nach oben

Acta Neuropathologica

Erschienen in:

25.03.2019 | Review

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

verfasst von: Dominique Campion, Camille Charbonnier, Gaël Nicolas

Erschienen in: Acta Neuropathologica | Ausgabe 2/2019

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRef

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRef

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRef

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRef

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

Titel: SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data
verfasst von: Dominique Campion
Camille Charbonnier
Gaël Nicolas
Publikationsdatum: 25.03.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 2/2019
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-01991-4

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Sozialer Aufstieg verringert Demenzgefahr

24.05.2024 Demenz Nachrichten

Ein hohes soziales Niveau ist mit die beste Versicherung gegen eine Demenz. Noch geringer ist das Demenzrisiko für Menschen, die sozial aufsteigen: Sie gewinnen fast zwei demenzfreie Lebensjahre. Umgekehrt steigt die Demenzgefahr beim sozialen Abstieg.

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Was nützt die Kraniektomie bei schwerer tiefer Hirnblutung?

17.05.2024 Hirnblutung Nachrichten

Eine Studie zum Nutzen der druckentlastenden Kraniektomie nach schwerer tiefer supratentorieller Hirnblutung deutet einen Nutzen der Operation an. Für überlebende Patienten ist das dennoch nur eine bedingt gute Nachricht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2019

Novel Alzheimer’s disease risk genes: exhaustive investigation is paramount

Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

Molecular progression of SHH-activated medulloblastomas

Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes