Scientists have known for years that the common H1 haplotype of the tau gene MAPT somehow raises a person’s risk of the rare neurodegenerative disorder progressive supranuclear palsy (PSP). It does so by more than fivefold, similar to what ApoE does for Alzheimer’s disease. But H1 encompasses multiple genes, variants, and subhaplotypes, and which ones bear the most blame has been unclear. In a new study, Michael Heckman and Dennis Dickson, Mayo Clinic, Jacksonville, Florida, led a team that analyzed hundreds of autopsy-confirmed cases of PSP to identify the handful of H1 haplotypes linked to disease. Some of the haplotypes also appeared to have perhaps affected the severity of tau pathology, though those associations were weak, the scientists found. Their results appeared March 18 in JAMA Neurology.
“The findings are based on solid ground by examining a large autopsy-confirmed cohort, and further delineate the genetic basis of the risk for PSP,” Franziska Hopfner, Ludwig-Maximilians University, and Günter Höglinger, Technical University, both in Munich, wrote to Alzforum (see full comment below). Hopfner and Hoeglinger suggest it will be valuable to follow up these associations in additional autopsy-confirmed PSP cohorts, and in similar cohorts with related neurodegenerative diseases such as other tauopathies, or synucleinopathies. “In ongoing and upcoming clinical trials, the combination of genetic markers such as subhaplotypes and their relation to tau pathology burden might help to stratify study participants and monitor treatment response to tau-specific therapy,” they wrote.
PSP, a pure tauopathy, causes movement problems and cognitive dysfunction (Nov 2018 conference news). A definitive diagnosis requires postmortem findings of neurofibrillary tangles and neuropil threads in the basal ganglia and brain stem. Early genetic studies implicated the H1 haplotype, and its H1c subhaplotype, as a genetic risk factor for the tauopathies PSP and corticobasal degeneration (Pittman et al., 2005). In a later genome-wide association study, two single-nucleotide polymorphisms (SNPs) in the H1 haplotype were the most strongly associated with disease (Höglinger et al., 2011). One, rs8070723, tracked with H1, while the other, rs242557, associated with PSP independent of H1/H2 status.
To more fully explore the effects of the different MAPT variants in H1, Heckman compared genotypes of 802 autopsy-confirmed PSP cases from the Mayo Clinic Brain Bank and 1,312 living, clinically normal controls. Variation at six SNPs defined 19 H1 subhaplotypes; more than 20 haplotypes exist, but the researchers analyzed only those they detected in more than 1 percent of the people in their study. Five subhaplotypes were significantly associated with the risk of PSP. The H1c subhaplotype upped disease risk by 2.15-fold, consistent with previous results. New associations were detected with H1d, H1g, and H1o, which increased risk by 1.86, 3.64, and 2.60-fold, respectively. H1z was associated with a 3.05-fold increase in risk that just missed statistical significance. As expected, H2 carriers had a significantly diminished chance of PSP.
The researchers also searched for associations between haplotypes and the extent of tau pathology. They rated the severity of four types of deposit: neurofibrillary tangles, neuropil threads, tufted astrocytes, and oligodendroglial coiled bodies, on a scale of zero to three, in 17 to 20 regions per brain. Brain-wide, none of the haplotypes were significantly linked with any type of tau pathology after adjustment for multiple testing. The investigators did detect suggestions of association of H2 with less tau pathology, and H1c and H1d with more, implying that risk alleles may affect the severity of pathology. The most consistent observation was a decrease in three of the four pathologies in H2 carriers. In specific brain regions, some of the associations became stronger, suggesting genetic variation may affect local pathology. “The mechanism by which MAPT haplotypes alter severity of tau pathology will be an important topic for future study,” the authors wrote.
In a comment, Rohan de Silva and colleagues from University College London wrote that the data point to a central role for the SNP rs242557. The H1c, H1d, H1g, and H1o risk subtypes all carry its risk allele. In previous GWAS analysis, this and adjacent SNPs were the only ones that showed significant association with disease, when considered separately from other H1 or H2 variants. Years ago, the London group speculated that variants that increased expression of tau should contribute to neurodegenerative disease. Indeed, rs242557 appears to be a functional variant whose risk allele possibly boosts transcription of the MAPT gene, and particularly the four-repeat isoform of tau, which accumulates in PSP (Myers et al, 2005).
However, not all the subhaplotypes with the rs242557 A allele were linked to PSP in the current study, hinting that the story may be more complicated. “Our results indicate that the increased risk of PSP associated with the H1 haplotype is driven primarily by four to five specific H1 subhaplotypes, and taking into account haplotype structure gives the most precise understanding of how MAPT variation alters the risk of PSP,” the authors conclude.—Pat McCaffrey
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No Available Further Reading
- Heckman MG, Brennan RR, Labbé C, Soto AI, Koga S, DeTure MA, Murray ME, Petersen RC, Boeve BF, van Gerpen JA, Uitti RJ, Wszolek ZK, Rademakers R, Dickson DW, Ross OA. Association of MAPT Subhaplotypes With Risk of Progressive Supranuclear Palsy and Severity of Tau Pathology. JAMA Neurol. 2019 Jun 1;76(6):710-717. PubMed.