title: Finding the missing heritability of complex diseases.
abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
authors.affiliation: National Human Genome Research Institute, Building 31, Room 4B09, 31 Center Drive, MSC 2152, Bethesda, Maryland 20892-2152, USA. manoliot@mail.nih.gov
authors.forename: Teri A
authors.initials: TA
authors.lastname: Manolio
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Hindorff
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Erin M
authors.initials: EM
authors.lastname: Ramos
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Judy H
authors.initials: JH
authors.lastname: Cho
authors.forename: Alan E
authors.initials: AE
authors.lastname: Guttmacher
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Leonid
authors.initials: L
authors.lastname: Kruglyak
authors.forename: Elaine
authors.initials: E
authors.lastname: Mardis
authors.forename: Charles N
authors.initials: CN
authors.lastname: Rotimi
authors.forename: Montgomery
authors.initials: M
authors.lastname: Slatkin
authors.forename: David
authors.initials: D
authors.lastname: Valle
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Clark
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Greg
authors.initials: G
authors.lastname: Gibson
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Trudy F C
authors.initials: TF
authors.lastname: Mackay
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
mesh_terms: D030342:Genetic Diseases, Inborn / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005826:Genetics, Medical / Q000379:methods* / Q000639:trends; D055106:Genome-Wide Association Study / Q000379:methods / Q000639:trends; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D010375:Pedigree