Genome Medicine (Jun 2022)

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

  • Catherine Schramm,
  • Camille Charbonnier,
  • Aline Zaréa,
  • Morgane Lacour,
  • David Wallon,
  • CNRMAJ collaborators,
  • Anne Boland,
  • Jean-François Deleuze,
  • Robert Olaso,
  • ADES consortium,
  • Flora Alarcon,
  • Dominique Campion,
  • Grégory Nuel,
  • Gaël Nicolas

DOI
https://doi.org/10.1186/s13073-022-01070-6
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 14

Abstract

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Abstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 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, APOE-ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-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 APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE-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 SORL1-LoF variant carriers in case-control study data. Conclusions We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.

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