Browsing by Author "Rosewood, Thea J."

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    Genome-Wide Association Analysis across Endophenotypes in Alzheimer's Disease: Main Effects and Disease Stage-Specific Interactions
    (MDPI, 2023-10-27) Rosewood, Thea J.; Nho, Kwangsik; Risacher, Shannon L.; Gao, Sujuan; Shen, Li; Foroud, Tatiana; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative; Medical and Molecular Genetics, School of Medicine
    The underlying genetic susceptibility for Alzheimer's disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs.
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    Pathway enrichment in genome‐wide analysis of longitudinal Alzheimer's disease biomarker endophenotypes
    (Wiley, 2024) Rosewood, Thea J.; Nho, Kwangsik; Risacher, Shannon L.; Liu, Shiwei; Gao, Sujuan; Shen, Li; Foroud, Tatiana; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative; Medical and Molecular Genetics, School of Medicine
    Introduction: The genetic pathways that influence longitudinal heterogeneous changes in Alzheimer's disease (AD) may provide insight into disease mechanisms and potential therapeutic targets. Methods: Longitudinal endophenotypes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) representing amyloid, tau, neurodegeneration (A/T/N), and cognition were selected. Genome-wide association analysis was performed using a linear mixed model (LMM) approach, followed by gene and pathway enrichment with significant and functionally relevant SNPs. Results: A total of 33 and 19 statistically significant pathways were identified associating with the intercept and longitudinal trajectory, respectively. The longitudinal intercept pathways represent eight groups: immune, metabolic, cell growth and survival, DNA maintenance, neuronal signaling, RAS/MAPK/ERK signaling pathways, vesicle and lysosomal transport, and transcription modification. Longitudinal trajectory pathways represented six groups: Immune, metabolic, cell signaling, cytoskeleton, and glycosylation. Discussion: Longitudinal enrichment identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition, providing new insight into AD course-related mechanisms and potential new therapeutic targets. Highlights: A systematic genome-wide analysis with longitudinal AD biomarker endophenotypes was performed. Enriched pathways were identified with functionally derived SNP to gene analysis. Fifty-two pathways were associated with longitudinal trajectory and intercept. Many of the identified pathways are specific steps in larger pathways implicated in AD. The identified pathways may provide therapeutic targets and areas for further study.