Genetic architecture: the shape of the genetic contribution to human traits and disease

• Published in: Nature reviews. Genetics Vol. 19; no. 2; pp. 110 - 124
• Main Authors: Timpson, Nicholas J., Greenwood, Celia M. T., Soranzo, Nicole, Lawson, Daniel J., Richards, J. Brent
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2018; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/212/2301; 631/208/2489/144; 631/208/457/649; 631/208/514/2254; 631/208/729; 692/700/478/174; Agriculture; Animal Genetics and Genomics; Biomedicine; Cancer Research; Gene Function; Genetic Diseases, Inborn - diagnosis; Genetic Diseases, Inborn - genetics; Genetic diversity; Genetic engineering; Genetic research; Genetic variability; Genetic variation; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype & phenotype; Human Genetics; Humans; Identification and classification; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable; review-article
• ISSN: 1471-0056; 1471-0064; 1471-0064
• DOI: 10.1038/nrg.2017.101

Key Points The genetic architecture of common diseases is central to the scientific and clinical goals of human genetics because it directly impacts biology, disease screening, diagnosis, prognosis and treatment. Genetic architecture is currently assessed by exploiting the differences in types of genetic variants ascertained through genome-wide association studies, whole-exome sequencing studies and whole-genome sequencing studies. Each of these has its own merits and disadvantages, but all are subject to the limitations of sample size. Gene mapping studies should thus be tailored to the unique contributions of each of these technologies. To date, the observed genetic architecture of highly heritable diseases and traits differs markedly and cannot be reliably predicted. Where large sample sizes are available, differences in detectable architecture still exist. The concept of variance explained is not always relevant to individual-level risk prediction or drug development, whereas the genetic architecture of a given trait or disease can be more pertinent. Genetic architecture is variable in time and place and can be theoretically influenced by phenotypic measurement, selection and decanalization. Interactions between genetic determinants of a trait or environmental influences contribute to genetic architecture. To date, few such interactions have been identified for most common diseases and traits, but this will likely change with increasing sample sizes. Genetic architecture describes the characteristics of genetic variation that are responsible for phenotypic variability. This Review discusses the types of genetic architecture that have been observed, how they can be measured and how genetic architecture informs the scientific and clinical goals of human genetics. Genetic architecture describes the characteristics of genetic variation that are responsible for heritable phenotypic variability. It depends on the number of genetic variants affecting a trait, their frequencies in the population, the magnitude of their effects and their interactions with each other and the environment. Defining the genetic architecture of a complex trait or disease is central to the scientific and clinical goals of human genetics, which are to understand disease aetiology and aid in disease screening, diagnosis, prognosis and therapy. Recent technological advances have enabled genome-wide association studies and emerging next-generation sequencing studies to begin to decipher the nature of the heritable contribution to traits and disease. Here, we describe the types of genetic architecture that have been observed, how architecture can be measured and why an improved understanding of genetic architecture is central to future advances in the field.