Browsing by Subject "Polygenic risk"

Now showing 1 - 3 of 3
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    Astrocyte Reactivity Polygenic Risk Score May Predict Cognitive Decline in Alzheimer’s Disease
    (World Scientific, 2025) Phillips, Jared M.; Schneider, Julie A.; Bennett, David A.; Crane, Paul K.; Risacher, Shannon L.; Saykin, Andrew J.; Dumitrescu, Logan C.; Hohman, Timothy J.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Alzheimer's disease (AD) is a polygenic disorder with a prolonged prodromal phase, complicating early diagnosis. Recent research indicates that increased astrocyte reactivity is associated with a higher risk of pathogenic tau accumulation, particularly in amyloid-positive individuals. However, few clinical tools are available to predict which individuals are likely to exhibit elevated astrocyte activation and, consequently, be susceptible to hyperphosphorylated tau-induced neurodegeneration. Polygenic risk scores (PRS) aggregate the effects of multiple genetic loci to provide a single, continuous metric representing an individual's genetic risk for a specific phenotype. We hypothesized that an astrocyte activation PRS could aid in the early detection of faster clinical decline. Therefore, we constructed an astrocyte activation PRS and assessed its predictive value for cognitive decline and AD biomarkers (i.e., cerebrospinal fluid [CSF] levels of Aβ1-42, total tau, and p-tau181) in a cohort of 791 elderly individuals. The astrocyte activation PRS showed significant main effects on cross-sectional memory (β = -0.07, p = 0.03) and longitudinal executive function (β = -0.01, p = 0.03). Additionally, the PRS interacted with amyloid positivity (p.intx = 0.02), whereby indicating that amyloid burden modifies the association between the PRS and annual rate of language decline. Furthermore, the PRS was negatively associated with CSF Aβ1-42 levels (β = -3.4, p = 0.07) and interacted with amyloid status, such that amyloid burden modifies the association between the PRS and CSF phosphorylated tau levels (p.intx = 0.08). These findings suggest that an astrocyte activation PRS could be a valuable tool for early disease risk prediction, potentially enabling intervention during the interval between pathogenic amyloid and tau accumulation.
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    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 Medicine
    Research 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.
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    The effect of Alzheimer's disease genetic factors on limbic white matter microstructure
    (Wiley, 2025) Lorenz, Anna; Sathe, Aditi; Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Kim, Michael E.; Gao, Chenyu; Newlin, Nancy R.; Ramadass, Karthik; Kanakaraj, Praitayini; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Shashikumar, Niranjana; Pechman, Kimberly R.; Jackson, Trevor Bryan; Workmeister, Abigail W.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Habes, Mohamad; Wang, Di; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Zhang, Panpan; Schilling, Kurt; Alzheimer's Disease Neuroimaging Initiative (ADNI)The BIOCARD Study Team; The Alzheimer's Disease Sequencing Project (ADSP); Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Bendlin, Barbara; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Radiology and Imaging Sciences, School of Medicine
    Introduction: White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences. Methods: To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores (PGSs) and WM metrics, and interactions with cognitive status. Results: AD PGSs, variants in TMEM106B, PTK2B, WNT3, and apolipoprotein E (APOE), and interactions involving MS4A6A were significantly linked to WM microstructure. Discussion: These findings implicate AD-related genetic factors related to neurodevelopment (WNT3), lipid metabolism (APOE), and inflammation (TMEM106B, PTK2B, MS4A6A) that contribute to alternations in WM microstructure in older adults. Highlights: AD risk variants in TMEM106B, PTK2B, WNT3, and APOE genes showed distinct associations with limbic FW-corrected WM microstructure metrics. Interaction effects were observed between MS4A6A variants and cognitive status. PGS for AD was associated with higher FW content in the limbic system.