Finding the missing heritability of complex diseases.
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.
Manolio
Teri A
TA
National Human Genome Research Institute, Building 31, Room 4B09, 31 Center Drive, MSC 2152, Bethesda, Maryland 20892-2152, USA. manoliot@mail.nih.gov
Collins
Francis S
FS
Cox
Nancy J
NJ
Goldstein
David B
DB
Hindorff
Lucia A
LA
Hunter
David J
DJ
McCarthy
Mark I
MI
Ramos
Erin M
EM
Cardon
Lon R
LR
Chakravarti
Aravinda
A
Cho
Judy H
JH
Guttmacher
Alan E
AE
Kong
Augustine
A
Kruglyak
Leonid
L
Mardis
Elaine
E
Rotimi
Charles N
CN
Slatkin
Montgomery
M
Valle
David
D
Whittemore
Alice S
AS
Boehnke
Michael
M
Clark
Andrew G
AG
Eichler
Evan E
EE
Gibson
Greg
G
Haines
Jonathan L
JL
Mackay
Trudy F C
TF
McCarroll
Steven A
SA
Visscher
Peter M
PM
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