Catherine Schramm (Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, 76000 Rouen)

Penetrance estimation of SORL1 loss-of-function variants adjusted on APOE genotypes suggest a non-monogenic inheritance

vendredi 19 février 2021, 9h30 - 10h30

Salle du conseil, espace Turing

For complex disorders, estimating the age-related penetrance associated with rare variants of strong effect is essential. However, rarity and co-occurrence with other risk factors make it difficult to estimate. In the context of Alzheimer Disease, we propose a family-based methodology to estimate the penetrance of SORL1 rare (allele frequency<1%) loss-of-function variants (LoF, odds ratios >7]) adjusted for APOE4, the main risk factor (allele frequency ~14%, odds ratios [3.4-14]). Our survival model combines: (i) a baseline for non-carriers of SORL1 LoF variants, stratified by APOE genotypes derived from a large cohort study and (ii) an additive effect of SORL1 LoF variants estimated from our family cohort: 34 pedigrees with a proband carrying a SORL1 protein-truncating (PTV) or a missense variant with in vitro LoF evidence, onset<75 years, information on relatives (379 phenotypes, 79 genotypes). We embedded this survival model into an Expectation-Maximisation (EM) algorithm to accommodate for missing genotypes. Confidence intervals were computed by bootstrap. To correct for ascertainment bias, proband phenotypes were omitted. Additionally, we used sequencing data from 7306 cases and 5852 controls from European ancestry to compute a population-based estimate of the age-dependent life-time risk associated with both APOE4 allele and SORL1 rare PTVs or predicted damaging missense variants. We provide penetrance estimation curves associated with SORL1 LoF variants at the digenic level. By age 75, we estimate SORL1 LoF variants to reach a 100% penetrance only among homozygous APOE4 carriers. Penetrance remained incomplete for heterozygous E4 carriers, even at age 75, and was lower for non-E4 carriers. This method could be applied to other diseases where penetrance estimates are required to help clinicians in genetic counselling or preventive treatment strategies.

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