Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, Wolock CJ, Kamalakaran S, Petrovski S, Tosto G, Vardarajan BN, Goldstein DB, Mayeux R, Alzheimer's Disease Sequencing Project. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol. 2018 Jul;5(7):832-842. Epub 2018 May 24 PubMed.

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  1. This work is based on an impressive number of sequencing data generated from Alzheimer’s patients and controls, and primarily analyzes loss-of-function (LOF) variants. The major result obtained in this analysis mainly replicates the association of rare variants of SORL1 with a particularly high risk of developing Alzheimer’s disease. These data thus confirm that LOF variants in SORL1 are particularly deleterious (Pottier et al., 2012; Nicolas et al., 2015; Bellenguez et al., 2017; Verheijen et al., 2016; Holstege et al., 2017). 

    Interestingly, these data also indicate that this type of very rare variant is found in cases regardless of their ethnic origin. There is thus no longer any doubt SORL1 is a major genetic determinant of Alzheimer's disease, by probably participating in a central pathophysiological pathway.

    In addition, common variants associated with decreased expression of SORL1 are also associated with increased risk of disease in GWAS studies (Rogaeva et al., 2007; Lambert et al., 2013; Young et al., 2015). It seems thus that a complete loss of function is particularly impacting, leading probably to earlier forms, while a decrease in expression leads to a low level of risk, likely in connection with a more insidious biological impact.

    Currently, it has been proposed that SORL1 underexpression modifies APP processing and potentially leads to Aβ peptide overproduction (Rogaeva et al., 2007). If this were to be confirmed, it would obviously be additional genetic evidence supporting the amyloid cascade hypothesis.

    Of note, beyond SORL1, three other genes could be of interest but these must be validated in independent populations. This indicates that the detection of the association of rare variants, as expected, requires significant statistical power to be able to detect new signals. Strong efforts are still needed.

    References:

    Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J, Thomas-Anterion C, Michon A, Croisile B, Etcharry-Bouyx F, Berr C, Dartigues JF, Amouyel P, Dauchel H, Boutoleau-Bretonnière C, Thauvin C, Frebourg T, Lambert JC, Campion D. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012 Apr 3; PubMed.

    Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Amouyel P, Munter HM, Bourque G, Lathrop M, Frebourg T, Redon R, Letenneur L, Dartigues JF, Génin E, Lambert JC, Hannequin D, Campion D, CNR-MAJ collaborators. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry. 2016 Jun;21(6):831-6. Epub 2015 Aug 25 PubMed.

    Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues JF, Tzourio C, Frebourg T, Lathrop M, Deleuze JF, Hannequin D, Genin E, Amouyel P, Debette S, Lambert JC, Campion D, CNR MAJ collaborators. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging. 2017 Nov;59:220.e1-220.e9. Epub 2017 Jul 14 PubMed.

    Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):213-24. Epub 2016 Mar 30 PubMed.

    Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 PubMed.

    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.

    Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Morón FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer's Disease Initiative (EADI), Genetic and Environmental Risk in Alzheimer's Disease, Alzheimer's Disease Genetic Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannefelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH Jr, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltuenen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P, Wang J, Uitterlinden AG, Rivadeneira F, Koudstgaal PJ, Longstreth WT Jr, Becker JT, Kuller LH, Lumley T, Rice K, Garcia M, Aspelund T, Marksteiner JJ, Dal-Bianco P, Töglhofer AM, Freudenberger P, Ransmayr G, Benke T, Toeglhofer AM, Bressler J, Breteler MM, Fornage M, Hernández I, Rosende Roca M, Ana Mauleón M, Alegrat M, Ramírez-Lorca R, González-Perez A, Chapman J, Stretton A, Morgan A, Kehoe PG, Medway C, Lord J, Turton J, Hooper NM, Vardy E, Warren JD, Schott JM, Uphill J, Ryan N, Rossor M, Ben-Shlomo Y, Makrina D, Gkatzima O, Lupton M, Koutroumani M, Avramidou D, Germanou A, Jessen F, Riedel-Heller S, Dichgans M, Heun R, Kölsch H, Schürmann B, Herold C, Lacour A, Drichel D, Hoffman P, Kornhuber J, Gu W, Feulner T, van den Bussche H, Lawlor B, Lynch A, Mann D, Smith AD, Warden D, Wilcock G, Heuser I, Wiltgang J, Frölich L, Hüll M, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Jöckel KH, Klopp N, Wichmann HE, Dickson DW, Graff-Radford NR, Ma L, Bisceglio G, Fisher E, Warner N, Pickering-Brown S. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013 Dec;45(12):1452-8. Epub 2013 Oct 27 PubMed.

    Young JE, Boulanger-Weill J, Williams DA, Woodruff G, Buen F, Revilla AC, Herrera C, Israel MA, Yuan SH, Edland SD, Goldstein LS. Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell. 2015 Apr 2;16(4):373-85. Epub 2015 Mar 12 PubMed.

    View all comments by Jean-Charles Lambert

  2. When the first rare protein-damaging SORL1 variants were identified by our group, the families were selected with the aim to identify a fourth autosomal-dominant gene. Probands presented with early onset AD (EOAD, onset before 65 years) and a positive family history of EOAD in first- and second-degree relatives (Pottier et al., 2012). However, segregation data was lacking to conclude about pathogenicity in the context of a putative monogenic inheritance.

    Since then, we and others have reported such variants in other families with diverse patterns of family history, including presence of other early onset cases, late-onset cases, and no family history of AD. Recently, we reported the case of a patient with biallelic SORL1 protein-truncating variants and a family history of both early and late-onset AD in the parents (Le Guennec et al., 2018). In addition, protein-truncating variants have been identified in population databases such as ExAC, although extremely rare (estimated number of carriers from allele counts: 41 out of ~60,000) and exceptionally in controls from case-control studies. The spectrum associated with carrier status of two or one protein-truncating SORL1 variants hence extends from familial early or late-onset AD, sporadic early or late-onset AD, to the status of control.

    We previously showed that rare SORL1 protein-truncating and missense, predicted-damaging variants, most of which are singleton variants, significantly increase the risk of EOAD with exome-wide significance in the ADES-FR study (p<10-6) (Nicolas et al., 2016; Bellenguez et al., 2017). They have a significantly greater effect on EOAD risk than on late-onset risk. In our latest work, 1.29 percent of EOAD cases (0.62 percent of all AD cases) carried a singleton protein-truncating variant, compared to one out of 1,273 controls (OR for EOAD: 16.22, 95 percent CI=[23.08-inf], p=3.4e-4).

    In this paper, Raghavan et al. took advantage of one of the largest existing case-control exome data sets and reached exome-wide significance for truncating variants. The proportion of protein-truncating variant carriers (0.27 percent) remains lower than in the ADES-FR study, probably because the ADSP case-control data set excludes cases with an age of onset  younger than 60 years. The extreme rarity of protein-truncating variants in controls in our case-control studies suggested a strong effect. In the Raghavan et al. data, the OR was estimated to be 36 (95 percent CI 5.8 – 1493.0), which is consistent with our previous results.

    Anyway, it is currently impossible to make a conclusion about the penetrance of SORL1 damaging variants without segregation data. Such data remain too limited in the literature to conclude full penetrance of some SORL1 variants. Even if we can provide enough evidence of Mendelian inheritance for some of the most damaging rare SORL1s, they remain less penetrant than most of the APP, PSEN1, and PSEN2 pathogenic variants. Up to now, SORL1 rare damaging coding variants are considered a strong risk factor.

    The word “pathogenic” should therefore not be used, nor genetic counseling proposed to families, until compelling co-segregation evidence has been reported in families.  

    Of note, the odds ratios of some TREM2 rare variants were even higher than SORL1’s in our latest case-control study (Bellenguez et al., 2017), suggesting that the same questions hold true for TREM2, although a Mendelian role is not under debate up to now.

    References:

    Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J, Thomas-Anterion C, Michon A, Croisile B, Etcharry-Bouyx F, Berr C, Dartigues JF, Amouyel P, Dauchel H, Boutoleau-Bretonnière C, Thauvin C, Frebourg T, Lambert JC, Campion D. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012 Apr 3; PubMed.

    Le Guennec K, Tubeuf H, Hannequin D, Wallon D, Quenez O, Rousseau S, Richard AC, Deleuze JF, Boland A, Frebourg T, Gaildrat P, Campion D, Martins A, Nicolas G. Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. J Alzheimers Dis. 2018;62(2):821-831. PubMed.

    Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Amouyel P, Munter HM, Bourque G, Lathrop M, Frebourg T, Redon R, Letenneur L, Dartigues JF, Génin E, Lambert JC, Hannequin D, Campion D, CNR-MAJ collaborators. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry. 2016 Jun;21(6):831-6. Epub 2015 Aug 25 PubMed.

    Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues JF, Tzourio C, Frebourg T, Lathrop M, Deleuze JF, Hannequin D, Genin E, Amouyel P, Debette S, Lambert JC, Campion D, CNR MAJ collaborators. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging. 2017 Nov;59:220.e1-220.e9. Epub 2017 Jul 14 PubMed.

    View all comments by Gael Nicolas

  3. This work clearly confirms the work of Holstege and colleagues showing that loss-of-function variants in SORL1 are associated with a large increase in risk of AD. These mutations confer very high risk that can be considered close to penetrant.

    The authors continue the trend of such findings. The ABCA7 gene, too, is a GWAS hit for AD, for which loss-of-function variants have a larger effect on risk. In general this type of relationship is likely to be found in other genes among the GWAS hits.

    It’s interesting that the yield of novel genes was so low.

    View all comments by John Hardy

  4. Family segregation studies and linkage analysis would be needed to confirm if SORL1 is equivalent to APP or PS as an autosomal-dominant gene. However, this is tremendous work and clearly implicates loss of SORL1 function as a very strong risk factor for AD.

    This could lead to compelling insights into the biology of SORL1, not only in terms of its well-characterized interactions with APP but potentially other roles in endocytosis and vesicular trafficking in the brain. For example, both truncation variants and non-synonymous coding variants in SORL1 have been associated with AD, raising the question if these missense variants impair an essential function of SORL1?

    Since SORL1 variants are implicated in both early and late-onset AD, it would also be interesting to understand genetic interactions between SORL1 and other vesicular trafficking genes associated with increased AD risk.

    In general, this study provides strong evidence that SORL1 and related pathways are viable candidates for investigation into therapeutic development.

    View all comments by Jessica Young

  5. The findings are interesting and add significance to previous studies on SORL1 implicated in AD. Some of those were cited and some were not, including our paper (Thonberg et al., 2017), which identifies three variants in SORL1 segregating with disease in familial AD with a mix of early onset and late-onset disease in the families.

    It would be interesting to know if the late-onset AD cases with deleterious SORL1 variants in the Mayeux paper have a positive family history and if other family members developed disease before 65 years, indicating an age-at-onset variability for SORL1 variants similar to our findings rather than, or in addition to, SORL1 being implicated in “sporadic late-onset AD.”

    In any event, it is an exciting paper, which together with previous studies clearly motivates further studies on SORL1 as an important player in AD pathogenesis.

    References:

    Thonberg H, Chiang HH, Lilius L, Forsell C, Lindström AK, Johansson C, Björkström J, Thordardottir S, Sleegers K, Van Broeckhoven C, Rönnbäck A, Graff C. Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene. Acta Neuropathol Commun. 2017 Jun 9;5(1):43. PubMed.

    View all comments by Caroline Graff

  6. The paper by Richard Mayeux and colleagues is indeed very interesting. It adds evidence for SORL1 actually being causative for AD, and strengthens the role of SORL1 in APP/Aβ metabolism.

    However, caution must still be taken when it comes to using this finding in clinical settings. Our advice is not to use it at all for risk assessment or similar when facing patients. At the moment, we cannot place it alongside APP and presenilin genes, as it is still questionable whether it is a true cause of autosomal inheritance.

    We hope the research field will be able to add data in the very near future.

    View all comments by Håkan Thonberg

  7. It is exciting to see that this huge effort underlines previous evidence that predicted loss-of-function mutations in SORL1 are strong risk factors for Alzheimer's dementia, even in patients with later disease onset.

    Considering the lack of reports of these mutations from cognitively healthy individuals, these mutations are likely to have a high penetrance, and several studies have documented increased familial clustering of AD among carriers of SORL1 loss-of-function mutations that would be in line with this (e.g. Pottier et al., 2012; Nicolas et al., 2015; Verheijen et al., 2016; Vardarajan et al., 2015).

    The current paper does not provide insight in potential familial inheritance; it will be important to investigate this further to get a better appreciation of possible patterns of inheritance as well as modifiers of penetrance. The wide spread in onset age among carriers is suggestive of the latter, and more in-depth understanding of these characteristics will be required before we could consider predictive testing in a clinical setting. It also re-emphasizes the need to design assays to experimentally determine which of the many SORL1 missense mutations that are being identified in sequencing studies will lead to loss of SORL1 functionality with similarly strong pathogenic effects.

    Of note, the paper used very stringent inclusion criteria for variants, hence the lack of association for other genes may in part be attributable to selecting against less rare loss-of-function mutations, as observed in, e.g., ABCA7.

    References:

    Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J, Thomas-Anterion C, Michon A, Croisile B, Etcharry-Bouyx F, Berr C, Dartigues JF, Amouyel P, Dauchel H, Boutoleau-Bretonnière C, Thauvin C, Frebourg T, Lambert JC, Campion D. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012 Apr 3; PubMed.

    Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Amouyel P, Munter HM, Bourque G, Lathrop M, Frebourg T, Redon R, Letenneur L, Dartigues JF, Génin E, Lambert JC, Hannequin D, Campion D, CNR-MAJ collaborators. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry. 2016 Jun;21(6):831-6. Epub 2015 Aug 25 PubMed.

    Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):213-24. Epub 2016 Mar 30 PubMed.

    Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, Reitz C, Reyes-Dumeyer D, Shen Y, Rogaeva E, St George-Hyslop P, Mayeux R. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015 Feb;77(2):215-27. PubMed.

    View all comments by Kristel Sleegers

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