Avrupa ve Çok Atalı Parkinson Hastalığı Çalışmalarının Bütünleştirici Meta-GWAS'ı Genetik Risk Mimarisini Artırır ve Çözülmemiş Aday Loci'ye Öncelik Verir

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Parkinson's disease (PD) is a highly polygenic neurodegenerative disorder whose genome-wide association study (GWAS) discoveries have largely arisen from European-ancestry cohorts. We integrated the Nalls et al. European PD GWAS with Kim et al. multi-ancestry summary statistics (GCST90275127), which exclude the Nalls dataset. Both resources were aligned to GRCh37, quality controlled, allele harmonized, and combined by fixed-effect inverse-variance weighting. After quality control, 6,477,357 harmonized variants entered meta-analysis, and 7,085 reached P < 5 × 10⁻⁸. The strongest signals mapped to established PD regions, including SNCA (rs356220; OR = 1.270, P = 6.17 × 10⁻⁸⁶) and GBA (rs2230288; OR = 1.989, P = 4.94 × 10⁻⁵⁸). Stringent locus analysis at P < 5 × 10⁻⁹ using a 1000 Genomes all-ancestry linkage disequilibrium reference identified 357 independent significant variants, 128 lead variants, and 73 genomic risk loci among reference-covered variants. Forty-two loci mapped to pre-Kim regions, three to Kim-published loci, and 28 remained unresolved candidates. Genomic inflation was elevated in the combined statistic (λGC = 1.875 among common non-MHC variants), requiring ancestry-aware calibration. These results refine established PD association architecture and prioritize unresolved loci for independent validation without establishing novel PD loci.

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