A cluster of cholesterol-related genes confers susceptibility for Alzheimer's disease.
OBJECTIVE
Polygenic diseases are related to the complex interplay of genetic variations. We evaluated whether clusters of cholesterol- and lipid-related genetic variations are associated with Alzheimer's disease.


METHODS
We analyzed 12 cholesterol-related single nucleotide polymorphisms and 48 control polymorphisms in 545 study participants (Alzheimer's disease group N = 284; control group N = 261). Diagnoses of Alzheimer's disease were made according to the NINCDS-ADRDA criteria. Multi-locus genetic association analysis was done with the set-association method. Dates of data collection were from January 2000 to December 2003.


RESULTS
We identified a cluster of polymorphisms in APOE, SOAT1, APOE 5'-untranslated region, OLR1, CYP46A1, LPL, LIPA, and APOA4 conferring significant (p = .0002) susceptibility for Alzheimer's disease. This gene cluster reached a diagnostic accuracy of 74% and correlated significantly (p = .018) with the levels of the brain cholesterol catabolite 24S-hydroxycholesterol in the cerebrospinal fluid.


CONCLUSIONS
Our results establish a novel approach for the identification of disease-related genetic clusters and demonstrate the need for multi-locus methods in the genetics of complex diseases.
Papassotiropoulos
Andreas
A
Division of Psychiatry Research, University of Zurich, Zurich, Switzerland. papas@bli.unizh.ch
Wollmer
M Axel
MA
Tsolaki
Magdalini
M
Brunner
Fabienne
F
Molyva
Dimitra
D
Lütjohann
Dieter
D
Nitsch
Roger M
RM
Hock
Christoph
C
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000235:genetics; D001054:Apolipoproteins A; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000235:genetics; D002784:Cholesterol / Q000235:genetics*; D000072556:Cholesterol 24-Hydroxylase; D003431:Cross-Cultural Comparison; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D006115:Greece / Q000208:ethnology; D006801:Humans; D006888:Hydroxycholesterols / Q000134:cerebrospinal fluid / Q000378:metabolism; D008297:Male; D005810:Multigene Family / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics; D051131:Receptors, Oxidized LDL; D012307:Risk Factors; D051127:Scavenger Receptors, Class E; D013250:Steroid Hydroxylases / Q000235:genetics; D013557:Switzerland / Q000208:ethnology; D044465:White People / Q000235:genetics
C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001057:Apolipoproteins E; D006888:Hydroxycholesterols; C495137:OLR1 protein, human; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; C044563:24-hydroxycholesterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase