|
|
| PMID |
|
|
| TITLE |
|
| Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis. |
|
| ABSTRACT |
|
| BACKGROUND |
NlmCategory: BACKGROUND |
| Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD. |
| METHODS AND FINDINGS |
NlmCategory: RESULTS |
| We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n=10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10-8 and trait specific scores using SNPs associated exclusively with each trait at p<5 × 10-8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR]=1.005, 95% CI 0.82-1.24, p = 0.962 per 1 unit increase in HDL-c; OR=0.901, 95% CI 0.65-1.25, p=0.530 per 1 unit increase in LDL-c; OR=1.104, 95% CI 0.89-1.37, p=0.362 per 1 unit increase in triglycerides; and OR=0.954, 95% CI 0.76-1.21, p=0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance. |
| CONCLUSIONS |
NlmCategory: CONCLUSIONS |
| Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD. Please see later in the article for the Editors' Summary. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| ecollection |
2014/09 |
| received |
2013/12/13 |
| accepted |
2014/07/23 |
| epublish |
2014/09/16 |
| entrez |
2014/09/17 06:00 |
| pubmed |
2014/09/17 06:00 |
| medline |
2015/06/16 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Proitsi P |
|
Proitsi |
Petroula |
P |
|
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom; Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong. |
| Lupton MK |
|
Lupton |
Michelle K |
MK |
|
Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. |
| Velayudhan L |
|
Velayudhan |
Latha |
L |
|
Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, United Kingdom. |
| Newhouse S |
|
Newhouse |
Stephen |
S |
|
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom. |
| Fogh I |
|
Fogh |
Isabella |
I |
|
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom. |
| Tsolaki M |
|
Tsolaki |
Magda |
M |
|
Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, United Kingdom. |
| Daniilidou M |
|
Daniilidou |
Makrina |
M |
|
Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, United Kingdom. |
| Pritchard M |
|
Pritchard |
Megan |
M |
|
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom. |
| Kloszewska I |
|
Kloszewska |
Iwona |
I |
|
Department of Old Age Psychiatry & Psychotic Disorders, Medical University of Lodz, Lodz, Poland. |
| Soininen H |
|
Soininen |
Hilkka |
H |
|
Department of Neurology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland. |
| Mecocci P |
|
Mecocci |
Patrizia |
P |
|
Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. |
| Vellas B |
|
Vellas |
Bruno |
B |
|
Department of Internal and Geriatrics Medicine, INSERM U 1027, Gerontopole, Hôpitaux de Toulouse, Toulouse, France. |
|
Alzheimer's Disease Neuroimaging Initiative |
|
|
|
|
|
| Williams J |
|
Williams |
Julie |
J |
|
MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom. |
|
GERAD1 Consortium |
|
|
|
|
|
| Stewart R |
|
Stewart |
Robert |
R |
|
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom. |
| Sham P |
|
Sham |
Pak |
P |
|
Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong. |
| Lovestone S |
|
Lovestone |
Simon |
S |
|
University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, United Kingdom. |
| Powell JF |
|
Powell |
John F |
JF |
|
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom. |
|
| INVESTIGATORS |
|
|
| JOURNAL |
|
| VOLUME: 11 |
| ISSUE: 9 |
| TITLE: PLoS medicine |
| ISOABBREVIATION: PLoS Med. |
| YEAR: 2014 |
| MONTH: Sep |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1549-1676 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: PLoS Med |
| COUNTRY: United States |
| ISSNLINKING: 1549-1277 |
| NLMUNIQUEID: 101231360 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
| Research Support, U.S. Gov't, Non-P.H.S. |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
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|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| 100140 |
Wellcome Trust |
United Kingdom |
| U01 AG024904 |
NIA NIH HHS |
United States |
| U24 AG021886 |
NIA NIH HHS |
United States |
|
Canadian Institutes of Health Research |
Canada |
|
Medical Research Council |
United Kingdom |
|
Wellcome Trust |
United Kingdom |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Aged |
|
| Aged, 80 and over |
|
| Alzheimer Disease |
genetics |
| Cholesterol |
genetics |
| Female |
genetics |
| Genetic Predisposition to Disease |
genetics |
| Genome-Wide Association Study |
methods |
| Humans |
methods |
| Longitudinal Studies |
methods |
| Male |
methods |
| Mendelian Randomization Analysis |
methods |
| Polymorphism, Single Nucleotide |
genetics |
| Risk Factors |
genetics |
| Triglycerides |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
Triglycerides |
| 97C5T2UQ7J |
Cholesterol |
|
| OTHER ID's |
|
| OTHERID |
SOURCE |
| PMC4165594 |
NLM |
|
|
