APOE-stratified genome-wide association meta-analysis for accelerated brain age in Korean population
Poster No:
850
Submission Type:
Abstract Submission
Authors:
Bo-Hyun Kim1, Kwangsik Nho2, Yen-Ning Huang3, Shannon Risacher2, Junpyo Kim4, Dahyun Yi5, Min Soo Byun6, Hee Jin Kim7, Hong-Hee Won8, Andrew Saykin2, Dong Young Lee5, Sangwon Seo4
Institutions:
1Samsung Medical Center, Seoul, Seoul, 2Indiana University School of Medicine, Indianapolis, IN, 3Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, 4Samsung medical center, Seoul, None, 5Seoul National University, Seoul, Korea, Republic of, 6Seoul National University College of Medicine, Seoul, Korea, Republic of, 7Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Seoul, 8SAIHST, Sungkyunkwan University, Samsung Medical Center, Seoul, Seoul
First Author:
Co-Author(s):
Yen-Ning Huang
Department of Radiology and Imaging Sciences, Indiana University School of Medicine
Indianapolis, IN
Department of Radiology and Imaging Sciences, Indiana University School of Medicine
Indianapolis, IN
Introduction:
Aging and APOE4 are key risk factors for Alzheimer's disease (AD) and have significant structural impacts on the brain. Machine learning approaches have been developed to estimate the biological age of
the brain from MRI scans. Here, we performed APOE4-stratified genome-wide association (GWAS) meta-analysis of accelerated brain aging in two independent Korean AD cohorts.
the brain from MRI scans. Here, we performed APOE4-stratified genome-wide association (GWAS) meta-analysis of accelerated brain aging in two independent Korean AD cohorts.
Methods:
Participants included 1,738 Korean older adults from two independent cohorts that consisted of preclinical and clinical stages of AD (n=1,209 from the K-ROAD cohort (Korea-Registries to Overcome and Accelerate Dementia Research Project) and n=529 from the KBASE cohort (Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease)). Brain age was estimated from structural MRI scans using brainageR. Brain age acceleration (predicted brain age - chronological age) was calculated for each participant. GWAS for brain age acceleration were performed using PLINK after accounting for age, sex, APOE4 carrier status, and diagnosis. In addition, APOE4-stratified (APOE4 carrier and non-carrier) GWAS meta-analyses for brain age acceleration were also performed. Meta-analysis was performed using METAL, followed by transcriptomic analysis. Polygenic risk scores for brain age acceleration were calculated with PRS-CS using GWAS meta-analysis summary statistics, followed by molecular imaging analysis.
Results:
GWAS meta-analysis using all individuals identified six intronic SNPs in the LRBA (Lipopolysaccharide responsive Beige-like Anchor) locus on chromosome 4 as significantly associated with brain age acceleration with the most significant signal at rs7699001 (Fig. 1; p < 5 × 10-8). APOE4-stratified GWAS meta-analysis identified two intergenic SNPs in the MYRFL (Myelin Regulatory Factor Like) locus on chromosome 12 as significantly associated with brain age acceleration with the most significant signal at rs789331 (Fig. 1; p=1.4 × 10-8) in the APOE4 non-carrier group. rs789331 in the MYRFL locus showed a significant interaction (Fig. 2; p=5.7 × 10-5) with APOE4 in the K-ROAD cohort and a marginal interaction effect (Fig. 2; p=8.2 × 10-2) in the KBASE cohort. LRBA is highly expressed in the brain, especially in microglia. The LRBA and MYRFL genes were differentially expressed in AD compared to cognitively normal older adults. rs7699001 and rs789331 were associated with expression levels of the LRBA and MYRFL genes, respectively, in tissue from several organs including brain. rs7690001 in the LRBA locus has been reported to be associated with inferior parietal cortical thickness in non-Hispanic whites (p= 5 ×10-3). rs789331 in the MYRFL locus was significantly associated with hippocampal volume (p=1.2 × 10-2). Polygenic risk scores of brain age acceleration in the K- ROAD cohort were significantly associated with amyloid-β deposition measured from amyloid PET scans (p=2.7 × 10-4).
·Fig.1 Manhattan plots of GWAS results (top), in APOE ε4 negative (middle), and APOE ε4 positive (bottom) groups.
·Fig 2 Box plots of association between genotypes of rs789331 and brain age acceleration in K-ROAD cohort (top) and KBASE cohort (bottom)
Conclusions:
LRBA and MYRFL are novel genetic risk factors for brain aging in the Korean population with relevance for AD. The microglial LRBA protein may be involved in phagocytosis, which has been implicated in aging processes and AD progression. The myelin regulatory factor is an important transcriptional factor for the central nervous system myelination. Replication in other populations and mechanistic follow-up studies are warranted.
Genetics:
Genetic Association Studies 1
Lifespan Development:
Aging 2
Keywords:
Aging
Meta- Analysis
Phenotype-Genotype
1|2Indicates the priority used for review
Provide references using author date format
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Willer, Cristen J., Yun Li, and Gonçalo R. Abecasis. "METAL: fast and efficient meta-analysis of genomewide association scans." Bioinformatics 26.17 (2010): 2190-2191.
Emery, Ben, et al. "Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination." Cell 138.1 (2009): 172-185.