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Background: Parkinson’s disease (PD) is clinically heterogeneous, yet the genetic architecture underlying this heterogeneity remains incompletely understood. We examined the genetic correlates of four complementary PD subtyping frameworks: clinical motor subtype (tremor-dominant [TD] vs. postural instability/gait difficulty [PIGD]), alpha-synuclein seed amplification assay status (SAA+ vs. SAA−), pathological subtype (brain-first vs. body-first, based on REM sleep behavior disorder), and data-driven subtype (diffuse malignant [DM] vs. mild-motor predominant [MMP] vs. intermediate [IM]). Methods: We analyzed 1,597 PD patients from the Parkinson’s Progression Markers Initiative (PPMI) with genetic testing for seven PD-associated genes (LRRK2, GBA, SNCA, PRKN, PINK1, PARK7, VPS35), including specific variant resolution (LRRK2 G2019S, R1441G/C/H; GBA N409S, severe variants; SNCA A53T), and APOE genotyping (ε2/ε3/ε4 alleles). Genetic variant frequencies were compared across subtypes using chi-square or Fisher’s exact tests with Benjamini–Hochberg false discovery rate (FDR) correction. Effect sizes were quantified using Cramér’s V. Multivariable logistic regression (statsmodels) estimated adjusted odds ratios with Wald-based 95% confidence intervals. Results: Among 1,390 genotyped PD patients, LRRK2 carriers constituted 13.7% (190/1,390; 170 G2019S, 18 R1441G/C/H), GBA 8.6% (119/1,390; 96 N409S, 23 severe), and SNCA 2.0% (28/1,390; all A53T). APOE ε4 carriers comprised 23.4% (323/1,380). SAA-negative patients were markedly enriched for LRRK2 variants (37.1% vs. 10.2%, P = 3.7 × 10⁻¹⁹, q < 0.001, V = 0.25), driven by G2019S (28.5% vs. 9.6%, P = 4.9 × 10⁻¹¹, q < 0.001) and R1441G/C/H (7.9% vs. 0.5%, P = 2.7 × 10⁻¹², q < 0.001). Body-first PD was enriched for GBA carriers (12.3% vs. 6.7%, P = 0.004, q = 0.021) and depleted for LRRK2 (7.9% vs. 15.0%, P = 0.002, q = 0.013). The DM subtype carried the highest GBA frequency (14.0% vs. MMP 5.9%, P < 0.001, q = 0.003). After FDR correction, 10 of 48 univariate tests remained significant. Clinical subtypes (TD vs. PIGD) showed only nominal LRRK2 differences that did not survive FDR correction. APOE genotype did not differ across any framework. Conclusions: PD subtypes defined by alpha-synuclein pathology (SAA), pathological onset pattern (brain-first/body-first), and data-driven classification (DM/MMP/IM) show distinct genetic profiles that survive multiple comparison correction. LRRK2 variants strongly associate with SAA-negativity (V = 0.25); GBA variants associate with the severe body-first onset and the diffuse malignant subtype.
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