Browsing by Author "Zhang, Michael"
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Item Alcohol Use Disorder Polygenic Score Compared With Family History and ADH1B(American Medical Association, 2024-12-02) Lai, Dongbing; Zhang, Michael; Abreu, Marco; Schwantes-An, Tae-Hwi; Chan, Grace; Dick, Danielle M.; Kamarajan, Chella; Kuang, Weipeng; Nurnberger, John I.; Plawecki, Martin H.; Rice, John; Schuckit, Marc; Porjesz, Bernice; Liu, Yunlong; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineImportance: Identification of individuals at high risk of alcohol use disorder (AUD) and subsequent application of prevention and intervention programs has been reported to decrease the incidence of AUD. The polygenic score (PGS), which measures an individual's genetic liability to a disease, can potentially be used to evaluate AUD risk. Objective: To assess the estimability and generalizability of the PGS, compared with family history and ADH1B, in evaluating the risk of AUD among populations of European ancestry. Design, setting, and participants: This genetic association study was conducted between October 1, 2023, and May 21, 2024. A 2-stage design was used. First, the pruning and thresholding method was used to calculate PGSs in the screening stage. Second, the estimability and generalizability of the best PGS was determined using 2 independent samples in the testing stage. Three cohorts ascertained to study AUD were used in the screening stage: the Collaborative Study on the Genetics of Alcoholism (COGA), the Study of Addiction: Genetics and Environment (SAGE), and the Australian Twin-Family Study of Alcohol Use Disorder (OZALC). The All of Us Research Program (AOU), which comprises participants with diverse backgrounds and conditions, and the Indiana Biobank (IB), consisting of Indiana University Health system patients, were used to test the best PGS. For the COGA, SAGE, and OZALC cohorts, cases with AUD were determined using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or Fifth Edition (DSM-5) criteria; controls did not meet any criteria or did not have any other substance use disorders. For the AOU and IB cohorts, cases with AUD were identified using International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, Tenth Revision (ICD-10) codes; controls were aged 21 years or older and did not have AUD. Exposure: The PGS was calculated using single-nucleotide variants with concordant effects in 3 large-scale genome-wide association studies of AUD-related phenotypes. Main outcomes and measures: The main outcome was AUD determined with DSM-IV or DSM-5 criteria and ICD-9 or ICD-10 codes. Generalized linear mixed models and logistic regression models were used to analyze related and unrelated samples, respectively. Results: The COGA, SAGE, and OZALC cohorts included a total of 8799 samples (6323 cases and 2476 controls; 50.6% were men). The AOU cohort had a total of 116 064 samples (5660 cases and 110 404 controls; 60.4% were women). The IB cohort had 6373 samples (936 cases and 5437 controls; 54.9% were women). The 5% of samples with the highest PGS in the AOU and IB cohorts were approximately 2 times more likely to develop AUD (odds ratio [OR], 1.96 [95% CI, 1.78-2.16]; P = 4.10 × 10-43; and OR, 2.07 [95% CI, 1.59-2.71]; P = 9.15 × 10-8, respectively) compared with the remaining 95% of samples; these ORs were comparable to family history of AUD. For the 5% of samples with the lowest PGS in the AOU and IB cohorts, the risk of AUD development was approximately half (OR, 0.53 [95% CI, 0.45-0.62]; P = 6.98 × 10-15; and OR, 0.57 [95% CI, 0.39-0.84]; P = 4.88 × 10-3) compared with the remaining 95% of samples; these ORs were comparable to the protective effect of ADH1B. PGS had similar estimabilities in male and female individuals. Conclusions and relevance: In this study of AUD risk among populations of European ancestry, PGSs were calculated using concordant single-nucleotide variants and the best PGS was tested in targeted datasets. The findings suggest that the PGS may potentially be used to evaluate AUD risk. More datasets with similar AUD prevalence as in general populations are needed to further test the generalizability of PGS.Item Associations between alcohol use disorder polygenic score and remission in participants from high-risk families and the Indiana Biobank(Wiley, 2024) Lai, Dongbing; Kuo, Sally I-Chun; Wetherill, Leah; Aliev, Fazil; Zhang, Michael; Marco, Abreu; Schwantes-An, Tae-Hwi; Dick, Danielle; Francis, Meredith W.; Johnson, Emma C.; Kamarajan, Chella; Kinreich, Sivan; Kuperman, Samuel; Meyers, Jacquelyn; Nurnberger, John I.; Liu, Yunlong; Edenberg, Howard J.; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Schuckit, Marc; Plawecki, Martin H.; Bucholz, Kathleen K.; McCutcheon, Vivia V.; Medical and Molecular Genetics, School of MedicineBackground: In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGSAUD ) was positively associated with AUD severity as measured by DSM-5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGSAUD would be negatively associated with remission. Methods: Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12-month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non-abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non-abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. Results: In COGA EA, PGSAUD was negatively associated with 12-month and non-abstinent remission (p ≤ 0.013, βs between -0.15 and -0.10) after adjusting for all covariates. In contrast to the COGA findings, PGSAUD was positively associated with remission (p = 0.004, β = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, β = 0.15). Conclusions: PGSAUD was negatively associated with 12-month and non-abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol-related health conditions that manifested in later life.Item Development and validation of an objective scoring tool to evaluate surgical dissection: Dissection Assessment for Robotic Technique (DART)(American Urological Association Education and Research, Inc., 2021) Vanstrum, Erik B.; Ma, Runzhuo; Maya-Silva, Jacqueline; Sanford, Daniel; Nguyen, Jessica H.; Lei, Xiaomeng; Chevinksy, Michael; Ghoreifi, Alireza; Han, Jullet; Polotti, Charles F.; Powers, Ryan; Yip, Wesley; Zhang, Michael; Aron, Monish; Collins, Justin; Daneshmand, Siamak; Davis, John W.; Desai, Mihir M.; Gerjy, Roger; Goh, Alvin C.; Kimmig, Rainer; Lendvay, Thomas S.; Porter, James; Sotelo, Rene; Sundaram, Chandru P.; Cen, Steven; Gill, Inderbir S.; Hung, Andrew J.; Urology, School of MedicinePurpose: Evaluation of surgical competency has important implications for training new surgeons, accreditation, and improving patient outcomes. A method to specifically evaluate dissection performance does not yet exist. This project aimed to design a tool to assess surgical dissection quality. Methods: Delphi method was used to validate structure and content of the dissection evaluation. A multi-institutional and multi-disciplinary panel of 14 expert surgeons systematically evaluated each element of the dissection tool. Ten blinded reviewers evaluated 46 de-identified videos of pelvic lymph node and seminal vesicle dissections during the robot-assisted radical prostatectomy. Inter-rater variability was calculated using prevalence-adjusted and bias-adjusted kappa. The area under the curve from receiver operating characteristic curve was used to assess discrimination power for overall DART scores as well as domains in discriminating trainees (≤100 robotic cases) from experts (>100). Results: Four rounds of Delphi method achieved language and content validity in 27/28 elements. Use of 3- or 5-point scale remained contested; thus, both scales were evaluated during validation. The 3-point scale showed improved kappa for each domain. Experts demonstrated significantly greater total scores on both scales (3-point, p< 0.001; 5-point, p< 0.001). The ability to distinguish experience was equivalent for total score on both scales (3-point AUC= 0.92, CI 0.82-1.00, 5-point AUC= 0.92, CI 0.83-1.00). Conclusions: We present the development and validation of Dissection Assessment for Robotic Technique (DART), an objective and reproducible 3-point surgical assessment to evaluate tissue dissection. DART can effectively differentiate levels of surgeon experience and can be used in multiple surgical steps.Item Genetic Variants Associated with Longitudinal Cognitive Performance in Older Breast Cancer Patients and Controls(MDPI, 2023-05-23) Nudelman, Kelly; Nho, Kwangsik; Zhang, Michael; McDonald, Brenna C.; Zhai, Wanting; Small, Brent J.; Wegel, Claire E.; Jacobsen, Paul B.; Jim, Heather S. L.; Patel, Sunita K.; Graham, Deena M. A.; Ahles, Tim A.; Root, James C.; Foroud, Tatiana; Breen, Elizabeth C.; Carroll, Judith E.; Mandelblatt, Jeanne S.; Saykin, Andrew J.; Medical and Molecular Genetics, School of MedicineBackground: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N = 325) and age-, racial/ethnic group-, and education-matched controls (N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1) gene (p = 1.624 × 10-8), and rs78786199 (chromosome 2, p = 1.925 × 10-8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.Item Genome-wide meta-analyses of cross substance use disorders in European, African, and Latino ancestry populations(Research Square, 2024-07-16) Lai, Dongbing; Zhang, Michael; Green, Nick; Abreu, Marco; Schwantes-An, Tae-Hwi; Parker, Clarissa; Zhang, Shanshan; Jin, Fulai; Sun, Anna; Zhang, Pengyue; Edenberg, Howard; Liu, Yunlong; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineGenetic risks for substance use disorders (SUDs) are due to both SUD-specific and SUD-shared genes. We performed the largest multivariate analyses to date to search for SUD-shared genes using samples of European (EA), African (AA), and Latino (LA) ancestries. By focusing on variants having cross-SUD and cross-ancestry concordant effects, we identified 45 loci. Through gene-based analyses, gene mapping, and gene prioritization, we identified 250 SUD-shared genes. These genes are highly expressed in amygdala, cortex, hippocampus, hypothalamus, and thalamus, primarily in neuronal cells. Cross-SUD concordant variants explained ~ 50% of the heritability of each SUD in EA. The top 5% individuals having the highest polygenic scores were approximately twice as likely to have SUDs as others in EA and LA. Polygenic scores had higher predictability in females than in males in EA. Using real-world data, we identified five drugs targeting identified SUD-shared genes that may be repurposed to treat SUDs.Item Identifying Genes Associated with Alzheimer’s Disease Using Gene-Based Polygenic Risk Score(IOS Press, 2023) Lai, Dongbing; Zhang, Michael; Li, Rudong; Zhang, Chi; Zhang, Pengyue; Liu, Yunlong; Gao, Sujuan; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineBackground: Except APOE, Alzheimer's disease (AD) associated genes identified in recent large-scale genome-wide association studies (GWAS) had small effects and explained a small portion of heritability. Many AD-associated genes have even smaller effects thereby sub-threshold p-values in large-scale GWAS and remain to be identified. For some AD-associated genes, drug targeting them may have limited efficacies due to their small effect sizes. Objective: The purpose of this study is to identify AD-associated genes with sub-threshold p-values and prioritize drugs targeting AD-associated genes that have large efficacies. Methods: We developed a gene-based polygenic risk score (PRS) to identify AD genes. It was calculated using SNPs located within genes and having the same directions of effects in different study cohorts to exclude cohort-specific findings and false positives. Gene co-expression modules and protein-protein interaction networks were used to identify AD-associated genes that interact with multiple other genes, as drugs targeting them have large efficacies via co-regulation or interactions. Results: Gene-based PRS identified 389 genes with 164 of them not previously reported as AD-associated. These 389 genes explained 56.12% -97.46% SNP heritability; and they were enriched in brain tissues and 164 biological processes, most of which are related to AD and other neurodegenerative diseases. We prioritized 688 drugs targeting 64 genes that were in the same co-expression modules and/or PPI networks. Conclusions: Gene-based PRS is a cost-effective way to identify AD-associated genes without substantially increasing the sample size. Co-expression modules and PPI networks can be used to identify drugs having large efficacies.Item Using polygenic risk scores and APOE e4 to evaluate the risk for Alzheimer’s disease in European ancestry populations(Wiley, 2025-01-03) Lai, Dongbing; Zhang, Michael; Foroud, Tatiana M.; Medical and Molecular Genetics, School of MedicineBackground: APOE e4 has been used to evaluate the risk for Alzheimer’s diseases (AD) but there exist other AD risk genes, and their effects can be collectively measured by polygenic risk scores (PRS). In this study, we sought to use both PRS (APOE excluded) and APOE e4 to evaluate the AD risk. Method: The discovery dataset was meta‐analysis of three large‐scale European ancestry AD GWAS (Kunkle et al, 2019, the UK Biobank, and the FinnGen consortium). SNPs within 500Kb from transcript starting and ending sites of APOE were excluded. PRS‐CS was used to calculate PRS. Target datasets were European ancestry samples from NIA Alzheimer’s disease centers (ADC, 2,413 cases and 3,423 controls) and All of Us research program (AOU, 1,177 cases and 60,607 controls). Participants having age at onset (cases) or age at the last interview (controls) <60 were excluded. The prevalence of AD were higher in ADC (41.35%) and lower in AOU (1.91%) than those in general populations; therefore, we combined ADC and AOU samples to approximate the PRS distribution in general populations. Then we dichotomized PRS as high (highest 10%) and other (the remaining 90%) based on the PRS distribution of combined sample. Cox proportional hazard model was used to test the effects of dichotomized PRS and e4 genotypes (0, 1, and 2 copies of e4 alleles) by adjusting for sex. Additionally, we performed sex stratified analyses in ADC only as numbers of high PRS and e4/e4 carriers in AOU in either sex were <5. Result: Results are summarized in Table 1. We used those having other PRS and no e4 as the reference group. In both ADC and AOU, high PRS or e4 were significantly associated with the AD risk (PRS hazard ratios (HRs): 1.31‐1.74, P‐values≤0.01; e4 HRs: 1.39‐8.68, P‐values≤2.80E‐06) but having both substantially increased the AD risk (HRs: 2.07‐14.26, P‐values≤6.80E‐05). In ADC, both high PRS and e4 had larger effects in females than in males. Conclusion: The effects of PRS were modest and cannot be used alone to evaluate the AD risk; however, PRS can potentially be used with APOE e4 to evaluate the AD risk.