SORLA Soars—Large Study Links Gene to Late-onset AD

It is touted as only the second genetic variant for late-onset Alzheimer disease. In yesterday’s Nature Genetics online, an international collaboration led by Peter St George-Hyslop at the University of Toronto reports that SORL1 is associated with increased risk for familial late-onset Alzheimer disease (LOAD) in several different ethnic groups. The gene is also known as SORLA (for sortilin-related receptor, low-density lipoprotein receptor class A repeat-containing protein). While SORL1 may not rival ApoE, the leading risk gene for LOAD, the researchers believe that the robustness of SORL1’s association means it may be comparable in importance. In addition, because SORL1 plays a crucial role in amyloid precursor protein (APP) processing, the finding turns the heat up under amyloid-β (Aβ), recently moved to the back burner as researchers searched for other causes of sporadic, or late-onset AD.

It was this biological connection that prompted St George-Hyslop and colleagues to look for a genetic association between SORL1 and AD. Work from Thomas Wilnow’s group at the Max Delbrueck Center for Molecular Medicine in Berlin, Germany, had suggested that the intracellular sorting receptor guides APP away from late endosomes, where the precursor is processed by β- and γ-secretases to generate Aβ (see ARF related news story and Andersen et al., 2005). James Lah at Emory University in Atlanta, Georgia, and colleagues had shown earlier that the level of SORL1 (also know as LR11) is reduced in the brains of people with the disease (see Scherzer et al., 2004). Armed with these clues, Ekaterina Rogaeva and colleagues looked for genetic links between AD, SORL1, and various other vacuolar sorting proteins, including VPS35, VPS26A, sortilin, and the sortilin-related receptors SORCS1-3.

The researchers first screened two independent late-onset FAD data sets (124 northern European FAD families and 228 Caribbean Hispanic FAD families) for intragenic single nucleotide polymorphisms (SNPs) that might be associated with the disease. SNPs in SORL1, SORCS1, and SORCS2 showed an association that was statistically significant, but on further analysis with additional SNPs, only the association with SORL1 remained robust. Alzgene meta-analysis also suggests a slight positive association between SORCS1 and AD. In the January Nature Genetics, Lars Bertram of Massachusetts General Hospital, Charlestown, and colleagues describe how this meta-analysis has identified more than a dozen more potential AD susceptibility genes in addition to ApoE (Alzgene is supported by the Alzforum) (Bertram et al., 2007).

Focusing on SORL1, Rogaeva and colleagues found that six SNPs turned up a positive association in one of the two data sets and also in at least one of four additional data sets used to replicate the analysis. These include case-control samples from northern European and Israeli Arab studies, and Caucasian and African American sibships from the MIRAGE study (hear related presentation from the 9th ICAD meeting). The work was done in collaboration with Lindsay Farrer and colleagues at Boston University School of Medicine and Richard Mayeux at Columbia University, New York.

The SNPs in question cluster at the 5’ and 3’ ends of the SORL1 gene, but not all SNPs are associated with LOAD in all samples tested. At the 5’ end, three SNPs (8-10 in this paper) associate with the disease in the Caribbean Hispanic FAD families and in the Israeli Arab and northern European case-control sample sets. At the 3’ end of the gene, two SNPs (19 and 23) associate with AD in the northern European FAD and case-control sample sets. Haplotype analysis also implicated the three 5’ SNPs, in addition to SNP 11, and two 3’ troikas (SNPs 22-24, and SNPs 23-25) as risk alleles for AD.

To verify the associations, the authors collaborated with Steven Younkin at the Mayo Clinic, Jacksonville, Florida, to analyze yet three different American cohorts of Caucasian European ancestry. Genotyping 10 SORL1 SNPS showed a statistical association between AD and three SNPs (23-25) in one cohort and one SNP (12) in a second cohort. Combined analysis of the three cohorts identified those four and two other risk alleles (SNPs 4 and 19).

All told, the analysis spanned nine data sets and approximately 6,000 individual samples. It represents a major collaborative effort. Statistically significant associations of SORL1 with AD turned up in six of the nine cohorts, while a borderline association was found in a seventh. Unlike ApoE, however, the analysis did not identify one SNP or haplotype that associates with all data sets. That might be revealed by further genotyping, the authors believe. “We don’t think the SNPs that we have used are anything more than simple tags or markers, and we don’t think that they are, themselves, likely to be disease-causing mutations,” said St George-Hyslop in a press briefing. “However, what they do do is identify specific regions of the SORL1 gene likely to be the site where these mutations occur.” The researchers are confident that the disease-causing mutations lie in the SORL1 gene because when they tested SNPs flanking the 5’ and 3’ ends of the gene, they found no association with AD.

Many people will be wondering how this new AD gene stacks up against ApoE as a risk factor and how much of LOAD can be attributed to SORL1 genetic variation. The researchers were reluctant to make that prediction. “It would be prudent for us to first identify the mutation or exact change in the gene that is causing this association,” said Mayeux. Secondly, he pointed out that because the study deliberately focused on families with AD, it is difficult to extrapolate to the general population. “At some point in the future, though, we will be able to go to an elderly population who are unselected for any reason, and determine what the attributable risk will be, once we identify the true variant in the SORL1 gene,” he added.

To find the true disease-causing variation(s), the authors genotyped the exons and intron-exon boundaries in DNA samples positive for the 5’ (SNPs 8-10) and 3’ (SNPS 22-24) haplotypes that associate with AD, but they could not find any pathogenic sequence variations. This leads them to suggest that the disease-causing mutations are likely to be intronic and that they somehow modulate SORL1 expression. In support of this notion, they found that lymphoblasts isolated from AD haplotype carriers express only half as much SORL1 as lymphoblasts from non-carriers.

One strength of the SORL1 association is that it dovetails well with some of the known biology of LOAD, namely the processing of APP. Rogaeva and colleagues found that SORL1 binds to APP in HEK cells and that overexpression of the sorting receptor reduces Aβ production, while underexpression does the opposite. This would suggest that, as in early onset familial AD, modulation of APP processing may be fundamental to disease etiology in at least some cases of late-onset disease.—Tom Fagan

Comments

    • User Profile Image Rudy Tanzi
      Massachusetts General Hospital
    • Posted:

    This new study showing association of SORL1 with late-onset Alzheimer disease (LOAD) provides further support for a role of this gene in AD, confirming earlier studies by Lah, Small, Gandy, Masters, and others implicating SORL1 in AD pathogenesis.

    The novelty of this study is the inclusion of genetic association of several SNPs in SORL1 with various samples of different ethnicities. The results for specific SNPs across samples are interesting but inconsistent, with various SNPs showing positive results in some samples and negative data in others. This is often the case for many novel AD candidate genes when tested in multiple samples, either in a single study or across multiple studies.

    The Alzgene.org database on Alzforum reveals no less than two dozen genes that exhibit statistically significant association with LOAD after meta-analyses of multiple samples. These can be found in the "Top Alzgene Results" box in the right margin of Alzgene. A full description of Alzgene and its findings can be found in Bertram et al., 2007 in this month's issue.

    By statistical analyses on Alzgene prior to this paper, SORL1 would be roughly the twenty-fifth gene to show statistically significant association with LOAD after testing in multiple independent samples. To the authors' credit, a sufficient number of independent samples were tested in this new SORL1 paper to already lend itself to meta-analysis on Alzgene. According to Lars Bertram, these findings are now being added to the site and are summarized here. The bottom line is that several of the meta-analyses for the SORL1 SNPs tested are significant. However, the effect on risk is very modest—the strongest allelic odds ratio for SORL1 is only 1.21. This means that the strongest effect of any SNP in SORL1 in the new study would increase risk for AD by 21 percent. In contrast, one copy of ApoE4 increases risk by about 300 percent.

    The top hits on the Alzgene site are ranked by strength of their effect on risk for AD. As expected, ApoE4 is number one. Based on the data in the new study by St George-Hyslop and colleagues, SORL1 would not make the top 10 list, but rank in at number 12 out of 25. So while SORL1 can be added to the list, its small effects on risk based on the multiple case-control samples tested, as well as the less impressive results across the family-based samples tested, would suggest that SORL1 will turn out to be a minor genetic risk factor for AD.

    Additional replication testing will be needed to see if the effects on risk hold up over time. As with all AD gene candidates proposed beyond the established four AD genes (APP, PSEN1, PSEN2, ApoE), the true validity of SORL1 as a novel AD gene will need to await the identification of validated pathogenic mutations or variants.

    References:

    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007 Jan;39(1):17-23. PubMed.

    View all comments by Rudy Tanzi
    • User Profile Image John Hardy
      Institute of Neurology, UCL
    • Posted:

    This work is welcome news from an excellent group of investigators. They will surely allow me to play devil’s advocate and caution two things. First, however enticing the cell biology might be, at this point it is a distraction. The question at hand is a genetic question, and to answer the genetics per se, the cell biology data is irrelevant. Unfortunately, journal editors often demand cell biology in genetics papers, even if it’s just an initial set of experiments.

    Second, while many sample series were used, there is not an exact replication of the haplotypic association between the sample series, making these "replications," in my view, suspect. In this, the work resembles our own work (Li et al., 2006 and Grupe et al., 2006 on other risk genes). In these cases, too, we obtained multiple, but not entirely convincing replications.

    Late-onset Alzheimer genetics is proving to be a very difficult problem. I personally doubt whether this is the new ApoE, but genuine attempts at replication will sort that out reasonably quickly.

    References:

    Li Y, Grupe A, Rowland C, Nowotny P, Kauwe JS, Smemo S, Hinrichs A, Tacey K, Toombs TA, Kwok S, Catanese J, White TJ, Maxwell TJ, Hollingworth P, Abraham R, Rubinsztein DC, Brayne C, Wavrant-De Vrièze F, Hardy J, O'Donovan M, Lovestone S, Morris JC, Thal LJ, Owen M, Williams J, Goate A. DAPK1 variants are associated with Alzheimer's disease and allele-specific expression. Hum Mol Genet. 2006 Sep 1;15(17):2560-8. PubMed.

    Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, Kauwe JS, Maxwell TJ, Cherny S, Doil L, Tacey K, van Luchene R, Myers A, Wavrant-De Vrièze F, Kaleem M, Hollingworth P, Jehu L, Foy C, Archer N, Hamilton G, Holmans P, Morris CM, Catanese J, Sninsky J, White TJ, Powell J, Hardy J, O'Donovan M, Lovestone S, Jones L, Morris JC, Thal L, Owen M, Williams J, Goate A. A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. Am J Hum Genet. 2006 Jan;78(1):78-88. PubMed.

    View all comments by John Hardy
    • User Profile Image Rudy Tanzi
      Massachusetts General Hospital
    • Posted:

    Update: With regard to my earlier comment on the SORL1-AD genetic association study by Rogaeva et al, I initially commented that on the Alzgene list of "Top Alzgene Results", SORL1 ranked 12th out of 25 genes. (Ranking is based on effects of SNPs in the gene on risk for AD, with APOE at number 1).

    Lars Bertram has now revised that ranking on the most updated "Top Alzgene Results" list:

    SORL1 ranks 18th out of 27 genes listed on "Top Alzgene Results" that have statistically significant effects on AD risk following meta-analyses.

    View all comments by Rudy Tanzi

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References

News Citations

  1. Sorrento: Sorting Out Shedding of Ectodomains

Paper Citations

  1. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6. PubMed.
  2. Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004 Aug;61(8):1200-5. PubMed.
  3. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007 Jan;39(1):17-23. PubMed.

Other Citations

  1. related presentation

External Citations

  1. Alzgene meta-analysis

Further Reading

No Available Further Reading

Primary Papers

  1. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.

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