Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer’s Disease

Background Rare variants in the SORL1 gene have been associated with increased risk of Alzheimer’s disease (AD). While protein-truncating variants (PTVs) are observed almost exclusively in AD patients, most variants are rare missense variants that can be benign, risk-increasing, and recent reports have indicated that some variants are causative for disease. However, since SORL1 is currently not considered an autosomal dominant Alzheimer Disease gene (ADAD), segregation analyses are not performed, which complicates the identification of additional clinically important missense variants. Methods We prioritized highly conserved and functionally relevant SORL1 missense variants by considering the functional effects of homologous variants on proteins that share domains with SORL1 (domain-mapping of disease mutations, DMDM) into. We used this variant prioritization approach to annotate SORL1 variants identified in a previously assembled exome sequencing dataset encompassing 18,959 AD cases and 21,893 non-demented controls, and we tested the effect of high, moderate, low and no priority missense variants and specific variant subtypes on disease risk and age at onset. Results High priority missense variants (HPV) associated with a 6.4-fold increased risk of AD (95%CI: 4.3 – 9.7, p=2.1×10−24), which concentrated on early onset AD (OREOAD 10.5, 95%CI: 6.8 - 16.3, p=3.0×10−29) vs. late onset AD (ORLOAD=4.5, 95%CI 2.85 - 6.94; p=4.9×10−11). The median age at onset of HPV carriers was >8-years earlier than carriers of wild-type SORL1 . Intriguingly, specific subtypes of HPVs, including those affecting residues in the YWTD-motif or the calcium cage, occurred only in AD cases and carriers of these variants had an earlier age at onset compared to carriers of PTVs, indicative of a dominant negative effect. Carriers of other HPVs had an age at onset that overlapped with carriers of PTVs, suggesting they lead to haploinsufficiency. Yet other variants had a slightly later age at onset than PTVs, suggesting that their effect on SORL1 function was milder than losing a copy. Variants annotated as moderate, low and no priority did not have an effect on AD. Conclusions Next to carriers of SORL1 PTVs, carriers of selected missense variants should be considered for segregation analyses, which will likely provide evidence for autosomal dominant inheritance for additional SORL1 missense variants. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by EU Joint Programme-Neurodegenerative Disease Research (JPND) Working Group. holstegelab was supported by: ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Amsterdam UMC VUmc gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.