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

ABSTRACT: 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 ?4 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-?5, 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-?B, 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.

SUBMITTER: Asanomi Y

PROVIDER: S-EPMC6585023 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Asanomi Yuya Y Shigemizu Daichi D Miyashita Akinori A Mitsumori Risa R Mori Taiki T Hara Norikazu N Ito Kaoru K Niida Shumpei S Ikeuchi Takeshi T Ozaki Kouichi K

Molecular medicine (Cambridge, Mass.) 20190620 1

<h4>Background</h4>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.<h4>Methods</h4>To identify rare vari ...[more]

PMID: 31216982

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Project description:Prior work in late-onset Alzheimer's disease (LOAD) has resulted in discrepant findings as to whether recent consanguinity and outbred autozygosity are associated with LOAD risk. In the current study, we tested the association between consanguinity and outbred autozygosity with LOAD in the largest such analysis to date, in which 20 LOAD GWAS datasets were retrieved through public databases. Our analyses were restricted to eight distinct ethnic groups: African-Caribbean, Ashkenazi-Jewish European, European-Caribbean, French-Canadian, Finnish European, North-Western European, South-Eastern European, and Yoruba African for a total of 21,492 unrelated subjects (11,196 LOAD and 10,296 controls). Recent consanguinity determination was performed using FSuite v1.0.3, according to subjects' ancestral background. The level of autozygosity in the outbred population was assessed by calculating inbreeding estimates based on the proportion (FROH) and the number (NROH) of runs of homozygosity (ROHs). We analyzed all eight ethnic groups using a fixed-effect meta-analysis, which showed a significant association of recent consanguinity with LOAD (N = 21,481; OR = 1.262, P = 3.6 × 10-4), independently of APOE ∗4 (N = 21,468, OR = 1.237, P = 0.002), and years of education (N = 9,257; OR = 1.274, P = 0.020). Autozygosity in the outbred population was also associated with an increased risk of LOAD, both for F ROH (N = 20,237; OR = 1.204, P = 0.030) and N ROH metrics (N = 20,237; OR = 1.019, P = 0.006), independently of APOE ∗4 [(F ROH, N = 20,225; OR = 1.222, P = 0.029) (N ROH, N = 20,225; OR = 1.019, P = 0.007)]. By leveraging the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data, we determined that LOAD subjects do not show an enrichment of rare, risk-enhancing minor homozygote variants compared to the control population. A two-stage recessive GWAS using ADSP data from 201 consanguineous subjects in the discovery phase followed by validation in 10,469 subjects led to the identification of RPH3AL p.A303V (rs117190076) as a rare minor homozygote variant increasing the risk of LOAD [discovery: Genotype Relative Risk (GRR) = 46, P = 2.16 × 10-6; validation: GRR = 1.9, P = 8.0 × 10-4]. These results confirm that recent consanguinity and autozygosity in the outbred population increase risk for LOAD. Subsequent work, with increased samples sizes of consanguineous subjects, should accelerate the discovery of non-additive genetic effects in LOAD.

Dataset Information

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

Publications

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

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