MAPT (tau) H1 haplotype

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

Early association studies from 2000 (Pastor and colleagues, Hospital Clínic, Barcelona); the first European-ancestry Parkinson's genome-wide study by Javier Simón-Sánchez, T. Gasser, A. B. Singleton and colleagues (Nat Genet 2009). Funders were not read.

What happened

• 2000. A Spanish study (Pastor et al., Ann Neurol 47:242–245) typed a tau intron-11 repeat in 152 Parkinson's patients, 52 Alzheimer's patients and 150 controls. The A0 allele was commoner in Parkinson's (79.3% versus 71% in controls), and A0/A0 homozygotes were 63.8% of patients versus 52.7% of controls.
• 2009. Simón-Sánchez et al. ran a genome-wide scan on 1,713 European-ancestry cases and 3,978 controls, then replicated in 3,361 cases and 4,573 controls. Two signals stood out: SNCA (rs2736990, odds ratio 1.23) and MAPT (rs393152, odds ratio 0.77 for the protective allele). Both were genome-wide significant.
• A US replication (Zabetian et al., Ann Neurol 2007; 1,762 cases, 2,010 controls) gave an H1/H1 odds ratio of 1.46 (95% CI 1.25–1.69).
• The Japanese GWAS published beside it found SNCA and LRRK2 but listed MAPT among loci that differ between populations, so the tau effect may not be universal (Satake et al. 2009).
• H1 was already linked to risk in progressive supranuclear palsy and corticobasal degeneration, both tau diseases (stated in the Zabetian introduction).

Why it moved us toward a cure

It showed that common variants near the synuclein gene (landmark 4) and the tau gene both shape risk, so protein misfolding pathways overlap across diseases. This was the first genome-wide proof that common variants matter in typical Parkinson's (the paper's own conclusion). The effect is small, so MAPT is not a direct drug target for Parkinson's.

Outcome

Open. The mechanism by which H1 raises risk in Parkinson's is unknown.

Sources

• Simón-Sánchez et al., Nat Genet 2009;41:1308–1312, DOI 10.1038/ng.487
• Pastor et al., Ann Neurol 2000;47:242–245, DOI 10.1002/1531-8249(200002)47:2<242::AID-ANA16>3.0.CO;2-L, PMID 10665497
• Zabetian et al., Ann Neurol 2007;62:137–144, PMC2836920
• Satake et al., Nat Genet 2009;41:1303–1307, DOI 10.1038/ng.485, PMID 19915576
• Not yet verified: Pastor's odds ratio (the abstract gives frequencies only); whether H1 still shows in the 2019 meta-analysis (landmark 19); the mechanism.