Rare TBK1 variant may confer protection in an APOE*4+ family.

Abstract

Rare variants are hypothesized to contribute greatly to the "missing heritability" in AD. APOE*4 is the strongest genetic risk factor for late-onset AD. As such, older, cognitively normal APOE*4 carriers may harbor rare protective variants. We prioritized candidate variants in families based on their segregation with protected APOE*4 carriers, genotyping rate, rarity, functional consequence, and presence in additional protected APOE*4 carriers. Families of European ancestry with at least one super protected member and either an additional super protected or protected member (see Table 1 for criteria) were identified in ADSP whole-exome sequencing (WES). Any unprotected members (Table 1) within the selected families were also used in the analysis. The WES variants for each family underwent an 8-step filtering approach (Figure 1), using the unrelated individuals in Table 2 for steps 7 and 8. A logistic regression on AD diagnosis adjusted for sex, 10 principal components, APOE*2, and APOE*4 in Europeans (Table 3) was performed on the remaining variants. The genes harboring these variants were further investigated using an Optimized SNP-set Kernel Association Test (SKAT-O) to determine whether nearby rare functional variants (sets: High/Moderate impact, CADD > 15, and CADD > 10) were associated with AD risk in ADSP Europeans. Nine families were selected for filtering, which resulted in 25 total variants for the logistic regression analysis. The TBK1 variant, rs755520364, demonstrated the strongest protective effect (OR = 0.08, p = 0.18) and the gene-level association with AD risk was significant in the SKAT-O including High/Moderate impact variants (p = 0.006, Table 4). Rs755520364, was shared by two super protected siblings and carried by 6 unrelated individuals (Figure 2). The variant-filtering approach applied here identified a TBK1 missense variant associated with reduced AD risk. Other rare TBK1 mutations have been associated with early-onset AD, frontotemporal dementia, and amyotrophic lateral sclerosis (Verheijen et al., 2018). TBK1 expression was shown to enhance tau hyperphosphorylation and its knockdown suppressed tau toxicity, suggesting that this gene is a relevant target to reduce AD pathology (Abreha et al., 2020). Future work should focus on elucidating the diverse functional effects of TBK1 mutations.