Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy

Abstract

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10^-5) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10^-9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10^-5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ɛ4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice.

Figure 1

Flowchart of SORL1 variant pathogenicity analysis. ^aSORL1 variants in the independent replication data set were reported by Verheijen et al. Pathogenicity screen was applied to SORL1 variants reported by ^bVardarajan et al. and ^cNicolas et al.

Figure 2

Only the rarest variants with the highest CADD scores are associated with increased AD risk. The 181 SORL1 variants detected in 5101 AD cases and controls from the combined analysis were first separated by their ExAC-MAF, and then by their CADD values (see also Table 2).

Figure 3

Protein position of SORL1 variants with MAF <1 × 10⁻⁴ in ExAC database. One hundred and twenty-one coding variants with ExAC-MAF <1 × 10⁻⁴ were detected the combined analysis of 5101 subjects (1895 cases and 3206 controls). Each symbol represents one case carrier (red) or control (green) carrier. Protein domains are depicted on the CADD=20 level, variants with CADD scores between 20 and 30 are considered ‘moderately damaging’ and variants with CADD scores >30 were considered ‘strongly damaging’. Markers outlined in black represent variants that were detected in multiple cases or in multiple controls.