussing these challenges provide a primer to the field. We cover general issues such as population structure, epistasis and gene-environment interactions, data-related issues such as ancestry diversity and rare genetic variants, and specific challenges related to heritability estimates, genetic association studies, and polygenic risk scores. We emphasize the interconnectedness of these problems and suggest promising avenues to address them.

Keywords: Causal variants; Complex human traits; Diversity; Epistatis; GWAS; Gene-environment interactions; Genome-wide association studies; GxE; GxG; Heritability; Human phenotypes; Linkage disequilibrium; Missing heritability; Non-additive genetic effects; PRS; Polygenic risk scores; Population structure; Rare variants; Recessive effects; Statistical genetics.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Gene-Environment Interaction
Genome-Wide Association Study*
Humans
Multifactorial Inheritance*
Phenotype
Polymorphism, Single Nucleotide