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.
Bibliographical noteFunding Information:
Publication fees were covered in part by the ISF grant number: 2753/20 (to M.L.).
We would like to thank Alexander (Sasha) Gusev, Alexander l. Young, Noah Zaitlen, Or Zuk, Sagiv Shifman, Shai Ben-Shahar, Shai Carmi, Shiri Shakedi, Regev Schweiger, and Yossi Farjoun for offering us their perspectives on open problems in the field. This review does not necessarily reflect their views, and all mistakes are ours. We also thank Vladimir Gritsenko and Yedael Y. Waldman for valuable feedback on our initial draft. The review history is available as Additional file 1. Andrew Cosgrove was the primary editor of this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
© 2022, The Author(s).
- Causal variants
- Complex human traits
- Gene-environment interactions
- Genome-wide association studies
- Human phenotypes
- Linkage disequilibrium
- Missing heritability
- Non-additive genetic effects
- Polygenic risk scores
- Population structure
- Rare variants
- Recessive effects
- Statistical genetics