Browsing by Subject "Genetic risk"
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Item Alzheimer’s Disease Polygenic Risk in the LEADS Cohort(Wiley, 2025-01-03) Nudelman, Kelly N.; Pentchev, Julian V.; Jackson, Trever; Eloyan, Ani; Dage, Jeffrey L.; Foroud, Tatiana M.; Hammers, Dustin B.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Medical and Molecular Genetics, School of MedicineBackground: Currently, it is unclear to what extent late‐onset Alzheimer’s disease (AD) risk variants contribute to early‐onset AD (EOAD). One method to clarify the contribution of late‐onset AD genetic risk to EOAD is to investigate the association of AD polygenic risk scores (PRS) with EOAD. We hypothesize that in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS), EOAD participants will have greater PRS than early‐onset amyloid‐negative cognitively‐impaired participants (EOnonAD) and controls, and investigate the association of AD PRS with age of disease onset (AoO) and cognitive performance. Methods: GWAS data was generated for LEADS participants, including those with EOAD, EOnonAD, and controls, with the Illumina Global Screening Array. A PRS was calculated using the 31 SNPs and weights published previously by Desikan et al. (2017) for LEADS participants with imputed GWAS data (N = 369). Logistic regression models including age, sex, PRS, and genetic ancestry principal components were tested to identify predictors of EOAD (N = 210) vs. EOnonAD (N = 69) and controls (N = 89). ANCOVA models were used to assess group differences in PRS scores. Kaplan‐Meier regression was used to assess differences in EOAD AoO for tertile‐binned PRS groups. Within EOAD, pre‐calculated cognitive domain scores for speed and attention, working memory, episodic memory, language, and visuospatial performance were assessed for correlation with PRS. Results: The AD PRS was a predictor of EOAD (p = 0.014), with the model explaining 10.5% of variance (X2 = 40.971, p<0.001). EOAD participants had higher PRS scores (mean = 0.0012, standard deviation (SD) = 0.015) compared to EOnonAD and controls (mean = ‐0.0018, SD = 0.015) (F = 6.602, p = 0.011). Survival analysis indicated no significant differences in EOAD AoO between PRS groups (X2 = 3.396, p = 0.183). In the EOAD group, PRS was associated with cognitive scores for speed and attention (r = 0.204, p = 0.007), language (r = 0.230, p = 0.002), and visuospatial performance (r = 0.166, p = 0.037). Conclusions: In the LEADS cohort, AD PRS is a predictor for EOAD, and is associated with cognitive performance, but does not predict EOAD AoO. This suggests that while late onset AD‐associated genetic variants contribute to disease risk and processes, they do not account for a large portion of disease risk, and do not explain differences in disease AoO in the LEADS cohort.Item Association of Alzheimer’s disease polygenic risk score with concussion severity and recovery metrics(Wiley, 2025-01-09) Dybing, Kaitlyn M.; McAllister, Thomas W.; Wu, Yu-Chien; McDonald, Brenna C.; McCrea, Michael A.; Broglio, Steven P.; Pasquina, Paul F.; Brooks, M. Alison; Mihalik, Jason P.; Guskiewicz, Kevin M.; Giza, Christopher C.; Goldman, Joshua; Duma, Stefan; Rowson, Steve; Svoboda, Steven; Cameron, Kenneth L.; Houston, Megan N.; Campbell, Darren E.; McGinty, Gerald; Jackson, Jonathan; Risacher, Shannon L.; Saykin, Andrew J.; Nudelman, Kelly N.; Radiology and Imaging Sciences, School of MedicineBackground: Shared genetic risk between Alzheimer’s disease (AD) and concussion may help explain the association between concussion and elevated risk for dementia. However, there has been little investigation into whether AD risk genes also associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate associations between AD genetic risk and concussion severity/recovery in the NCAA‐DoD Grand Alliance CARE Consortium (CARE) dataset. Method: There were 1,917 injuries in the dataset upon project initiation. After removing repeated injuries, related participants, and those without genetic/outcome data, we had 931 participants. Outcomes were number of days to return to play (RTP) as a recovery measure, and four severity measures (scores on SAC and BESS, SCAT symptom severity and total number of symptoms). We calculated PRS using a published score (de Rojas et al., 2021) and performed a linear regression (MLR) of RTP by PRS in normal (<24 days) and long (>24 days) RTP subgroups. We then compared severity measures by PRS using MLR. Next, we used t‐tests to examine outcomes by APOE genotype in military and civilian subgroups. We also performed chi‐squared tests of RTP category (normal vs. long) by APOE genotype. Finally, we analyzed outcomes by PRS in European or African genetic ancestry subgroups using MLR. Result: Higher PRS was associated with longer injury to RTP interval in the normal RTP (<24 days) subgroup (estimate = 0.0412, SE = 0.182, p = 0.0237). 1 SD increase in PRS resulted in a 0.412 day (9.89 hours) increase to the interval. This may be clinically meaningful in the collegiate athlete environment. We did not identify any other significant differences. Conclusion: Our preliminary results provide limited evidence for an impact of AD PRS on concussion recovery, though the pattern was inconsistent and its clinical significance is uncertain. Future studies should attempt to replicate these findings in larger samples with longer follow‐up using PRS calculated from multiple/diverse populations, which will be especially relevant for diverse datasets like CARE.Item An exploratory genome-wide analysis of genetic risk for alcoholic hepatitis(Taylor & Francis, 2017-11) Beaudoin, James J.; Long, Nanye; Liangpunsakul, Suthat; Puri, Puneet; Kamath, Patrick S.; Shah, Vijay; Sanyal, Arun J.; Crabb, David W.; Chalasani, Naga P.; Urban, Thomas J.; TREAT Consortium; Medicine, School of MedicineOBJECTIVES: To elucidate the genetic variability between heavy drinkers with and without alcoholic hepatitis (AH). MATERIALS AND METHODS: An exploratory genome-wide association study (GWAS; NCT02172898) was conducted comparing 90 AH cases with 93 heavy drinking matched controls without liver disease in order to identify variants or genes associated with risk for AH. Individuals were genotyped using the multi-ethnic genotyping array, after which the data underwent conventional quality control. Using bioinformatics tools, pathways associated with AH were explored on the basis of individual variants, and based on genes with a higher 'burden' of functional variation. RESULTS: Although no single variant reached genome-wide significance, an association signal was observed for PNPLA3 rs738409 (p = .01, OR 1.9, 95% CI 1.1-3.1), a common single nucleotide polymorphism that has been associated with a variety of liver-related pathologies including alcoholic cirrhosis. Using the improved gene set enrichment analysis for GWAS tool, it was shown that, based on the single variants' trait-association p-values, multiple pathways were associated with risk for AH with high confidence (false discovery rate [FDR] < 0.05), including several pathways involved in lymphocyte activation and chemokine signaling, which coincides with findings from other research groups. Several Tox Functions and Canonical Pathways were highlighted using Ingenuity Pathway Analysis, with an especially conspicuous role for pathways related to ethanol degradation, which is not surprising considering the phenotype of the genotyped individuals. CONCLUSION: This preliminary analysis suggests a role for PNPLA3 variation and several gene sets/pathways that may influence risk for AH among heavy drinkers.Item Genetic risk for primordial prevention of cardiometabolic disease(2019-06) Wessel, Jennifer; Smith, MitchellThe prevalence of obesity and type 2 diabetes (T2D) in children has risen dramatically. We hypothesized that providing child’s genetic risk information, to families at high T2D risk, would serve as a motivator to improve behaviors related to the development of risk factors for T2D. We conducted a pilot intervention study of parents (n=51) and their children (n=44) aged 2-8. Family’s physical activity, children’s eating behaviors related to obesity (CEBQ); and parent’s attitudes and motivations for lifestyle change were collected at baseline and 3-month follow-up (3MFU). At baseline, saliva samples were collected from children for genotyping of obesity and T2D risk variants identified in genome-wide association studies. Parents were on average 35±6 years old, BMI 31±7 kg/m2, 60% mothers, 31% black and 7% Latino. Children were 4±2 years with a BMI of 72±26 percentiles. At the risk disclosure session, anxiety (STAI-S) and depressive symptoms (POMS) of parents were measured immediately before and after disclosure of child’s risk; and a significant increase in tension (X =2.58, p=0.03) and anxiety (X =-2.98, p=0.002) was observed. Parents then received a quasi-motivational interviewing and behavioral education intervention. After receiving the intervention parents reported a significant increase in their confidence to change their family’s behaviors (X =-0.31, p=0.002) compared to pre-disclosure. This led to 100% of parents committing to a personalized diet or activity change. At 3MFU, children demonstrated a reduction in their desire to drink (X =1.52, p=0.002) and responsiveness to food (X =1.86, p=0.005). In parents, no elevation in depressiveness or anxiety remained. No change in BMI or physical activity was observed in either group. Our data suggest returning genetic risk results can motivate commitment to behavior change. Future work will test whether combining genetic risk with an established lifestyle intervention may facilitate lowering T2D risk.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 Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders(Springer Nature, 2023) Hatoum, Alexander S.; Colbert, Sarah M. C.; Johnson, Emma C.; Huggett, Spencer B.; Deak, Joseph D.; Pathak, Gita; Jennings, Mariela V.; Paul, Sarah E.; Karcher, Nicole R.; Hansen, Isabella; Baranger, David A. A.; Edwards, Alexis; Grotzinger, Andrew; Substance Use Disorder Working Group of the Psychiatric Genomics Consortium; Tucker-Drob, Elliot M.; Kranzler, Henry R.; Davis, Lea K.; Sanchez-Roige, Sandra; Polimanti, Renato; Gelernter, Joel; Edenberg, Howard J.; Bogdan, Ryan; Agrawal, Arpana; Medical and Molecular Genetics, School of MedicineGenetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci for published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent SNPs were genome-wide significant (P < 5e-8) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targetsItem Offspring of parents with an alcohol use disorder prefer higher levels of brain alcohol exposure in laboratory experiments involving computer-assisted self-infusion of ethanol (CASE)(SpringerLink, 2009-03) Zimmermann, Ulrich S.; Mick, Inge; Laucht, Manfred; Vitvitskiy, Victor; Plawecki, Martin H.; Mann, Karl F.; O’Connor, Sean; Psychiatry, School of MedicineRationale: Acute alcohol effects may differ in social drinkers with a positive family history of alcohol use disorders (FHP) compared to FH negative (FHN) controls. Objectives: To investigate whether FHP subjects prefer higher levels of brain alcohol exposure than do FHN controls. Materials and methods: Twenty-two young healthy nondependent social drinkers participated in two identical sessions of computer-assisted self-infusion of ethanol (CASE); the first for practicing the procedures, the second to test hypotheses. All 12 FHP (four women) and ten FHN (three women) participants received a priming exposure, increasing arterial blood alcohol concentration (aBAC) to 30 mg% at 10 min and decreasing it to 15 mg% at 25 min. A 2-h self-administration period followed, during which only the subjects could increase their aBAC by pressing a button connected to a computer controlling the infusion pump. Infusion rate profiles were calculated instantaneously to increase aBAC by precisely 7.5 mg% within 2.5 min after each button press, followed by a steady descent. Subjects were instructed to produce the same alcohol effects as they would do at a weekend party. Results: The mean and maximum aBAC during the self-administration period and the number of alcohol requests (NOAR) were significantly higher in the FHP vs. FHN participants. Conclusions: This is the first laboratory experiment demonstrating higher alcohol self-administration in FHP compared to FHN subjects. A practice session increases the sensitivity of CASE experiments for detection of subtle differences in human alcohol self-administration.Item Reply: Polygenic risk score in cirrhosis: Does the etiology matter?(Wolters Kluwer, 2025-01-16) Schwantes-An, Tae-Hwi; Morgan, Timothy R.; Seth, Devanshi; Medical and Molecular Genetics, School of MedicineItem Role of Candidate Gene Variants in Modulating the Risk and Severity of Alcoholic Hepatitis(Wiley, 2021) Beaudoin, James J.; Liang, Tiebing; Tang, Qing; Banini, Bubu A.; Shah, Vijay H.; Sanyal, Arun J.; Chalasani, Naga P.; Gawrieh, Samer; Biostatistics, School of Public HealthBackground: Alcoholic hepatitis (AH) is a severe and life-threatening alcohol-associated liver disease. Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH. Methods: A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O-acyltransferase domain containing 7 (MBOAT7), and a copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity. Results: We found significant associations between AH risk and the risk alleles of rs738409 (p = 0.0081) and HP (p = 0.0371), but not rs72613567 (p = 0.3132), rs58542926 (p = 0.2180), or rs641738 (p = 0.7630), after adjusting for patient's age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR = 1.59 (95% CI: 1.15-2.22), p = 0.0055] and HP*2 [OR = 1.38 (95% CI: 1.04-1.82), p = 0.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End-stage Liver Disease (MELD) score, both measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (p = 0.0921). Conclusion: PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.