Age-at-onset and progression GWAS

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Cornelis Blauwendraat and the IPDGC (age at onset, 2019); Hirotaka Iwaki and colleagues (13 cohorts, 2019); the COURAGE-PD consortium (Grover et al., 2022); Ana Martínez Carrasco, Huw Morris and colleagues (motor progression, 2023).

What happened

The 90-signal risk map of landmark 19 asks who gets the disease. These studies ask when and how fast.

• Age at onset (Blauwendraat 2019). 28,568 patients. Common variants explained about 11% of the variation in age at onset, against about 27% of overall risk. Two genome-wide signals: SNCA and a coding variant in TMEM175 (a lysosome channel, landmark 87). GBA, BAG3, SCARB2 and MCCC1 were significant after correction. Well-known risk loci such as MAPT and GCH1 did not alter onset age.
• 13 cohorts (Iwaki 2019). 4,307 patients, 23,423 visits, 31 risk variants tested. GBA variants were linked to daytime sleepiness (p.N370S, hazard ratio 3.28), possible REM sleep behaviour disorder (p.T408M, odds ratio 6.48) and, as in earlier work, faster motor and cognitive decline. The paper has an erratum (Neurol Genet 2019;5(4):e354, 15 Aug 2019) that corrects the abstract's results to read "T allele of rs114128760" and changes nothing else (read in PMC6705618, checked 23 Oct 2026). A variant near LRRK2 was linked to faster motor worsening (hazard ratio 1.33). Onset age was linked to TMEM175, GPNMB and CCDC62.
• COURAGE-PD (2022). 8,535 patients. No genome-wide hit alone; the TMEM175 link replicated nominally. Combined with the largest public IPDGC data set (25,950 patients in total), SNCA and a new signal at BST1 reached genome-wide significance.
• Motor progression (2023). 3,572 patients in five cohorts and a trial. One signal at GJA5 (1q12) for axial (trunk and gait) progression, tied to expression of ACP6, a mitochondrial lipid enzyme.

Why it moved us toward a cure

Trials need to know who will worsen fast. These scans point to lysosome and synuclein genes and give the first progression targets. They also show that risk and progression have different genetics. They support covariates such as GBA status in trial design.

Outcome

Open. Sample sizes are small by GWAS standards, onset age is self-reported, and progression is noisy. The GP2 programme (landmark 78) is the route to larger data.

Sources

• Blauwendraat et al., Mov Disord 2019;34:866–875, DOI 10.1002/mds.27659
• Iwaki et al., Neurol Genet 2019;5:e348, DOI 10.1212/NXG.0000000000000348
• Grover et al., Neurology 2022;99:e698, DOI 10.1212/WNL.0000000000200699
• Martínez Carrasco et al., Neurol Genet 2023;9:e200092, DOI 10.1212/NXG.0000000000200092
• Not yet verified: any published GP2 progression analysis (none found; a 2025 GP2/IPDGC congress abstract on age at onset reports the largest analysis still finds only SNCA and TMEM175, from a search summary); Tan et al. 2021 progression GWAS (not found in Europe PMC, not read); full texts.