PMID- 18344982

OWN - NLM
STAT- MEDLINE
DA - 20080327
DCOM- 20080430
LR - 20100921
IS - 1476-4687 (Electronic)
IS - 0028-0836 (Linking)
VI - 452
IP - 7186
DP - 2008 Mar 27
TI - Variations in DNA elucidate molecular networks that cause disease.
PG - 429-35
AB - Identifying variations in DNA that increase susceptibility to disease is o
ne of
the primary aims of genetic studies using a forward genetics approach. How
ever,
identification of disease-susceptibility genes by means of such studies pr
ovides
limited functional information on how genes lead to disease. In fact, in m
ost
cases there is an absence of functional information altogether, preventing
a
definitive identification of the susceptibility gene or genes. Here we dev
elop an
alternative to the classic forward genetics approach for dissecting comple
x
disease traits where, instead of identifying susceptibility genes directly
affected by variations in DNA, we identify gene networks that are perturbe
d by
susceptibility loci and that in turn lead to disease. Application of this
method
to liver and adipose gene expression data generated from a segregating mou
se
population results in the identification of a macrophage-enriched network
supported as having a causal relationship with disease traits associated w
ith
metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl),
lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validat
ed as
previously unknown obesity genes, strengthening the association between th
is
network and metabolic disease traits. Our analysis provides direct experim
ental
support that complex traits such as obesity are emergent properties of mol
ecular
networks that are modulated by complex genetic loci and environmental fact
ors.
AD - Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seat
tle,
Washington 98109, USA.
FAU - Chen, Yanqing
AU - Chen Y
FAU - Zhu, Jun
AU - Zhu J
FAU - Lum, Pek Yee
AU - Lum PY
FAU - Yang, Xia
AU - Yang X
FAU - Pinto, Shirly
AU - Pinto S
FAU - MacNeil, Douglas J
AU - MacNeil DJ
FAU - Zhang, Chunsheng
AU - Zhang C
FAU - Lamb, John
AU - Lamb J
FAU - Edwards, Stephen
AU - Edwards S
FAU - Sieberts, Solveig K
AU - Sieberts SK
FAU - Leonardson, Amy
AU - Leonardson A
FAU - Castellini, Lawrence W
AU - Castellini LW
FAU - Wang, Susanna
AU - Wang S
FAU - Champy, Marie-France
AU - Champy MF
FAU - Zhang, Bin
AU - Zhang B
FAU - Emilsson, Valur
AU - Emilsson V
FAU - Doss, Sudheer
AU - Doss S
FAU - Ghazalpour, Anatole
AU - Ghazalpour A
FAU - Horvath, Steve
AU - Horvath S
FAU - Drake, Thomas A
AU - Drake TA
FAU - Lusis, Aldons J
AU - Lusis AJ
FAU - Schadt, Eric E
AU - Schadt EE
LA - eng
SI - GEO/GSE2814
SI - GEO/GSE3086
SI - GEO/GSE7026
SI - GEO/GSE7027
SI - GEO/GSE7028
SI - GEO/GSE7029
GR - P01 HL028481-24/HL/NHLBI NIH HHS/United States
GR - P01 HL028481-240010/HL/NHLBI NIH HHS/United States
GR - P01 HL030568-250011/HL/NHLBI NIH HHS/United States
GR - R01 DK071673-03/DK/NIDDK NIH HHS/United States
PT - Journal Article
PT - Research Support, N.I.H., Extramural
DEP - 20080316
PL - England
TA - Nature
JT - Nature
JID - 0410462
RN - 0 (Apolipoprotein A-II)
RN - 0 (Lactb protein, mouse)
RN - 0 (Membrane Proteins)
RN - 0 (Ribosomal Proteins)
RN - 0 (amyloidogenic apolipoprotein A-II, mouse)
RN - EC 3.1.1.34 (Lipoprotein Lipase)
RN - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN - EC 3.1.3.16 (Ppm1l, protein, mouse)
SB - IM
MH - Adipose Tissue/metabolism
MH - Animals
MH - Apolipoprotein A-II/genetics
MH - Chromosomes, Mammalian/genetics
MH - Female
MH - Gene Regulatory Networks/*genetics
MH - Genetic Predisposition to Disease/*genetics
MH - Genetic Variation/*genetics
MH - Linkage Disequilibrium
MH - Lipoprotein Lipase/genetics
MH - Liver/metabolism
MH - Lod Score
MH - Macrophages/metabolism
MH - Male
MH - Membrane Proteins/genetics
MH - Metabolic Syndrome X/enzymology/*genetics/metabolism
MH - Mice
MH - Obesity/enzymology/*genetics/metabolism
MH - Phenotype
MH - Phosphoprotein Phosphatases/deficiency/genetics/metabolism
MH - Quantitative Trait Loci
MH - Reproducibility of Results
MH - Ribosomal Proteins/genetics
PMC - PMC2841398
MID - NIHMS175495
OID - NLM: NIHMS175495
OID - NLM: PMC2841398
EDAT- 2008/03/18 09:00
MHDA- 2008/05/01 09:00
CRDT- 2008/03/18 09:00
PHST- 2007/10/05 [received]
PHST- 2008/01/28 [accepted]
PHST- 2008/03/16 [aheadofprint]
AID - nature06757 [pii]
AID - 10.1038/nature06757 [doi]
PST - ppublish
SO - Nature. 2008 Mar 27;452(7186):429-35. Epub 2008 Mar 16.