Conflict of interest statement: No conflicts declared.
Research Review: Polygenic methods and their application to psychiatric traits
Article first published online: 1 AUG 2014
© 2014 Association for Child and Adolescent Mental Health.
Journal of Child Psychology and Psychiatry
Volume 55, Issue 10, pages 1068–1087, October 2014
How to Cite
Wray, N. R., Lee, S. H., Mehta, D., Vinkhuyzen, A. A.E., Dudbridge, F. and Middeldorp, C. M. (2014), Research Review: Polygenic methods and their application to psychiatric traits. Journal of Child Psychology and Psychiatry, 55: 1068–1087. doi: 10.1111/jcpp.12295
- Issue published online: 8 SEP 2014
- Article first published online: 1 AUG 2014
- Manuscript Accepted: 13 MAR 2014
- Australian Research Council. Grant Numbers: FT0991360, DE130100614
- Australian National Health and Medical Research Council. Grant Numbers: 613602, 1047956, 1011506
- Netherlands Organisation for Health Research and Development. Grant Number: 91210020
- Polygenic risk scoring;
- genome-wide association studies;
- psychiatric disorders;
- SNP analyses;
- disease traits
Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years.
Methods and scope
We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability.
Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs.
Increasing the sample size for genome wide association studies of psychiatric disorders will lead to the identification of more associated genetic variants, as already found for schizophrenia. These loci provide the starting point of functional analyses that might eventually lead to new prevention and treatment options and to improved biological validity of diagnostic constructs. Polygenic analyses will contribute further to our understanding of complex genetic traits as sample sizes increase and as sample resources become richer in phenotypic descriptors, both in terms of clinical symptoms and of nongenetic risk factors.