Advances and challenges in quantitative delineation of the genetic architecture of complex traits

Abstract

Background: Genome-wide association studies (GWAS) have been widely adopted in studies of human complex traits and diseases.

Results: This review surveys areas of active research: quantifying and partitioning trait heritability, fine mapping functional variants and integrative analysis, genetic risk prediction of phenotypes, and the analysis of sequencing studies that have identified millions of rare variants. Current challenges and opportunities are highlighted.

Conclusion: GWAS have fundamentally transformed the field of human complex trait genetics. Novel statistical and computational methods have expanded the scope of GWAS and have provided valuable insights on the genetic architecture underlying complex phenotypes.

Author summary

Genome-wide association studies have identified a large number of genotype-phenotype associations for a wide variety of complex traits and diseases. Here we provide an overview of recent developments in quantitative methods that make use of GWAS discoveries for probing into the biology underlying specific associations, for depicting the genetic architecture of complex phenotypes, as well as for genetic risk predictions. Methodological challenges are highlighted in the hope to inspire innovation.

Graphical abstract

Keywords

genome-wide association study / heritability / rare variants / biobank / colocalization / eQTL / polygenic risk scores / transcriptome-wide association study

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ACKNOWLEDGMENTS

This work is supported by NIH R35GM127063 (HT) and NIH AG066206 (ZH).

COMPLIANCE WITH ETHICS GUIDELINES

The authors Hua Tang and Zihuai He declare that they have no conflict of interests.

The article is a review article and does not contain any human or animal subjects performed by any of the authors.

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