Repeat Variants, Biomarkers, and Molecular Signatures in Parkinson’s Disease: ATXN2, ATXN3, CACNA1A, PRNP, TBP, C9ORF72, TOMM40, APOE, and POLG—A Swedish Perspective

Parkinson's disease (PD), the second most common neurodegenerative disorder globally, has a notably high prevalence in Sweden (136/10⁵). Although monogenic forms represent only a small subset of PD cases, several genetic factors-including nucleotide repeat expansions (NREs) in <i>ATXN2</i>, <i>ATXN3</i>, <i>C9ORF72</i>, <i>TBP</i>, <i>POLG</i>, <i>TOMM40</i>, <i>CACNA1A</i>, and <i>PRNP</i>-have been implicated in neurodegenerative conditions with parkinsonian features. However, their contribution to PD pathogenesis in the Swedish population remains understudied. We analyzed DNA from 161 Swedish PD patients and 546 controls and evaluated clinical and CSF biomarkers (tau, phospho-tau, and β-amyloid). Intermediate <i>ATXN2</i> CAG expansions were significantly associated with PD (3.40%, <i>p</i> = 0.0027), and novel promoter structural variations were identified. <i>C9ORF72</i> G4C2 expansions were also linked to PD (2.48%, <i>p</i> = 0.0018), with distinct methylation patterns in PD cases. POLG Not-10/Not-11Q alleles were positively associated (9.62%, <i>p</i> = 0.014), while <i>TOMM40</i> showed partial associations for rare genotypes (14.28%, <i>p</i> = 0.0014). Pathological expansions in <i>TBP</i> were marginally significant, while <i>ATXN3</i>, <i>CACNA1A</i>, and <i>PRNP</i> showed no associations. Two-way ANOVA identified significant interactions between <i>APOE E3</i>/<i>E4</i> and <i>POLG</i> 10/11Q genotypes, affecting age at diagnosis (<i>p</i> = 0.025) and CSF β-amyloid levels. Regression highlighted tau as a key predictor of age at diagnosis (<i>p</i> = 0.02). Longitudinally, <i>APOE E4</i> predicted cognitive decline (<i>p</i> = 0.015), and <i>TOMM40</i> haplotypes correlated with motor deficits. In conclusion, <i>ATXN2</i>, <i>C9ORF72</i>, and <i>POLG</i> emerge as key genetic risk factors for PD in the Swedish population, with <i>TOMM40</i> and <i>TBP</i> contributing partially. Altered CSF biomarker patterns support the existence of distinct molecular subtypes and warrant further investigation of novel <i>ATXN2</i> variants as potential PD modifiers.