A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer's disease.

BACKGROUND

Late-onset Alzheimer's disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found rare risk variants for LOAD with large effect sizes, these variants are hardly detectable in the Japanese population.

METHODS

To identify rare variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro functional analyses of the variant(s) to reveal possible functions associated with LOAD risk.

RESULTS

Via step-by-step selection of whole-exome variants, we found seven candidate risk variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10, odds ratio = 6.1). The amino acid change in SHARPIN resulted in aberrant cellular localization of the variant protein and attenuated the activation of NF-κB, a central mediator of inflammatory and immune responses.

CONCLUSIONS

Our work identified a rare functional SHARPIN variant as a previously unknown genetic risk factor for LOAD. The functional alteration in SHARPIN induced by the rare coding variant is associated with an attenuated inflammatory/immune response that may promote LOAD development.