rs17649553 — MAPT H1/H2 Haplotype Tag

The MAPT H1/H2 Haplotype — An Ancient Inversion That Shapes Tauopathy Risk

About 3 million years ago, a 900-kilobase inversion occurred on chromosome 17q21¹¹ a 900-kilobase inversion occurred on chromosome 17q21
This inversion created two distinct haplotype clades that have been recombinationally suppressed since, accumulating independent sequence variations, creating two distinct evolutionary lineages of the microtubule-associated protein tau (MAPT) gene: H1 and H2. This SNP, rs17649553, is one of several markers that can distinguish between these two haplotypes, which have profoundly different effects on the risk of developing neurodegenerative diseases involving abnormal tau protein deposits.

The MAPT gene encodes tau, a protein primarily expressed in neurons that stabilizes microtubules and supports axonal transport²² stabilizes microtubules and supports axonal transport
Microtubules are the cell's internal transportation system, and tau helps maintain their structure. When tau becomes abnormally phosphorylated and aggregates, it forms neurofibrillary tangles — pathological hallmarks of tauopathies including Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease, and some forms of Parkinson's disease and frontotemporal dementia (FTD).

The Haplotype Structure

Because of the ancient inversion, H1 and H2 exist in complete linkage disequilibrium across nearly 900kb³³ H1 and H2 exist in complete linkage disequilibrium across nearly 900kb
Any SNP in this region can tag the haplotype, as recombination between them has been suppressed for millions of years. The H1 haplotype is evolutionarily dynamic and contains numerous subhaplotypes (H1a, H1b, H1c, etc.), while H2 is more homogeneous. Population distribution is striking: H2 is rare in Africans, almost absent in East Asians, but found at approximately 20% frequency in Europeans⁴⁴ H2 is rare in Africans, almost absent in East Asians, but found at approximately 20% frequency in Europeans
This population-specific distribution suggests selection pressure in European populations.

The Evidence for Parkinson Disease

A 2007 study of 1,762 Parkinson's disease patients and 2,010 controls found a robust association between the H1/H1 diplotype and PD risk (OR 1.46, 95% CI 1.25-1.69, p = 8×10⁻⁷)⁵⁵ A 2007 study of 1,762 Parkinson's disease patients and 2,010 controls found a robust association between the H1/H1 diplotype and PD risk (OR 1.46, 95% CI 1.25-1.69, p = 8×10⁻⁷)
The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. A meta-analysis of 23 Caucasian case-control series (7,736 patients, 9,339 controls) estimated an overall OR of 0.78 for H2 versus H1⁶⁶ A meta-analysis of 23 Caucasian case-control series (7,736 patients, 9,339 controls) estimated an overall OR of 0.78 for H2 versus H1
This suggests H2 may be protective against Parkinson's disease.

Progressive Supranuclear Palsy and Other 4R Tauopathies

The association is even stronger for PSP. The H1 haplotype is found in approximately 94% of PSP patients compared to around 78% in healthy adults⁷⁷ The H1 haplotype is found in approximately 94% of PSP patients compared to around 78% in healthy adults
Nearly all PSP patients are H1 homozygotes, though H1 appears necessary but not sufficient to cause disease. PSP is a rare atypical parkinsonian disorder characterized by vertical supranuclear gaze palsy, unprovoked falls, axial rigidity, and cognitive decline, with predominant accumulation of 4-repeat tau in neurons and glia⁸⁸ with predominant accumulation of 4-repeat tau in neurons and glia
The 4R:3R tau isoform ratio appears critical in PSP pathogenesis.

Corticobasal degeneration and Alzheimer's disease also show H1 associations, though the specific subhaplotypes involved differ. The H1c subhaplotype, tagged by rs242557, is specifically associated with increased Alzheimer's disease risk in APOE ε4 non-carriers⁹⁹ The H1c subhaplotype, tagged by rs242557, is specifically associated with increased Alzheimer's disease risk in APOE ε4 non-carriers
Different H1 subhaplotypes confer risk for different tauopathies.

The Pick's Disease Paradox

In a striking reversal, a 2024 study of 338 pathologically confirmed Pick's disease cases found the H2 haplotype associated with increased risk¹⁰¹⁰ a 2024 study of 338 pathologically confirmed Pick's disease cases found the H2 haplotype associated with increased risk
This is opposite to the protective effect seen in PSP and CBD. Pick's disease is a 3-repeat tauopathy characterized by Pick bodies in the frontal and temporal lobes. This finding suggests the H1/H2 polymorphism may affect the balance of 3R and 4R tau isoforms through alternative splicing of exon 10¹¹¹¹ the H1/H2 polymorphism may affect the balance of 3R and 4R tau isoforms through alternative splicing of exon 10
H1 may promote 4R tau, while H2 may favor 3R tau.

Frontotemporal Dementia

The majority of genetic FTD is caused by mutations in C9ORF72, MAPT, or GRN genes¹²¹² The majority of genetic FTD is caused by mutations in C9ORF72, MAPT, or GRN genes
About 10-20% of all FTD cases are genetic. While pathogenic mutations in MAPT cause familial FTD with autosomal dominant inheritance, the common H1 haplotype also contributes to sporadic FTD risk, particularly the H1c subclade¹³¹³ the common H1 haplotype also contributes to sporadic FTD risk, particularly the H1c subclade
A 2024 GWAS of 4,685 sporadic FTD cases found genome-wide significant association at the MAPT locus (p = 2.5×10⁻¹²).

Mechanism and Splicing

Studies using whole-locus genomic MAPT expression vectors demonstrate that intronic variants like rs1800547 and rs17651213 regulate haplotype-specific splicing of exon 3¹⁴¹⁴ Studies using whole-locus genomic MAPT expression vectors demonstrate that intronic variants like rs1800547 and rs17651213 regulate haplotype-specific splicing of exon 3
The splicing factors hnRNP F and hnRNP Q mediate this haplotype-specific regulation. The H2 haplotype is associated with lower total MAPT expression and altered isoform ratios compared to H1¹⁵¹⁵ The H2 haplotype is associated with lower total MAPT expression and altered isoform ratios compared to H1
This may explain the differential tauopathy risk profiles. Specifically, H1 appears to favor production of 4R tau isoforms, which may explain its association with 4R tauopathies like PSP and CBD.

Aging and Bradykinesia

Even in neurologically healthy older adults, the H2 haplotype is associated with age-related motor impairment, particularly bradykinesia (slowness of movement)¹⁶¹⁶ the H2 haplotype is associated with age-related motor impairment, particularly bradykinesia (slowness of movement)
This suggests MAPT variants influence aging-related functional decline independent of clinical disease. The mechanism appears distinct from classical Parkinson's disease and may involve cortico-nigro-striatal pathways different from those typically affected in PD.

Interactions

The H1/H2 haplotype interacts with other genetic risk factors. In Huntington's disease (a secondary tauopathy), H2 carriers show more rapid cognitive decline compared to H1 carriers¹⁷¹⁷ H2 carriers show more rapid cognitive decline compared to H1 carriers
This suggests tau pathology contributes to HD progression. In APOE ε4 non-carriers, the MAPT H1 haplotype becomes a more prominent risk factor for Alzheimer's disease¹⁸¹⁸ In APOE ε4 non-carriers, the MAPT H1 haplotype becomes a more prominent risk factor for Alzheimer's disease
This suggests genetic interactions between the two major AD risk loci.

The relationship between MAPT haplotypes and alpha-synuclein pathology (the hallmark of Parkinson's disease) remains incompletely understood, though interaction analyses have not found evidence of epistatic effects between SNCA and MAPT loci¹⁹¹⁹ interaction analyses have not found evidence of epistatic effects between SNCA and MAPT loci
The two risk factors appear to act independently.