Browsing by Author "Pérez-Palma, Eduardo"
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Item Analysis of common genetic variation underlying comorbidities in neurodegenerative diseases(Universidad del Desarrollo. Facultad de Medicina, 2024) Hernández Astudillo, Carlos Felipe; Pérez-Palma, Eduardo; Klein Posternack, AndrésIntroduction: Parkinson's Disease (PD) and Alzheimer's Disease (AD) are complex neurodegenerative disorders often accompanied by comorbidities such as type 2 diabetes (T2D), epilepsy, major depressive disorder (MDD), and migraine headaches (MH). These comorbidities, like PD and AD, are influenced by cumulative genetic risks measurable through Polygenic Scores (PGS). However, a significant knowledge gap exists as comorbidity PGS in PD and AD has not been adequately assessed, highlighting the need for further Investigation in this area. Objective: To investigate the relationship between comorbidity PGS and their manifestation in individuals with PD and AD, addressing the hypothesis that comorbidity-PGSs are significantly associated with the risk of developing these conditions in neurodegenerative diseases. Methods and Results: Using data from the UK Biobank, we evaluated the relationship between comorbidity PGS and their manifestation in individuals with PD and AD. Our findings indicate that individuals with higher PGS values for comorbidities are at greater risk of developing these conditions alongside PD and AD. Specifically, in PD patients, elevated PGS were significantly associated with increased risks of T2D (OR: 2.2, p-value: 1.27 × 10-15), MDD (OR: 1.3, p-value: 3.01 × 10-3), MH (OR: 1.8, p-value: 0.0251), and epilepsy (OR: 1.6, p-value: 8.45 × 10-3). Similarly, in AD patients, higher PGS for T2D (OR: 2.1, p-value: 1.10 × 10 11 and epilepsy (OR: 1.4, p-value: 0.0208) were linked to an increased risk of comorbidity development and earlier disease onset. The analysis for PD also revealed sex-specific genetic predispositions, with women more susceptible to MDD and MH, while men were more prone to T2D. Conclusions: These findings highlights the importance of integrating comorbidity-specific PGS into the assessment of genetic risk in neurodegenerative diseases. By characterizing the genetic predisposition to comorbidities in PD and AD patients, this study advances our understanding of shared genetic pathways and the mechanisms driving disease progression. Furthermore, the methods and pipelines developed here are applicable to the investigation of other complex diseases. Future research should focus on validating these findings in larger, more diverse cohorts, particularly in underrepresented populations, to enhance the precision and applicability of genetic risk assessments.Publication Polygenic score analysis identifies distinct genetic risk profiles in Alzheimer’s disease comorbidities(2025) Hernández, Carlos F.; Villaman, Camilo; Leu, Costin; Lal, Dennis; Mata, Ignacio; Klein, Andrés; Pérez-Palma, EduardoAlzheimer’s disease (AD) is usually accompanied by comorbidities such as type 2 diabetes (T2D), epilepsy, major depressive disorder (MDD), and migraine headaches (MH) that can significantly affect patient management and progression. As AD, these comorbidities have their own cumulative common genetic risk component that can be explored in a single individual through polygenic scores. Utilizing data from the UK Biobank, we investigated the correlation between polygenic scores (PGS) for these comorbidities and their actual presentation in AD patients. We show that individuals with higher PGS values showed an elevated risk of developing T2D (OR 2.1, p = 1.07 × 10−11) and epilepsy (OR 1.5, p = 0.0176). High T2D-PGS is also associated with an earlier AD onset in individuals at high genetic risk for AD (AD-PGS). In contrast, no significant genetic associations were found for MDD and MH. Our findings show distinct common genetic risk factors for T2D and epilepsy carried by AD patients that are associated with increased prevalence and earlier disease onset. These results highlight the contribution of common genetic variation to the broader clinical landscape of AD and will contribute to future tailored patient management strategies for individuals at high genetic risk.