Skip to main content

Advertisement

SpringerLink
Log in

SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Massive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) cases as compared to controls: TREM2, SORL1, and ABCA7. SORL1 encodes SorLA, a key protein involved in the processing of the amyloid-beta (Aβ) precursor protein (APP) and the secretion of the Aβ peptide, the aggregation of which triggers AD pathophysiology. Common SORL1 single nucleotide polymorphisms had originally been associated with AD with modest odds ratios (ORs). The association of AD with rare SORL1 coding variants has been demonstrated at the gene level by aggregating protein-truncating (PTV) and rare predicted damaging missense variants. In addition to the loss of SorLA function induced by PTVs, a few missense variants were studied in vitro, showing diverse degrees of decreased SorLA function and leading to increased Aβ secretion. However, the exact functional consequences of most of the missense variants remain to be determined as well as corresponding levels of AD risk. Hereby we review the evidence of the association of SORL1 common and rare variants with AD risk and conduct a meta-analysis of published data on SORL1 rare variants in five large sequencing studies. We observe a significant enrichment in PTVs with ORs of 12.29 (95% confidence interval = [4.22–35.78]) among all AD cases and 27.50 [7.38–102.42] among early-onset cases. Rare [minor allele frequency (MAF) < 1%] and ultra-rare (MAF < 10−4) missense variants that are predicted damaging by 3/3 bioinformatics tools also show significant associations with corresponding ORs of 1.87 [1.54–2.28] and 3.14 [2.30–4.28], respectively. Per-domain analyses show significant association with the APP-binding CR cluster class A repeats and the Aβ-binding VPS10P domains, as well as the fibronectin type III domain, the function of which remains to be specified. These results further support a critical role for SORL1 rare coding variants in AD, although functional and segregation analyses are required to allow an accurate use in a clinical setting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Alexopoulos P, Guo LH, Kratzer M, Westerteicher C, Kurz A, Perneczky R (2011) Impact of SORL1 single nucleotide polymorphisms on Alzheimer’s disease cerebrospinal fluid markers. Dement Geriatr Cogn Disord 32:164–170. https://doi.org/10.1159/000332017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci USA 102:13461–13466. https://doi.org/10.1073/pnas.0503689102

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Andersen OM, Rudolph IM, Willnow TE (2016) Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease. Acta Neuropathol 132:653–665. https://doi.org/10.1007/s00401-016-1615-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Andersen OM, Schmidt V, Spoelgen R, Gliemann J, Behlke J, Galatis D et al (2006) Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry 45:2618–2628. https://doi.org/10.1021/bi052120v

    Article  PubMed  CAS  Google Scholar 

  5. Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G et al (2017) Contribution to Alzheimer’s disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging 59:220 e221–220 e229. https://doi.org/10.1016/j.neurobiolaging.2017.07.001

    Article  CAS  Google Scholar 

  6. Bettens K, Brouwers N, Engelborghs S, De Deyn PP, Van Broeckhoven C, Sleegers K (2008) SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population. Hum Mutat 29:769–770. https://doi.org/10.1002/humu.20725

    Article  PubMed  Google Scholar 

  7. Bis JC, Jian X, Kunkle BW, Chen Y, Hamilton-Nelson KL, Bush WS et al (2018) Whole exome sequencing study identifies novel rare and common Alzheimer’s-associated variants involved in immune response and transcriptional regulation. Mol Psychiatry. https://doi.org/10.1038/s41380-018-0112-7

    Article  PubMed  PubMed Central  Google Scholar 

  8. Caglayan S, Bauerfeind A, Schmidt V, Carlo AS, Prabakaran T, Hubner N et al (2012) Identification of Alzheimer disease risk genotype that predicts efficiency of SORL1 expression in the brain. Arch Neurol 69:373–379. https://doi.org/10.1001/archneurol.2011.788

    Article  PubMed  Google Scholar 

  9. Caglayan S, Takagi-Niidome S, Liao F, Carlo AS, Schmidt V, Burgert T et al (2014) Lysosomal sorting of amyloid-beta by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation. Sci Transl Med 6:223ra220. https://doi.org/10.1126/scitranslmed.3007747

    Article  CAS  Google Scholar 

  10. Cuccaro ML, Carney RM, Zhang Y, Bohm C, Kunkle BW, Vardarajan BN et al (2016) SORL1 mutations in early- and late-onset Alzheimer disease. Neurol Genet 2:e116. https://doi.org/10.1212/NXG.0000000000000116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Cuenco KT, Lunetta KL, Baldwin CT, McKee AC, Guo J, Cupples LA et al (2008) Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease. Arch Neurol 65:1640–1648. https://doi.org/10.1001/archneur.65.12.1640

    Article  PubMed Central  Google Scholar 

  12. Cuyvers E, De Roeck A, Van den Bossche T, Van Cauwenberghe C, Bettens K, Vermeulen S et al (2015) Mutations in ABCA7 in a Belgian cohort of Alzheimer’s disease patients: a targeted resequencing study. Lancet Neurol 14:814–822. https://doi.org/10.1016/S1474-4422(15)00133-7

    Article  PubMed  CAS  Google Scholar 

  13. Dodson SE, Andersen OM, Karmali V, Fritz JJ, Cheng D, Peng J et al (2008) Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer’s disease. J Neurosci 28:12877–12886. https://doi.org/10.1523/JNEUROSCI.4582-08.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Fernandez MV, Black K, Carrell D, Saef B, Budde J, Deming Y et al (2016) SORL1 variants across Alzheimer’s disease European American cohorts. Eur J Hum Genet 24:1828–1830. https://doi.org/10.1038/ejhg.2016.122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O et al (2011) APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 16:903–907. https://doi.org/10.1038/mp.2011.52

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Gomez-Tortosa E, Ruggiero M, Sainz MJ, Villarejo-Galende A, Prieto-Jurczynska C, Venegas Perez B et al (2018) SORL1 variants in familial Alzheimer’s disease. J Alzheimers Dis 61:1275–1281. https://doi.org/10.3233/JAD-170590

    Article  PubMed  CAS  Google Scholar 

  17. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127. https://doi.org/10.1056/NEJMoa1211851

    Article  PubMed  CAS  Google Scholar 

  18. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M et al (2017) Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy. Eur J Hum Genet 25:973–981. https://doi.org/10.1038/ejhg.2017.87

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S et al (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488:96–99. https://doi.org/10.1038/nature11283

    Article  PubMed  CAS  Google Scholar 

  20. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116. https://doi.org/10.1056/NEJMoa1211103

    Article  PubMed  CAS  Google Scholar 

  21. Kunkle B, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC et al (2019) Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing. Nat Genet. https://doi.org/10.1038/s41588-019-0358-2

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. https://doi.org/10.1038/ng.2802

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Le Guennec K, Nicolas G, Quenez O, Charbonnier C, Wallon D, Bellenguez C et al (2016) ABCA7 rare variants and Alzheimer disease risk. Neurology 86:2134–2137. https://doi.org/10.1212/WNL.0000000000002627

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Le Guennec K, Tubeuf H, Hannequin D, Wallon D, Quenez O, Rousseau S et al (2018) Biallelic loss of function of SORL1 in an early onset Alzheimer’s disease patient. J Alzheimers Dis 62:821–831. https://doi.org/10.3233/JAD-170981

    Article  PubMed  CAS  Google Scholar 

  25. Lee JH, Cheng R, Schupf N, Manly J, Lantigua R, Stern Y et al (2007) The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch Neurol 64:501–506. https://doi.org/10.1001/archneur.64.4.501

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. https://doi.org/10.1038/nature19057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Li Y, Rowland C, Catanese J, Morris J, Lovestone S, O’Donovan MC et al (2008) SORL1 variants and risk of late-onset Alzheimer’s disease. Neurobiol Dis 29:293–296. https://doi.org/10.1016/j.nbd.2007.09.001

    Article  PubMed  CAS  Google Scholar 

  28. Louwersheimer E, Cohn-Hokke PE, Pijnenburg YA, Weiss MM, Sistermans EA, Rozemuller AJ et al (2017) Rare genetic variant in SORL1 may increase penetrance of Alzheimer’s disease in a family with several generations of APOE-varepsilon4 homozygosity. J Alzheimers Dis 56:63–74. https://doi.org/10.3233/JAD-160091

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Louwersheimer E, Ramirez A, Cruchaga C, Becker T, Kornhuber J, Peters O et al (2015) Influence of genetic variants in SORL1 gene on the manifestation of Alzheimer’s disease. Neurobiol Aging 36(1605):e1613–e1620. https://doi.org/10.1016/j.neurobiolaging.2014.12.007

    Article  CAS  Google Scholar 

  30. Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E et al (2013) SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS One 8:e58618. https://doi.org/10.1371/journal.pone.0058618

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM et al (2010) Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42:30–35. https://doi.org/10.1038/ng.499

    Article  PubMed  CAS  Google Scholar 

  32. Nicolas G, Acuna-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M, Lelieveld S et al (2018) Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer’s disease. Alzheimers Dement 14:1632–1639. https://doi.org/10.1016/j.jalz.2018.06.3056

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nicolas G, Charbonnier C, Campion D (2016) From common to rare variants: the genetic component of Alzheimer disease. Hum Hered 81:129–141. https://doi.org/10.1159/000452256

    Article  PubMed  CAS  Google Scholar 

  34. Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B et al (2016) SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Mol Psychiatry 21:831–836. https://doi.org/10.1038/mp.2015.121

    Article  PubMed  CAS  Google Scholar 

  35. Noda Y, Kuzuya A, Tanigawa K, Araki M, Kawai R, Ma B et al (2018) Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid beta production in Alzheimer’s disease. Mol Brain 11:61. https://doi.org/10.1186/s13041-018-0401-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI et al (2006) The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci 26:1596–1603. https://doi.org/10.1523/JNEUROSCI.4946-05.2006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S et al (2012) High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry 17:875–879. https://doi.org/10.1038/mp.2012.15

    Article  PubMed  CAS  Google Scholar 

  38. Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R et al (2018) Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer’s disease. Ann Clin Transl Neurol 5:832–842. https://doi.org/10.1002/acn3.582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Reitz C, Cheng R, Rogaeva E, Lee JH, Tokuhiro S, Zou F et al (2011) Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Arch Neurol 68:99–106. https://doi.org/10.1001/archneurol.2010.346

    Article  PubMed  PubMed Central  Google Scholar 

  40. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  41. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177. https://doi.org/10.1038/ng1943

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Rohe M, Carlo AS, Breyhan H, Sporbert A, Militz D, Schmidt V et al (2008) Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. J Biol Chem 283:14826–14834. https://doi.org/10.1074/jbc.M710574200

    Article  PubMed  CAS  Google Scholar 

  43. Sassi C, Ridge PG, Nalls MA, Gibbs R, Ding J, Lupton MK et al (2016) Influence of coding variability in APP-Abeta Metabolism genes in sporadic Alzheimer’s disease. PLoS One 11:e0150079. https://doi.org/10.1371/journal.pone.0150079

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen OM et al (2007) SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem 282:32956–32964. https://doi.org/10.1074/jbc.M705073200

    Article  PubMed  CAS  Google Scholar 

  45. Schmidt V, Subkhangulova A, Willnow TE (2017) Sorting receptor SORLA: cellular mechanisms and implications for disease. Cell Mol Life Sci 74:1475–1483. https://doi.org/10.1007/s00018-016-2410-z

    Article  PubMed  CAS  Google Scholar 

  46. Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J et al (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet 49:1373–1384. https://doi.org/10.1038/ng.3916

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H et al (2015) Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nat Genet 47:445–447. https://doi.org/10.1038/ng.3246

    Article  PubMed  CAS  Google Scholar 

  48. Syama A, Sen S, Kota LN, Viswanath B, Purushottam M, Varghese M et al (2018) Mutation burden profile in familial Alzheimer’s disease cases from India. Neurobiol Aging 64:158 e157. https://doi.org/10.1016/j.neurobiolaging.2017.12.002

    Article  CAS  Google Scholar 

  49. Thonberg H, Chiang HH, Lilius L, Forsell C, Lindstrom AK, Johansson C et al (2017) Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene. Acta Neuropathol Commun 5:43. https://doi.org/10.1186/s40478-017-0441-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M et al (2015) Coding mutations in SORL1 and Alzheimer disease. Ann Neurol 77:215–227. https://doi.org/10.1002/ana.24305

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Llado A et al (2016) A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease. Acta Neuropathol 132:213–224. https://doi.org/10.1007/s00401-016-1566-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Young JE, Boulanger-Weill J, Williams DA, Woodruff G, Buen F, Revilla AC et al (2015) Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell 16:373–385. https://doi.org/10.1016/j.stem.2015.02.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank Magalie Lecourtois, Anne Rovelet–Lecrux and Olivier Quenez for their help. We are grateful to Henne Holstege for providing variant information on the EOAD subset from the Dutch study (Holstege et al. [18]) and to the NIAGADS for granting us access to the ADSP data. This work was supported by the Fondation pour la Recherche Médicale (Grant DEQ 20170336711).

Author information

Authors and Affiliations

  1. Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, 76000, Rouen, France

    Dominique Campion, Camille Charbonnier & Gaël Nicolas

  2. Department of Research, Rouvray Psychiatric Hospital, Sotteville-Lès-Rouen, France

    Dominique Campion

Authors
  1. Dominique Campion
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Camille Charbonnier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gaël Nicolas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dominique Campion or Gaël Nicolas.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 482 kb)

Supplementary material 2 (XLSX 85 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Campion, D., Charbonnier, C. & Nicolas, G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol 138, 173–186 (2019). https://doi.org/10.1007/s00401-019-01991-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-019-01991-4

Keywords

Search

Navigation