title: Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes.
abstract: 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.
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (CIC-IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: Blanco-Gómez
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (CIC-IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Castillo-Lluva
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (CIC-IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Del Mar Sáez-Freire
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (CIC-IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Hontecillas-Prieto
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory (LBNL), University of California, Berkeley, CA, USA.
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (CIC-IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Castellanos-Martín
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (CIC-IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Pérez-Losada
mesh_terms: D000818:Animals; D030342:Genetic Diseases, Inborn / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005826:Genetics, Medical; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype
keywords: complex diseases; heritability; intermediate phenotype or endophenotype; missing heritability