Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1088-93. PubMed.

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Comments

  1. We carried out the most powerful genomewide study of Alzheimer disease (AD), involving over 16,000 people from eight countries, and identified two new genes that increase a person’s risk of developing the disease. These are CLU or clusterin and PICALM.

    We compared over half a million differences in the DNA of each of 4,000 people with AD with 8,000 people without the disease. In addition to the APOE gene—a known risk factor—CLU and PICALM showed overwhelming evidence for a relationship with AD. These findings were replicated in a further sample of over 2,000 Alzheimer’s sufferers and 2,000 controls.

    The findings are significant and conclusive.

    We also found strong evidence that other genes play a role in disease risk. Putting our data together with the results of Philippe Amouyel’s study, a third risk gene was confirmed; CR1, complement receptor 1 gene.

    This combination of discoveries forms an important breakthrough in the current impetus to discover the causes of AD.

    Three of the risk genes, APOE, CLU, and CR1, have roles in protecting the brain from damage. Perhaps the changes we see in these genes remove this protection or may even turn them into killers.

    Our results may highlight new targets for treatments. For example, clusterin has a role in dampening down inflammation in the brain. Up until now increased inflammation seen in the brains of Alzheimer’s sufferers had been viewed as a secondary effect of disease. Our results suggest the possibility that inflammation may be primary to disease development.

    If we were able to remove the detrimental effects of these genes through treatments, we could reduce the proportion of people developing Alzheimer’s by 20 percent. In the UK alone this would prevent just under 100,000 people developing the disease. So the significance of these results is truly meaningful.

    View all comments by Julie Williams

  2. Two of the most important implications of this study are that it establishes that this approach works and suggests that larger studies are likely to identify other genes conferring similar risks to AD. For this reason we are planning an even larger study of 60,000 participants. This should allow us to identify other genes of relevance to AD.

    We are also undertaking more complex analyses of our current data—using new analytic approaches we have developed in Cardiff. These allow many genes to be analyzed at once and identify patterns in the data that implicate specific biological processes.

    The identification of multiple genetic risk factors should allow us to triangulate down onto specific biological processes. These might be related to β amyloid deposition, but they might also identify completely new disease mechanisms.

    The key thing about genetics is that it allows us to distinguish events of primary importance from those that are occurring as a consequence of the disease—downstream if you like—and these primary events are likely to be the best targets for new treatments.

    It’s also possible that in the future we might be able to use the results of genetic tests as part of a battery of indicators to identify those who might benefit from early intervention with new therapies. I should stress that the current genes on their own are not strong predictors of risk and are not suitable for risk testing.

    This study is one of the first major successes for the new MRC Centre in Cardiff which has been established this year to undertake genetic work in neurodegenerative diseases like AD and PD—as well as psychiatric disorders like schizophrenia and manic depression. This centre is allowing us to look not only at individual diseases, but also the overlap between them; we are currently looking to see whether the AD genes we have identified are involved in other forms of dementia such as Parkinson’s.

    View all comments by Michael Owen

  3. By Jean-Charles Lambert and Philippe Amouyel

    We conducted a GWAS in 2,032 AD cases and 5,328 controls from the prospective population-based 3C study. We next replicated our most interesting hits in independent collections from Belgium, Finland, Italy and Spain totalling 3,978 AD cases and 3,297 controls. This replication work, the largest performed so far, strongly supports the association of CLU and CR1 with the risk of developing AD

    It is with enthusiasm that we learned the validation of our observations in the Harold et al. GWA study. The combination of these genetic results and the available pathophysiological data seem to strongly support the involvement of these genes in AD.

    However, it is important to keep in mind that in view of the large number of analyses performed, high-throughput approaches involve finding a balance between the risk of observing significant results by chance and the risk of rejecting biologically valid hypotheses on purely statistical grounds.
    Although no solution has been found to improve this dilemma, several approaches can be developed. It is possible to increase the statistical power associated with GWASs by performing meta-analyses. Other complementary approaches could also consist in better analyzing SNPs nominally associated with the risk of developing AD (p

    View all comments by Jean-Charles Lambert

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This paper appears in the following:

News

  1. Paper Alert: GWAS Hits Clusterin, CR1, PICALM Formally Published
  2. LOADing Up—Largest GWAS to Date Confirms Two, Adds Two Risk Genes
  3. Repeat Offenders—CLU, CR1, PICALM Hold Up in Association Studies
  4. Studying the Oldest Old—Chances for Longevity Spelled Out in Genes?
  5. Research Brief: Clusterin Grabs Spotlight Among Elite Few LOAD Genes
  6. DC: Is Alzheimer's Rooted in the Early Life?
  7. Getting a CLU—Does Genetic Risk Factor Mediate Aβ Toxicity?
  8. Can a Fly Screen Trap Alzheimer’s Gene Candidates?
  9. Top AD Trends of 2009
  10. In Astrocytes, ApoE4 Bungles Endocytosis, PICALM Picks Up the Slack

Mutations

  1. APOE c.-286T>G (rs405509)

Research Timeline Event

  1. GWAS identify risk loci in or near CLU, PICALM, CR1