Abstract
BackgroundGenome-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.MethodsOne 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.ResultsIn 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.ConclusionThe 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.
Highlights
Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD)
We examined whether amyloid β (Aβ) associated Single nucleotide polymorphism (SNP) are associated with AD dementia (ADD) risk using cognitively unimpaired (CU) and ADD participants using the following logistic model: ADD = β0 + β1 age + β2 sex + β3 education + β4 identified SNPs
All significant SNPs fell within the 500 kb region surrounding APOE and lost genome-wide significance when we adjusted for the APOE ɛ4 allele (Table S1)
Summary
Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD). Most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Previous studies have evaluated the genetic basis of Aβ deposition using positron emission tomography (PET) imaging [6,7,8,9,10] and identified several novel Aβ associated genetic variants outside the APOE region from European ancestry [11]. It should be noted that most previous GWAS were conducted in individuals of European ancestry, and non-European populations are underrepresented in genetic discovery efforts [16,17,18]
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