Pérez-Palma, EduardoKlein Posternack, AndrésHernández Astudillo, Carlos Felipe2025-04-082025-04-082024https://hdl.handle.net/11447/9952Tesis presentada a la Facultad de Medicina – Clínica Alemana de la Universidad del Desarrollo para optar al grado académico de Doctor en Ciencias e Innovación en Medicina.Introduction: 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.138 p.en090036SNeurodegenerative disordersComorbiditiesThesis