Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability.” Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases.JPL was partially supported by FEDER and MICINN (PLE2009-119, SAF2014-56989-R), Instituto de Salud Carlos III (PI07/0057, PI10/00328, PIE14/00066), Junta de Castilla y León (CSI034U13, BIO/SA31/15), “Proyectos integrados IBSAL 2015” (IBY15/00003), the Eugenio Rodriguez Pascual”, the “Fundacion Inbiomed” (Instituto Oncologico Obra Social de la Caja Guipozcoa-San Sebastian, Kutxa), and the “Fundacion Sandra Ibarra de Solidaridad frente al Cancer”. CR-C is funded by Q3718001E (2009–2010) y GRS 612/A/11 (2011–2012) and “the Fundacion Eugenio Rodrıguez Pascual”. AC was supported by FIS (PI07/0057) and MICINN (PLE2009-119). SCLL was funded by a JAEdoc Fellowship (CSIC)/FSE. JHM was supported by the National Institutes of Health, a National Cancer Institute grant (R01 CA116481), and the Low-Dose Scientific Focus Area, Office of Biological & Environmental Research, US Department of Energy (DE-AC02-05CH11231).Peer Reviewe