Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population

Abstract

Background Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10−8). Prediction performance for Aβ positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74–0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. Conclusion The novel genetic variants associated with FGL2 decreased risk of Aβ positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease

“…Furthermore, summary statistics data was obtained from six additional cohorts that processed the raw genotype and phenotype data according to the same pipeline. These cohorts included Memento [ 24 ], Mayo Clinic Study of Aging (MCSA) [ 25 ], Wisconsin Registry for Alzheimer's Prevention (WRAP) [ 26 ], Berkeley Aging Cohort study (BACS) [ 27 ], Korean study [ 28 ], and MISSION-AD. Part of the data used in the preparation of this article was obtained from the ADNI database (adni.loni.usc.edu).…”

Transferability of Alzheimer Disease Polygenic Risk Score Across Populations and Its Association With Alzheimer Disease-Related Phenotypes

“…A subset of 1214 participants in data set 1 underwent either 18F-florbetaben or 18F-flutemetamol PET (eMethods in the Supplement ). 20 Aβ positivity was determined by visual assessments.…”

A review of brain imaging biomarker genomics in Alzheimer’s disease: implementation and perspectives

“…FERMT2 gene had a stage-dependent association with brain amyloidosis 2018 Scelsi et al [ 79 ] ADNI (226 HC, 125 AD, 92 SMC, 501 MCI) Genome-wide genotyping Multivariate imaging—Multivariate genetic PGS-based association Aβ PET SUVR, HV Hippocampus The finding identified a genome-wide significant locus implicating LCORL rs6850306. The possession of a minor allele at rs6850306 was protective against conversion from MCI to AD 2019 Li et al [ 80 ] ADNI (155 HC, 125 AD, 72 SMC, 422 MCI) Genome-wide genotyping Univariate imaging—Multivariate genetic GWAS Florbetapir composite SUVR Frontal, anterior/ posterior cingulate, lateral parietal/ temporal regions The study identified 24 consensus modules enriched by robust genetic signals in a genome wide association analysis, including a few novel genes ( ABL1 , ABLIM2 ) 2021 Kim et al [ 81 ] Korean cohort ( n = 1474) Genome- wide genotyping Univariate imaging—multivariate genetic GWAS Aβ PET SUVR Whole brain In addition to APOE , nine SNPs of FGL2 gene on chromosome 7 were identified, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level 2021 Liu et al [ 82 ] Multiple cohorts ( n = 767/ 1373) Summary statistics Multivariate imaging—Multivariate genetic PGS-based association Aβ PET SUVR, HV, entorhinal, middle temporal gyrus volumes Whole brain cortex, Hippocampus, entorhinal cortex PGS was associated with the increased cortical amyloid burdens (PiB-PET and AV45-PET), but decreased hippocampus and entorhinal cortex volumes …”