Assessing the Heritability of Complex Traits in Humans: Methodological Challenges and Opportunities.

The goal of this review article is to provide a conceptual based summary of how heritability estimates for complex traits such as obesity are determined and to explore the future directions of research in the heritability field. The target audience are researchers who use heritability data rather than those conducting heritability studies. The article provides an introduction to key concepts critical to understanding heritability studies including: i) definitions of heritability: broad sense versus narrow sense heritability; ii) how data for heritability studies are collected: twin, adoption, family and population-based studies; and iii) analytical techniques: path analysis, structural equations and mixed or regressive models of complex segregation analysis. For each section, a discussion of how the different definitions and methodologies influence heritability estimates is provided. The general limitations of heritability studies are discussed including the issue of "missing heritability" in which heritability estimates are significantly higher than the variance explained by known genetic variants. Potential causes of missing heritability include restriction of many genetic association studies to single nucleotide polymorphisms, gene by gene interactions, epigenetics, and gene by environment interactions. Innovative strategies of accounting for missing heritability including modeling techniques and improved software are discussed.