Chunk #1 — Historical context and background for modeling complex traits — A brief history of the foundation of the theories underlying statistical genetics
Ultimately, this synthesis of statistical and evolutionary theory to complex traits established the fundamental models still used today. In 1901, Pearson and Lee proposed the liability threshold model, asserting a normal risk distribution for binary outcomes (2), and Wright carried its application forward to genetics (3). These models proposed that many small genetic and environmental factors combine additively to give rise to phenotypic variation. Advances to Wright’s work considered additive genetic variation along a continuum for binary human diseases and traits, introducing the statistical theory of the modern liability-threshold model (4). Such models are relevant to essentially all common psychiatric disorders. Remarkably prescient work conducted 50 years ago by Gottesman and Shields compiled incidence data for schizophrenia in families, and proposed a then-overlooked but now widely-accepted argument that risk for schizophrenia is both highly heritable and polygenic (5). That is, many genetic risk factors of small effects across the genome account, in aggregate, for a substantial fraction of total psychiatric disease risk (Figure 1).
