Top

Published in:

Open Access 01-08-2016 | Original Paper

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease

Authors: Jan Verheijen, Tobi Van den Bossche, Julie van der Zee, Sebastiaan Engelborghs, Raquel Sanchez-Valle, Albert Lladó, Caroline Graff, Håkan Thonberg, Pau Pastor, Sara Ortega-Cubero, Maria A. Pastor, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Jordi Clarimon, Alberto Lleó, Juan Fortea, Alexandre de Mendonça, Madalena Martins, Oriol Grau-Rivera, Ellen Gelpi, Karolien Bettens, Ligia Mateiu, Lubina Dillen, Patrick Cras, Peter P. De Deyn, Christine Van Broeckhoven, Kristel Sleegers

Published in: Acta Neuropathologica | Issue 2/2016

Abstract

The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer’s disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD.

Available only for authorised users

Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X 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. doi:10.1073/pnas.0503689102 CrossRefPubMedPubMedCentral

Andersen OM, Schmidt V, Spoelgen R, Gliemann J, Behlke J, Galatis D, McKinstry WJ, Parker MW, Masters CL, Hyman BT et al (2006) Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry 45:2618–2628. doi:10.1021/bi052120v CrossRefPubMed

Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics (Oxford, England) 30:2114–2120. doi:10.1093/bioinformatics/btu170 CrossRef

Brouwers N, Sleegers K, Van Broeckhoven C (2008) Molecular genetics of Alzheimer’s disease: an update. Ann Med 40:562–583. doi:10.1080/07853890802186905 CrossRefPubMed

Cacace R, Van den Bossche T, Engelborghs S, Geerts N, Laureys A, Dillen L, Graff C, Thonberg H, Chiang HH, Pastor P et al (2015) Rare variants in PLD3 do not affect risk for early-onset Alzheimer disease in a European consortium cohort. Human Mutat. doi:10.1002/humu.22908

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

Caglayan S, Takagi-Niidome S, Liao F, Carlo AS, Schmidt V, Burgert T, Kitago Y, Fuchtbauer EM, Fuchtbauer A, Holtzman DM 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. doi:10.1126/scitranslmed.3007747 CrossRef

Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F et al (1999) Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 65:664–670. doi:10.1086/302553 CrossRefPubMedPubMedCentral

Chen H, Lumley T, Brody J, Heard-Costa NL, Fox CS, Cupples LA, Dupuis J (2014) Sequence kernel association test for survival traits. Genet Epidemiol 38:191–197. doi:10.1002/gepi.21791 CrossRefPubMedPubMedCentral

10.

Cuyvers E, De Roeck A, Van den Bossche T, Van Cauwenberghe C, Bettens K, Vermeulen S, Mattheijssens M, Peeters K, Engelborghs S, Vandenbulcke M et al (2015) Mutations in ABCA7 in a Belgian cohort of Alzheimer’s disease patients: a targeted resequencing study. Lancet Neurol 14:814–822. doi:10.1016/s1474-4422(15)00133-7 CrossRefPubMed

11.

Cuyvers E, van der Zee J, Bettens K, Engelborghs S, Vandenbulcke M, Robberecht C, Dillen L, Merlin C, Geerts N, Graff C et al (2015) Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study. Neurobiol Aging 36(2005):e2015–e2022. doi:10.1016/j.neurobiolaging.2015.02.014

12.

Engelborghs S, Dermaut B, Goeman J, Saerens J, Marien P, Pickut BA, Van den Broeck M, Serneels S, Cruts M, Van Broeckhoven C et al (2003) Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects. J Neurol Neurosurg Psychiatry 74:1148–1151CrossRefPubMedPubMedCentral

13.

Fjorback AW, Andersen OM (2012) SorLA is a molecular link for retromer-dependent sorting of the Amyloid precursor protein. Commun Integr Biol 5:616–619. doi:10.4161/cib.21433 CrossRefPubMedPubMedCentral

14.

Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, Wu C, Militz D, Schmidt V, Madsen P, Nyengaard JR et al (2012) Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosc Off J Soc Neurosci 32:1467–1480. doi:10.1523/jneurosci.2272-11.2012 CrossRef

15.

Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198CrossRefPubMed

16.

Hermey G (2009) The Vps10p-domain receptor family. Cell Mol Life Sci CMLS 66:2677–2689. doi:10.1007/s00018-009-0043-1 CrossRefPubMed

17.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc 8:1–13. doi:10.1016/j.jalz.2011.10.007 CrossRef

18.

Prince M, Albanese E, Guerchet M, Prina M (2014) World Alzheimer Report 2014: Dementia and risk reduction: an analysis of protective and modifiable risk factors. Alzheimer's Disease International, London

19.

Jarmolowicz AI, Chen HY, Panegyres PK (2015) The patterns of inheritance in early-onset dementia: Alzheimer’s disease and frontotemporal dementia. Am J Alzheimer’s Dis Other Dement 30:299–306. doi:10.1177/1533317514545825 CrossRef

20.

Jin C, Liu X, Zhang F, Wu Y, Yuan J, Zhu J, Zhang F, Wang G, Cheng Z (2013) An updated meta-analysis of the association between SORL1 variants and the risk for sporadic Alzheimer’s disease. J Alzheimer’s Dis JAD 37:429–437. doi:10.3233/jad-130533 PubMed

21.

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14:R36. doi:10.1186/gb-2013-14-4-r36 CrossRefPubMedPubMedCentral

22.

Kitago Y, Nagae M, Nakata Z, Yagi-Utsumi M, Takagi-Niidome S, Mihara E, Nogi T, Kato K, Takagi J (2015) Structural basis for amyloidogenic peptide recognition by sorLA. Nat Struct Mol Biol. doi:10.1038/nsmb.2954 PubMed

23.

Koboldt DC, Chen K, Wylie T, Larson DE, McLellan MD, Mardis ER, Weinstock GM, Wilson RK, Ding L (2009) VarScan: variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics (Oxford, England) 25:2283–2285. doi:10.1093/bioinformatics/btp373 CrossRef

24.

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

25.

Lee S, Wu MC, Lin X (2012) Optimal tests for rare variant effects in sequencing association studies. Biostatistics (Oxford, England) 13:762–775. doi:10.1093/biostatistics/kxs014 CrossRef

26.

Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England) 25:1754–1760. doi:10.1093/bioinformatics/btp324 CrossRef

27.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods (San Diego, Calif) 25:402–408. doi:10.1006/meth.2001.1262 CrossRef

28.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303. doi:10.1101/gr.107524.110 CrossRefPubMedPubMedCentral

29.

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944CrossRefPubMed

30.

McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc 7:263–269. doi:10.1016/j.jalz.2011.03.005 CrossRef

31.

McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F (2010) Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics (Oxford, England) 26:2069–2070. doi:10.1093/bioinformatics/btq330 CrossRef

32.

Mehmedbasic A, Christensen SK, Nilsson J, Ruetschi U, Gustafsen C, Poulsen AS, Rasmussen RW, Fjorback AN, Larson G, Andersen OM (2015) SorLA complement-type repeat domains protect the amyloid precursor protein against processing. J Biol Chem 290:3359–3376. doi:10.1074/jbc.M114.619940 CrossRefPubMed

33.

Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, Kawarabayashi T, Shoji M, Tomita N, Arai H et al (2013) SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese. Koreans and Caucasians. PloS One 8:e58618. doi:10.1371/journal.pone.0058618 CrossRefPubMedPubMedCentral

34.

Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. doi:10.1007/s00401-011-0910-3 CrossRefPubMed

35.

Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K et al (2015) SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Mol Psychiatry. doi:10.1038/mp.2015.121

36.

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

37.

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

38.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Human Genetics 81:559–575. doi:10.1086/519795 CrossRef

39.

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

40.

Reumers J, De Rijk P, Zhao H, Liekens A, Smeets D, Cleary J, Van Loo P, Van Den Bossche M, Catthoor K, Sabbe B et al (2012) Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing. Nat Biotechnol 30:61–68. doi:10.1038/nbt.2053 CrossRef

41.

Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP (2011) Integrative genomics viewer. Nat Biotechnol 29:24–26. doi:10.1038/nbt.1754 CrossRefPubMedPubMedCentral

42.

Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177. doi:10.1038/ng1943 CrossRefPubMedPubMedCentral

43.

Satya RV, Zavaljevski N, Reifman J (2012) A new strategy to reduce allelic bias in RNA-Seq readmapping. Nucleic acids Res 40:e127. doi:10.1093/nar/gks425 CrossRefPubMed

44.

Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ (2004) Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol 61:1200–1205. doi:10.1001/archneur.61.8.1200 CrossRefPubMed

45.

van der Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J, Engelborghs S, Philtjens S, Vandenbulcke M, Sleegers K, Sieben A et al (2013) A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Human Mutat 34:363–373. doi:10.1002/humu.22244 CrossRef

46.

van der Zee J, Van Langenhove T, Kovacs GG, Dillen L, Deschamps W, Engelborghs S, Matej R, Vandenbulcke M, Sieben A, Dermaut B et al (2014) Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration. Acta Neuropathol 128:397–410. doi:10.1007/s00401-014-1298-7 CrossRefPubMedPubMedCentral

47.

Van Durme J, Delgado J, Stricher F, Serrano L, Schymkowitz J, Rousseau F (2011) A graphical interface for the FoldX forcefield. Bioinformatics (Oxford, England) 27:1711–1712. doi:10.1093/bioinformatics/btr254 CrossRef

48.

Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, Reitz C, Reyes-Dumeyer D, Shen Y, Rogaeva E et al (2015) Coding mutations in SORL1 and Alzheimer disease. Ann Neurol 77:215–227. doi:10.1002/ana.24305 CrossRefPubMedPubMedCentral

49.

Wang L, Wang S, Li W (2012) RSeQC: quality control of RNA-seq experiments. Bioinformatics (Oxford, England) 28:2184–2185. doi:10.1093/bioinformatics/bts356 CrossRef

50.

Wang Z, Lei H, Zheng M, Li Y, Cui Y, Hao F (2015) Meta-analysis of the Association between Alzheimer Disease and variants in GAB2, PICALM, and SORL1. Mol Neurobiol. doi:10.1007/s12035-015-9546-y PubMedCentral

51.

Weckx S, Del-Favero J, Rademakers R, Claes L, Cruts M, De Jonghe P, Van Broeckhoven C, De Rijk P (2005) novoSNP, a novel computational tool for sequence variation discovery. Genome Res 15:436–442. doi:10.1101/gr.2754005 CrossRefPubMedPubMedCentral

52.

Willnow TE, Carlo AS, Rohe M, Schmidt V (2010) SORLA/SORL1, a neuronal sorting receptor implicated in Alzheimer’s disease. Rev Neurosci 21:315–329CrossRefPubMed

53.

Wingo TS, Lah JJ, Levey AI, Cutler DJ (2012) Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol 69:59–64. doi:10.1001/archneurol.2011.221 CrossRefPubMed

54.

Young JE, Boulanger-Weill J, Williams DA, Woodruff G, Buen F, Revilla AC, Herrera C, Israel MA, Yuan SH, Edland SD 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. doi:10.1016/j.stem.2015.02.004 CrossRefPubMedPubMedCentral

Title: A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease
Authors: Jan Verheijen
Tobi Van den Bossche
Julie van der Zee
Sebastiaan Engelborghs
Raquel Sanchez-Valle
Albert Lladó
Caroline Graff
Håkan Thonberg
Pau Pastor
Sara Ortega-Cubero
Maria A. Pastor
Luisa Benussi
Roberta Ghidoni
Giuliano Binetti
Jordi Clarimon
Alberto Lleó
Juan Fortea
Alexandre de Mendonça
Madalena Martins
Oriol Grau-Rivera
Ellen Gelpi
Karolien Bettens
Ligia Mateiu
Lubina Dillen
Patrick Cras
Peter P. De Deyn
Christine Van Broeckhoven
Kristel Sleegers
Publication date: 01-08-2016
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 2/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1566-9

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2016

Neuropathological signs of inflammation correlate with mitochondrial DNA deletions in mesial temporal lobe epilepsy

Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology

Inside out: the role of nucleocytoplasmic transport in ALS and FTLD

Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci

The importance of nerve microenvironment for schwannoma development

A rapidly progressive dementia case with pathological diagnosis of FTLD-UPS