Table 1.

Potential Explanations for Incomplete Genetic Architecture of Complex Diseases

Explanation	Rationale	Comments
Common Genetic Variants	More common variants are likely to be found in GWAS with larger sample sizes.	Effect sizes of known GWAS loci may be underestimated since functional variants have often not yet been found.
Rare Genetic Variants	Resequencing studies (e.g. whole exome, whole genome) could identify rare genetic determinants of large effect size.	Limited evidence for rare variants of major effect in complex diseases accounting for large amount of genetic variation
Interactions	Gene-gene and gene-environment interactions are likely important for complex diseases.	Limited evidence for statistical interactions in complex diseases; network-based approaches may be helpful to identify these interactions.
Inaccurate Heritability Estimates	Heritability estimates are typically performed assuming that gene-gene and gene-environment interactions are not present.	Limiting pathway model suggests that epistasis could account for missing heritability in complex diseases (Zuk et al., 2012)
Phenotypic and Genetic Heterogeneity	Most complex diseases are likely syndromes with multiple potentially overlapping disease subtypes.	Improvements in phenotyping of complex diseases will be required to understand genetic architecture.