Browsing by Author "Lai, Dongbing"
Now showing 1 - 10 of 71
Results Per Page
Sort Options
Item Alcohol use disorder is associated with higher risks of Alzheimer's and Parkinson's diseases: A study of US insurance claims data(Wiley, 2022-11-21) Zhang, Pengyue; Edenberg, Howard J.; Nurnberger, John; Lai, Dongbing; Cheng, Feixiong; Liu, Yunlong; Biostatistics, School of Public HealthIntroduction: Alcohol use disorder (AUD) is on the ascendancy in the US older adult population. The association between AUD and adverse brain outcomes remains inconclusive. Method: In a retrospective cohort design using US insurance claim data (2007-2020), 129,182 individuals with AUD were matched with 129,182 controls by age, sex, race, and clinical characteristics. We investigated the association between AUD and adverse brain outcomes using Cox analysis, Kaplan-Meier analysis, and log-rank test. Results: After adjusting for covariates, AUD was associated with a higher risk of Alzheimer's disease (female adjusted hazard ratio [HR] = 1.78, 95% confidence interval [CI]: 1.68-1.90, p < 0.001; male adjusted HR = 1.80, 95% CI: 1.71-1.91, p < 0.001) and a higher risk of Parkinson's disease (female adjusted HR = 1.49, 95% CI: 1.32-1.68, p < 0.001; male adjusted HR = 1.42, 95% CI: 1.32-1.52, p < 0.001) in the overall sample. In separate analyses of Black, White, and Hispanic individuals, those with AUD had higher risk of Alzheimer's disease (adjusted HRs ≥1.58; Ps ≤ 0.001). A significantly elevated risk for Parkinson's disease was found only in the White subpopulation (female adjusted HR = 1.55, 95% CI: 1.36-1.77, p < 0.001; male adjusted HR = 1.45, 95% CI: 1.33-1.57, p < 0.001). Conclusions: AUD is associated with Alzheimer's disease. AUD is associated with Parkinson's disease in White people. Cognitive screening and neurological examination among older adults with AUD hold the promise for early detection of Alzheimer's disease and Parkinson's disease. Highlights: Alcohol use disorder is associated with Alzheimer's disease and dementia. Alcohol use disorder is associated with Parkinson's disease in White people.Item Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats(Wiley Blackwell (Blackwell Publishing), 2014-05) Yong, Weidong; Spence, John Paul; Eskay, Robert; Fitz, Stephanie D.; Damadzic, Ruslan; Lai, Dongbing; Foroud, Tatiana; Carr, Lucinda G.; Shekhar, Anantha; Chester, Julia A.; Heilig, Markus; Liang, Tiebing; Department of Medicine, IU School of MedicineBACKGROUND: Corticotropin-releasing hormone (CRH) and urocortins (UCNs) bind to corticotropin-releasing hormone type 2 receptor (CRF2 receptor ), a Gs protein-coupled receptor that plays an important role in modulation of anxiety and stress responses. The Crhr2 gene maps to a quantitative trait locus (QTL) for alcohol preference on chromosome 4 previously identified in inbred alcohol-preferring (iP) and-nonpreferring (iNP) F2 rats. METHODS: Real-time polymerase chain reaction was utilized to screen for differences in Crhr2 mRNA expression in the central nervous system (CNS) of male iP and iNP rats. DNA sequence analysis was then performed to screen for polymorphism in Crhr2 in order to identify genetic variation, and luciferase reporter assays were then applied to test their functional significance. Next, binding assays were used to determine whether this polymorphism affected CRF2 receptor binding affinity as well as CRF2 receptor density in the CNS. Finally, social interaction and corticosterone levels were measured in the P and NP rats before and after 30-minute restraint stress. RESULTS: Crhr2 mRNA expression studies found lower levels of Crhr2 mRNA in iP rats compared to iNP rats. In addition, DNA sequencing identified polymorphisms in the promoter region, coding region, and 3'-untranslated region between the iP and iNP rats. A 7 bp insertion in the Crhr2 promoter of iP rats altered expression in vitro as measured by reporter assays, and we found that CRF2 receptor density was lower in the amygdala of iP as compared to iNP rats. Male P rats displayed decreased social interaction and significantly higher corticosterone levels directly following 30-minute restraint when compared to male NP rats. CONCLUSIONS: This study identified Crhr2 as a candidate gene of interest underlying the chromosome 4 QTL for alcohol consumption that was previously identified in the P and NP model. Crhr2 promoter polymorphism is associated with reduced mRNA expression in certain brain regions, particularly the amygdala, and lowered the density of CRF2 receptor in the amygdala of iP compared to iNP rats. Together, these differences between the animals may contribute to the drinking disparity as well as the anxiety differences of the P and NP rats.Item Allele-specific expression and high-throughput reporter assay reveal functional genetic variants associated with alcohol use disorders(Springer Nature, 2021-04) Rao, Xi; Thapa, Kriti S.; Chen, Andy B.; Lin, Hai; Gao, Hongyu; Reiter, Jill L.; Hargreaves, Katherine A.; Ipe, Joseph; Lai, Dongbing; Xuei, Xiaoling; Wang, Yue; Gu, Hongmei; Kapoor, Manav; Farris, Sean P.; Tischfield, Jay; Foroud, Tatiana; Goate, Alison M.; Skaar, Todd C.; Mayfield, R. Dayne; Edenberg, Howard J.; Liu, Yunlong; Medical and Molecular Genetics, School of MedicineGenome-wide association studies (GWAS) of complex traits, such as alcohol use disorders (AUD), usually identify variants in non-coding regions and cannot by themselves distinguish whether the associated variants are functional or in linkage disequilibrium with the functional variants. Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with AUD may cause expression differences, we integrated data from deep RNA-seq and GWAS of four postmortem brain regions from 30 subjects with AUD and 30 controls to analyze allele-specific expression (ASE). We identified 88 genes with differential ASE in subjects with AUD compared to controls. Next, to test one potential mechanism contributing to the differential ASE, we analyzed single nucleotide polymorphisms (SNPs) in the 3′ untranslated regions (3′UTR) of these genes. Of the 88 genes with differential ASE, 61 genes contained 437 SNPs in the 3′UTR with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25 SNPs that affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these SNPs are in binding sites of miRNAs and RNA-binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE. In sum, we demonstrate that a combination of computational and experimental approaches provides a powerful strategy to uncover functionally relevant variants associated with the risk for AUD.Item Allele-specific expression and high-throughput reporter assay reveal functional genetic variants associated with alcohol use disorders.(Springer, 2021-04) Rao, Xi; Thapa, Kriti S.; Chen, Andy B.; Lin, Hai; Gao, Hongyu; Reiter, Jill L.; Hargreaves, Katherine A.; Ipe, Joseph; Lai, Dongbing; Xuei, Xiaoling; Wang, Yue; Gu, Hongmei; Kapoor, Manav; Farris, Sean P.; Tischfield, Jay; Foroud, Tatiana; Goate, Alison M.; Skaar, Todd C.; Mayfield, R. Dayne; Edenberg, Howard J.; Liu, YunlongGenome-wide association studies (GWAS) of complex traits, such as alcohol use disorders (AUD), usually identify variants in non-coding regions and cannot by themselves distinguish whether the associated variants are functional or in linkage disequilibrium with the functional variants. Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with AUD may cause expression differences, we integrated data from deep RNA-seq and GWAS of four postmortem brain regions from 30 subjects with AUD and 30 controls to analyze allele-specific expression (ASE). We identified 88 genes with differential ASE in subjects with AUD compared to controls. Next, to test one potential mechanism contributing to the differential ASE, we analyzed single nucleotide polymorphisms (SNPs) in the 3' untranslated regions (3'UTR) of these genes. Of the 88 genes with differential ASE, 61 genes contained 437 SNPs in the 3'UTR with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25 SNPs that affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these SNPs are in binding sites of miRNAs and RNA-binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE. In sum, we demonstrate that a combination of computational and experimental approaches provides a powerful strategy to uncover functionally relevant variants associated with the risk for AUD.Item Analysis of the Combined Effect of rs699 and rs5051 on Angiotensinogen Expression and Hypertension(bioRxiv, 2023-04-08) Powell, Nicholas R.; Shugg, Tyler; Leighty, Jacob; Martin, Matthew; Kreutz, Rolf P.; Eadon, Michael T.; Lai, Dongbing; Lu, Tao; Skaar, Todd C.; Medicine, School of MedicineHypertension (HTN) involves genetic variability in the renin-angiotensin system and characterizing this variability will help advance precision antihypertensive treatments. We previously reported that angiotensinogen (AGT) mRNA is endogenously bound by mir-122-5p and that rs699 A>G significantly decreases reporter mRNA in the functional mirSNP assay PASSPORT-seq. The AGT promoter variant rs5051 C>T is in linkage disequilibrium (LD) with rs699 A>G and increases AGT transcription. We hypothesized that the increased AGT by rs5051 C>T counterbalances AGT decrease by rs699 A>G, and when these variants occur independently, would translate to HTN-related phenotypes. The independent effect of each of these variants is understudied due to their LD, therefore, we used in silico, in vitro, in vivo, and retrospective clinical and biobank analyses to assess HTN and AGT expression phenotypes where rs699 A>G occurs independently from rs5051 C>T. In silico, rs699 A>G is predicted to increase mir-122-5p binding strength by 3%. Mir-eCLIP assay results show that rs699 is 40-45 nucleotides from the strongest microRNA binding site in the AGT mRNA. Unexpectedly, rs699 A>G increases AGT mRNA in a plasmid cDNA HepG2 expression model. GTEx and UK Biobank analyses demonstrate that liver AGT expression and HTN phenotypes were not different when rs699 A>G occurs independently from rs5051 C>T, allowing us to reject the original hypothesis. However, both GTEx and our in vitro experiments suggest rs699 A>G confers cell-type specific effects on AGT mRNA abundance. We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a 4-fold larger effect than in White participants. Further studies are warranted to determine if the altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.Item Automatic Detection of Associatons Among Terms Related to Alzheimer's Disease from Medline AbstractsLai, Dongbing; Mukhopadhyay, SnehasisAlzheimer's disease is a progressive, age-related, degenerative brain disorder, which is one of the most serious diseases in old people. The patients' memory is lost and their personality and behavior are changed gradually; furthermore, this process is irreversible until the patients die [1]. Alzheimer's disease first attacks the entorhinal cortex; then to the hippocampus, which help to control short-term memory; then to other regions, especially the cerebral cortex, which is very important in using language and reasoning [1 , 2]. After its attack, the neurons degenerate and lose synapses and eventually die [1 , 2]. According to the age of having this disease, Alzheimer's disease can be divided to early-onset (usually at age 30 to 60) and late-onset (at age of 65 or older) [1]. About 5% to 10% of Alzheimer's disease cases are early onset [1 ]. Another way to describe Alzheimer's disease is according to the inheritance pattern. In this way, Alzheimer's disease also can be divided to: sporadic Alzheimer's disease, which has no certain inheritance pattern; and familial Alzheimer's disease (FAD), which has certain inheritance pattern [1]. All FAD are early onset [1 ]. Alzheimer's disease is a progressive disease and the progression of symptoms can be divided into mild, moderate and severe phases [2, 3]. The symptoms of mild Alzheimer's disease include loss of memory, disorientation, and difficulty of performing routine tasks. [2]. Patients in this phase can live independently [3]. The moderate symptoms include having great difficulty in daily living, wandering, personality changes, agitation and anxiety [2]. Patients in this phase should be cared by other people. People in severe phase lose all communication functions, almost cannot think, and need total care [2].Item Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis(American Society of Nephrology, 2017-07-07) Moe, Sharon M.; Wetherill, Leah; Decker, Brian Scott; Lai, Dongbing; Abdalla, Safa; Long, Jin; Vatta, Matteo; Foroud, Tatiana M.; Chertow, Glenn M.; Medicine, School of MedicineBACKGROUND AND OBJECTIVES: We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. RESULTS: There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). CONCLUSIONS: These modest associations, if validated, may provide explanations for differences in CKD-mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.Item Charcot-Marie-Tooth gene, SBF2, associated with taxaneinduced peripheral neuropathy in African Americans(Impact Journals, 2016-12-13) Schneider, Bryan P.; Lai, Dongbing; Shen, Fei; Jiang, Guanglong; Radovich, Milan; Li, Lang; Gardner, Laura; Miller, Kathy D.; O’Neill, Anne; Sparano, Joseph A.; Xue, Gloria; Foroud, Tatiana; Sledge Jr., George W.; Department of Medicine, IU School of MedicinePURPOSE: Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. EXPERIMENTAL DESIGN: Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. RESULTS: Five genes had a p-value < 10-4 for grade 3-4 TIPN analysis and three genes had a p-value < 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10-6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. CONCLUSION: Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.Item Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence(medRxiv, 2023-04-29) Barr, Peter B.; Neale, Zoe; Schulman, Jessica; Mullins, Niamh; Zhang, Jian; Chorlian, David B.; Kamarajan, Chella; Kinreich, Sivan; Pandey, Ashwini K.; Pandey, Gayathri; Saenz de Viteri, Stacey; Acion, Laura; Bauer, Lance; Bucholz, Kathleen K.; Chan, Grace; Chao, Michael; Dick, Danielle M.; Edenberg, Howard J.; Foroud, Tatiana; Goate, Alison; Hesselbrock, Victor; Johnson, Emma C.; Kramer, John; Lai, Dongbing; Plawecki, Martin H.; Salvatore, Jessica E.; Wetherill, Leah; Agrawal, Arpana; Porjesz, Bernice; Meyers, Jacquelyn L.; Medical and Molecular Genetics, School of MedicineResearch has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder, despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) explored clinical risk factors associated with SA, 2) conducted a genome-wide association study of SA, 3) examined whether individuals with a SA had elevated polygenic scores for comorbid psychiatric conditions (e.g., alcohol use disorders, lifetime suicide attempt, and depression), and 4) explored differences in electroencephalogram neural functional connectivity between those with and without a SA. One gene-based finding emerged, RFX3 (Regulatory Factor X, located on 9p24.2) which had supporting evidence in prior research of SA among individuals with major depression. Only the polygenic score for suicide attempts was associated with reporting a suicide attempt (OR = 1.20, 95% CI = 1.06, 1.37). Lastly, we observed decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences among those participants who reported a SA relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.Item Epigenetic changes on rat chromosome 4 contribute to disparate alcohol drinking behavior in alcohol-preferring and -nonpreferring rats(Elsevier, 2020-12) Spence, John Paul; Lai, Dongbing; Reiter, Jill L.; Cao, Sha; Bell, Richard L.; Williams, Kent E.; Liang, Tiebing; Pediatrics, School of MedicineBackground: Paternal alcohol abuse is a well-recognized risk factor for the development of an alcohol use disorder (AUD). In addition to genetic and environmental risk factors, heritable epigenetic factors also have been proposed to play a key role in the development of AUD. However, it is not clear whether epigenetic factors contribute to the genetic inheritance in families affected by AUD. We used reciprocal crosses of the alcohol-preferring (P) and -nonpreferring (NP) rat lines to test whether epigenetic factors also impacted alcohol drinking in up to two generations of offspring. Methods: F1 offspring derived by reciprocal breeding of P and NP rats were tested for differences in alcohol consumption using a free-choice protocol of 10% ethanol, 20% ethanol, and water that were available concurrently. In a separate experiment, an F2 population was tested for alcohol consumption not only due to genetic differences. These rats were generated from inbred P (iP) and iNP rat lines that were reciprocally bred to produce genetically identical F1 offspring that remained alcohol-naïve. Intercrosses of the F1 generation animals produced the F2 generation. Alcohol consumption was then assessed in the F2 generation using a standard two-bottle choice protocol, and was analyzed using genome-wide linkage analysis. Alcohol consumption measures were also analyzed for sex differences. Results: Average alcohol consumption was higher in the F1 offspring of P vs. NP sires and in the F2 offspring of F0 iP vs. iNP grandsires. Linkage analyses showed the maximum LOD scores for alcohol consumption in both male and female offspring were on chromosome 4 (Chr 4). The LOD score for both sexes considered together was higher when the grandsire was iP vs. iNP (5.0 vs. 3.35, respectively). Furthermore, the F2 population displayed enhanced alcohol consumption when the P alleles from the F0 sire were present. Conclusions: These results demonstrate that epigenetic and/or non-genetic factors mapping to rat chromosome 4 contribute to a transgenerational paternal effect on alcohol consumption in the P and NP rat model of AUD.