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Browsing by Author "Jung, Sang-Hyuk"
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Item An interpretable Alzheimer's disease oligogenic risk score informed by neuroimaging biomarkers improves risk prediction and stratification(Frontiers Media, 2023-10-26) Suh, Erica H.; Lee, Garam; Jung, Sang-Hyuk; Wen, Zixuan; Bao, Jingxuan; Nho, Kwangsik; Huang, Heng; Davatzikos, Christos; Saykin, Andrew J.; Thompson, Paul M.; Shen, Li; Kim, Dokyoon; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineIntroduction: Stratification of Alzheimer's disease (AD) patients into risk subgroups using Polygenic Risk Scores (PRS) presents novel opportunities for the development of clinical trials and disease-modifying therapies. However, the heterogeneous nature of AD continues to pose significant challenges for the clinical broadscale use of PRS. PRS remains unfit in demonstrating sufficient accuracy in risk prediction, particularly for individuals with mild cognitive impairment (MCI), and in allowing feasible interpretation of specific genes or SNPs contributing to disease risk. We propose adORS, a novel oligogenic risk score for AD, to better predict risk of disease by using an optimized list of relevant genetic risk factors. Methods: Using whole genome sequencing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n = 1,545), we selected 20 genes that exhibited the strongest correlations with FDG-PET and AV45-PET, recognized neuroimaging biomarkers that detect functional brain changes in AD. This subset of genes was incorporated into adORS to assess, in comparison to PRS, the prediction accuracy of CN vs. AD classification and MCI conversion prediction, risk stratification of the ADNI cohort, and interpretability of the genetic information included in the scores. Results: adORS improved AUC scores over PRS in both CN vs. AD classification and MCI conversion prediction. The oligogenic model also refined risk-based stratification, even without the assistance of APOE, thus reflecting the true prevalence rate of the ADNI cohort compared to PRS. Interpretation analysis shows that genes included in adORS, such as ATF6, EFCAB11, ING5, SIK3, and CD46, have been observed in similar neurodegenerative disorders and/or are supported by AD-related literature. Discussion: Compared to conventional PRS, adORS may prove to be a more appropriate choice of differentiating patients into high or low genetic risk of AD in clinical studies or settings. Additionally, the ability to interpret specific genetic information allows the focus to be shifted from general relative risk based on a given population to the information that adORS can provide for a single individual, thus permitting the possibility of personalized treatments for AD.Item Identifying genetic variants for amyloid β in subcortical vascular cognitive impairment(Frontiers Media, 2023-04-18) Kim, Hang-Rai; Jung, Sang-Hyuk; Kim, Beomsu; Kim, Jaeho; Jang, Hyemin; Kim, Jun Pyo; Kim, So Yeon; Na, Duk L.; Kim, Hee Jin; Nho, Kwangsik; Won, Hong-Hee; Seo, Sang Won; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineBackground: The genetic basis of amyloid β (Aβ) deposition in subcortical vascular cognitive impairment (SVCI) is still unknown. Here, we investigated genetic variants involved in Aβ deposition in patients with SVCI. Methods: We recruited a total of 110 patients with SVCI and 424 patients with Alzheimer's disease-related cognitive impairment (ADCI), who underwent Aβ positron emission tomography and genetic testing. Using candidate AD-associated single nucleotide polymorphisms (SNPs) that were previously identified, we investigated Aβ-associated SNPs that were shared or distinct between patients with SVCI and those with ADCI. Replication analyses were performed using the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Rush Memory and Aging Project cohorts (ROS/MAP). Results: We identified a novel SNP, rs4732728, which showed distinct associations with Aβ positivity in patients with SVCI (P interaction = 1.49 × 10-5); rs4732728 was associated with increased Aβ positivity in SVCI but decreased Aβ positivity in ADCI. This pattern was also observed in ADNI and ROS/MAP cohorts. Prediction performance for Aβ positivity in patients with SVCI increased (area under the receiver operating characteristic curve = 0.780; 95% confidence interval = 0.757-0.803) when rs4732728 was included. Cis-expression quantitative trait loci analysis demonstrated that rs4732728 was associated with EPHX2 expression in the brain (normalized effect size = -0.182, P = 0.005). Conclusion: The novel genetic variants associated with EPHX2 showed a distinct effect on Aβ deposition between SVCI and ADCI. This finding may provide a potential pre-screening marker for Aβ positivity and a candidate therapeutic target for SVCI.Item Identifying highly heritable brain amyloid phenotypes through mining Alzheimer's imaging and sequencing biobank data(World Scientific, 2022) Bao, Jingxuan; Wen, Zixuan; Kim, Mansu; Zhao, Xiwen; Lee, Brian N.; Jung, Sang-Hyuk; Davatzikos, Christos; Saykin, Andrew J.; Thompson, Paul M.; Kim, Dokyoon; Zhao, Yize; Shen, Li; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineBrain imaging genetics, an emerging and rapidly growing research field, studies the relationship between genetic variations and brain imaging quantitative traits (QTs) to gain new insights into the phenotypic characteristics and genetic mechanisms of the brain. Heritability is an important measurement to quantify the proportion of the observed variance in an imaging QT that is explained by genetic factors, and can often be used to prioritize brain QTs for subsequent imaging genetic association studies. Most existing studies define regional imaging QTs using predefined brain parcellation schemes such as the automated anatomical labeling (AAL) atlas. However, the power to dissect genetic underpinnings under QTs defined in such an unsupervised fashion could be negatively affected by heterogeneity within the regions in the partition. To bridge this gap, we propose a novel method to define highly heritable brain regions. Based on voxelwise heritability estimates, we extract brain regions containing spatially connected voxels with high heritability. We perform an empirical study on the amyloid imaging and whole genome sequencing data from a landmark Alzheimer’s disease biobank; and demonstrate the regions defined by our method have much higher estimated heritabilities than the regions defined by the AAL atlas. Our proposed method refines the imaging endophenotype constructions in light of their genetic dissection, and yields more powerful imaging QTs for subsequent detection of genetic risk factors along with better interpretability.Item Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population(BMC, 2021-06-21) Kim, Hang-Rai; Jung, Sang-Hyuk; Kim, Jaeho; Jang, Hyemin; Kang, Sung Hoon; Hwangbo, Song; Kim, Jun Pyo; Kim, So Yeon; Kim, Beomsu; Kim, Soyeon; Jeong, Jee Hyang; Yoon, Soo Jin; Park, Kyung Won; Kim, Eun-Joo; Yoon, Bora; Jang, Jae-Won; Hong, Jin Yong; Choi, Seong Hye; Noh, Young; Kim, Ko Woon; Kim, Si Eun; Lee, Jin San; Jung, Na-Yeon; Lee, Juyoun; Kim, Byeong C.; Son, Sang Joon; Hong, Chang Hyung; Na, Duk L.; Seo, Sang Won; Won, Hong-Hee; Kim, Hee Jin; Radiology and Imaging Sciences, School of MedicineBackground: 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.