Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

Abstract

Enormous progress in mapping complex traits in humans has been made in the last 5 yr. There has been early success for prevalent diseases with complex phenotypes. These studies have demonstrated clearly that, while complex traits differ in their underlying genetic architectures, for many common disorders the predominant pattern is that of many loci, individually with small effects on phenotype. For some traits, loci of large effect have been identified. For almost all complex traits studied in humans, the sum of the identified genetic effects comprises only a portion, generally less than half, of the estimated trait heritability. A variety of hypotheses have been proposed to explain why this might be the case, including untested rare variants, and gene-gene and gene-environment interaction. Effort is currently being directed toward implementation of novel analytic approaches and testing rare variants for association with complex traits using imputed variants from the publicly available 1000 Genomes Project resequencing data and from direct resequencing of clinical samples. Through integration with annotations and functional genomic data as well as by in vitro and in vivo experimentation, mapping studies continue to characterize functional variants associated with complex traits and address fundamental issues such as epistasis and pleiotropy. This review focuses primarily on the ways in which genome-wide association studies (GWASs) have revolutionized the field of human quantitative genetics.M ANY phenotypes are quantitative in nature, and complex in etiology, with multiple environmental and genetic causes. The observation that complex traits cluster in relation to genetic relatedness suggests heritability, and advances in theoretical and experimental genetics, combined with analytical developments and high-throughput genomics, have provided an unprecedented view into the mode of inheritance and genetic architecture of complex traits.

Celiac Disease as a Model for the Evolution of Multifactorial Disease in Humans

“…The genetic architecture of CD may be such that most loci contributing to CD risk have only minor effects on risk, meaning that selection against CD would have miniscule to nonexistent effects on any single risk locus (Stranger et al 2011). HLA has long been observed to be under balancing selection in human populations and ancestral hominins.…”

Cell surface membrane proteins as personalized biomarkers: where we stand and where we are headed

“…This is even more relevant in the cases of complex, multigenic diseases, in which the polymorphic variants of membrane proteins are often participating factors. In these cases, only huge genomewide association studies (GWAS) allowed the recognition of the signifi cance of genetic factors in disease development [62,63].…”

The genomics of adaptation

“…This situation is well illustrated by studies of human evolutionary history: it was anticipated that extensive genomic and financial resources would help provide a detailed understanding of the molecular basis of numerous human adaptations and diseases. The picture emerging from several years of intense research is, however, somewhat sobering [20,36,61,62]. Candidate loci as well as genomic scans have resulted in some spectacular discoveries, including signals of independent incomplete sweeps at lactase promoters in Europe and Africa [63,64] or genes underlying adaptation to high altitude [65].…”