Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

Medientyp: E-Artikel
Titel: Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes
Beteiligte: Schramm, Catherine; Charbonnier, Camille; Zaréa, Aline; Lacour, Morgane; Wallon, David; Andriuta, Daniela; Anthony, Pierre; Auriacombe, Sophie; Balageas, Anna-Chloé; Ballan, Guillaume; Barbay, Mélanie; Beaufils, Emilie; Béjot, Yannick; Belliard, Serge; Benaiteau, Marie; Bennys, Karim; Blanc, Frédéric; Bombois, Stéphanie; Boutoleau Bretonnière, Claire; Branger, Pierre; Carlier, Jasmine; Cartz-Piver, Leslie; Cassagnaud, Pascaline; Castelnovo, Giovanni; [...]
Erschienen: Springer Science and Business Media LLC, 2022
Erschienen in: Genome Medicine
Sprache: Englisch
DOI: 10.1186/s13073-022-01070-6
ISSN: 1756-994X
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Beschreibung: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) <jats:italic>SORL1</jats:italic> variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, <jats:italic>APOE</jats:italic>-ε4, make such estimations difficult.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>We proposed to estimate the age-related penetrance of <jats:italic>SORL1</jats:italic>-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of <jats:italic>SORL1-</jats:italic>LoF variants, stratified by <jats:italic>APOE-ε4</jats:italic>, derived from the Rotterdam study (<jats:italic>N</jats:italic> = 12,255), and (ii) an age-dependent proportional hazard effect for <jats:italic>SORL1-</jats:italic>LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of <jats:italic>APOE</jats:italic>-ε4-stratified <jats:italic>SORL1-</jats:italic>LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p><jats:italic>SORL1-</jats:italic>LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among <jats:italic>APOE</jats:italic>-ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of <jats:italic>SORL1-</jats:italic>LoF variant carriers in case-control study data.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We conclude that <jats:italic>SORL1-</jats:italic>LoF variants should be interpreted in light of <jats:italic>APOE</jats:italic> genotypes for future clinical applications.</jats:p> </jats:sec>
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