Overview

Pathogenicity: Progressive Supranuclear Palsy : Likely Pathogenic, Corticobasal Degeneration : Likely Pathogenic, Frontotemporal Dementia : Likely Pathogenic, Alzheimer's Disease : Not Classified, Parkinson's Disease : Not Classified
Position: (GRCh38/hg38):Chr17:45942346 G>A
Position: (GRCh37/hg19):Chr17:44019712 G>A
dbSNP ID: rs242557
Coding/Non-Coding: Non-Coding
DNA Change: Allele
Expected RNA Consequence: Allele
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Intron 1

Findings

This common intronic variant lies between the core promoter region of MAPT and the first coding exon. The A allele is found in the MAPT H1, but not H2, haplotype. More specifically, c.-17-19976 is part of the common H1c subhaplotype, for which it is sometimes used as a tag. Both H1c and c.-17-19976A are associated with an elevated risk of progressive supranuclear palsy, and possibly other primary tauopathies (see table below). Although some studies indicate c.-17-19976G>A may modify MAPT transcription and/or splicing (see Biological Effects below), these findings remain inconclusive and the degree to which other variants inherited with c.-17-19976G>A underlie or contribute to disease risk is unknown. Associations with other neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), have been examined, but results have been negative or inconsistent. 

The variant’s global frequency in gnomAD was 0.36, with the highest frequency in East Asians (0.56), in which G, rather than A is the minor allele, and lowest in Ashkenazi Jews (0.29) (gnomAD v4.1.0, Jul 2024). 

Progressive supranuclear palsy (PSP) | Other primary tauopathies | Alzheimer’s disease (AD) | Parkinson’s disease (PD) | Non-neurological effects | Biological effects

Progressive supranuclear palsy (PSP)
The A allele of c.-17-19976G>A is associated with an increased risk of PSP, at least in individuals of European ancestry (see table below). In addition to being a component of the H1c subhaplotype, it is part of the less common H1d, H1g, and H1o subhaplotypes—all associated with elevated PSP risk.

However, c.-17-19976G>A does not account for PSP-subhaplotype associations completely (Rademakers et al., 2005; Pittman et al., 2005; Höglinger et al., 2011; Jun 2011 news). A case-control study including 802 pathologically-confirmed PSP cases helped clarify this issue by showing that not all subhaplotypes with the A allele were linked to PSP (H1m), and conversely, three subhaplotypes that included the G allele (H1b, H1h, and H1r) were more frequent in PSP patients than controls (Heckman et al., 2019; Mar 2019 news). The authors suggested that associations observed for c.-17-19976G>A may be mostly driven by the H1c and H1d haplotypes.

Interestingly, copy numbers of duplications in the MAPT chromosomal region that affect chromosomal structure (α, β, and γ) may also shape how different subhaplotypes influence PSP risk. As reported in a preprint, the proportion of MAPT subhaplotypes associated with increased risk of PSP rose from 34 percent in a haplotype containing single β and γ sequences (H1β1γ1) to 77 percent in a haplotype with four γ duplications (H1β1γ4) (Wang et al., 2024).

Several studies have examined c.-17-19976G>A’s effects on the expression of PSP phenotypes, including neuropathological features, age at onset, and cognitive function. For example, the A allele was found to be associated with more severe PSP pathology, including phosphorylated tau-immunoreactive coiled bodies (Allen et al., 2016; Kouri et al., 2021) and tufted astrocytes (Allen et al., 2016). In addition, Rademakers and colleagues found the PSP association to be strongest in young patients, with the odds ratio approximately doubling with a reduction of 10 years in age (Rademakers et al., 2005). However, a joint analysis of PSP and corticobasal degeneration (CBD) cases did not identify an association of the variant with age at onset (Myers et al., 2007).  Surprisingly, one study found that PSP patients carrying the c.-17-19976A allele performed better than non-carriers on tests of general cognition, executive function, and attention (Gerstenecker et al., 2017). The authors hypothesized that c.-17-19976G>A’s effects may vary between PSP subtypes.

Other primary tauopathies
Several studies have also identified associations between c.-17-19976G>A and CBD (see table below). The link was first reported in a U.S. study of 44 pathologically confirmed CBD cases (Pittman et al., 2005), and subsequently confirmed in a study of 16 Spanish patients (Cruchaga et al., 2009). Several years later, a study including 219 pathologically confirmed cases and 3,750 controls from the U.S., also identified an association with CBD, but it was considered only “nominally significant” (Kouri et al., 2015). A more recent study, including 230 neuropathologically confirmed cases and 1,312 controls, suggests a situation similar to that of PSP in which associations are not consistent across H1 subhaplotypes (Valentino et al., 2024). The H1c and H1d subhaplotypes, which carry the c.-17-19976A allele, were associated with increased risk for CBD, but so was the H1b subhaplotype which carries the G allele.

The c.-17-19976G>A variant was also found to be associated with frontotemporal dementia (FTD), as revealed by a genome-wide analysis of 3,756 patients with sporadic FTD and 11,233 controls in which c.-17-19976G>A was used to tag the H1c suhaplotype (Manzoni et al., 2024). In contrast, no significant association was found between c.-17-19976G>A and the risk of Pick’s disease (Valentino et al., 2024).

Alzheimer’s disease (AD)
Studies examining the association of c.-17-19976G>A with AD risk have yielded mixed results, with most studies of large cohorts indicating no association (see table below). A study including 8,507 European-American AD cases and 9,835 controls, for example, failed to detect a significant association after individual analyses of two cohorts, as well as joint analysis of both (Allen et al., 2014). Also of note, the research group that originally reported associations of AD with both the H1c subhaplotype and specifically c.-17-19976G>A (Myers et al., 2005) did not replicate the c.-17-19976G>A finding in a different cohort, and analysis of both cohorts together also yielded negative results (Myers et al., 2007).  Furthermore, a study that used two haplotype analysis tools to replicate results from Myers and colleagues concluded neither c.-17-19976G>A nor the H1c subhaplotype have a causal role in the pathogenesis of late-onset AD (Mukherjee et al., 2007). A meta-analysis of 12 studies also failed to reveal a significant association, both before and after stratifying by ancestry (Zhang et al., 2017).

A meta-analysis of six studies including 1,877 AD patients and 1,699 controls of Caucasian ancestry is among the few studies that has identified a positive association between c.-17-19976G>A and AD (Yuan et al., 2018). However, only the comparison of genotypes GG vs. GA+AA yielded a positive association, while analyses of GG+GA vs. AA, GG vs. AA, GG vs. GA, and GA vs. AA failed to reach statistical significance (allelic associations were not reported). Another study, of a Chinese Han cohort, reported a positive association, but it found the G allele, rather than the A allele, to be associated with AD (Liu et al., 2013). In this population, the G allele is the minor allele.

Although some studies have suggested the APOE4 allele is an important modifier of c.-17-19976G>A-mediated AD risk, results have been inconsistent. For example, one study identified a significant association between c.-17-19976A and AD only in APOE4 non-carriers (Myers et al., 2005), while two other studies identified an association only in APOE4 carriers (Abraham et al., 2009; Zhou and Wang 2017), with Abraham and colleagues' findings failing to survive correction for multiple comparisons (Abraham et al., 2009). A fourth study, in Chinese Han individuals, found significant associations with the G allele in both APOE4 carriers and non-carriers with a stronger association in APOE4 carriers (Liu et al., 2013).   
Associations involving the H1c haplotype and AD have been mixed as well. Myers and colleagues reported an association with AD (Myers et al., 2005; Myers et al., 2007), but others have not observed a significant link (e.g., Seto-Salvia 2011 21403021; Mukherjee et al., 2007; Abraham et al., 2009; Sánchez-Juan et al., 2019). The larger of these negative studies, including 4,124 Spanish AD cases and 3,290 controls, found the H1c subhaplotype to be nominally associated with AD risk, but the association failed to reach statistical significance after adjusting by population sub-structure (Sánchez-Juan et al., 2019).

Reports of associations between c.-17-19976G>A and AD endophenotypes have also yielded unclear results. A study including approximately 517 brain samples of AD patients from the U.S. found no association between the variant and AD pathology (Wider et al., 2012). A smaller study of AD cerebrospinal fluid (CSF) biomarkers in a Croatian cohort (113 AD patients), also failed to identify an association (Leko et al., 2018). However, a dose-dependent effect of c.-17-19976G>A on CSF tau levels was reported in another small Caucasian cohort (89 cases and controls; trend model: P=0.002, uncorrected; Laws et al., 2007). Also, two studies of cognitively healthy individuals suggested c.-17-19976A-associated phenotypes in brain regions vulnerable to AD: variations in cortical morphology in young healthy adults (Huang et al., 2023) and tau deposition in the hippocampi of non-demented elders (Shen et al., 2019).

Parkinson’s disease (PD)
c.-17-19976G>A does not appear to be an important contributor to PD risk (see table below) or PD endophenotypes. Indeed, the authors of a large study of the GEO-PD consortium concluded that the association they identified—not statistically significant after correction for multiple testing—was likely due to c.-17-19976G>A being in linkage disequilibrium with the causal variant rs1052553 (Elbaz et al., 2011).  Moreover, another study, including 1,218 Caucasian PD patients and 1,401 controls, also found no effect of c.-17-19976G>A on PD risk (Wider et al., 2010).

The few reports that have found significant associations involved moderate effects (see table below). For example, the authors of one meta-analysis study concluded c.-17-19976G>A was only “mildly associated” with PD risk in Caucasians (Zhang et al., 2017), while another detected a moderately significant association only when applying a genotypic recessive model in Caucasian (p=0.049) and Asian (p=0.046) populations (Chen et al., 2015). As shown in the table, allelic associations did not reach significance in this study. Moreover, an earlier study, using small cohorts, identified a weak association in the Finnish, but not the Greek or Taiwanese groups (Fung et al., 2006).

The association of PD with c.-17-19976G>A in the context of a subhaplotype is also unclear. De Silva and colleagues, for example, found no association between PD and the H1c haplotype (Vandrovcova et al., 2009). On the other hand, Tolosa and co-workers reported an H1 subhaplotype carrying the G allele as increased in PD (Ezquerra et al., 2011).

Regarding endophenotypes, c.-17-19976G>A was not associated with Lewy body pathology in evaluations of Caucasian PD autopsies (Wider et al., 2012), nor with PD age at onset in a Chinse cohort (Huang et al., 2015). Moreover, in a study assessing cognitive decline in PD, an association with the MAPT H1c subhaplotype was reported, but it did not reach statistical significance (Wang et al., 2016).

Non-neurological effects
Several studies have identified associations of c.-17-19976G>A with cardiac arrythmia, although effect sizes were small (GWAS Catalog www.ebi.ac.uk/gwas/variants/rs242557, Aug 2024). A multi-ethnic genome-wide association study (GWAS) including over 500,000 participants revealed an association with atrial fibrillation (G allele: OR=1.04, CI=1.03-1.06, p=4x10^-9; Roselli et al., 2018), as did a GWAS of over 77,000 individuals of European ancestry (A allele: β=0.041 unit decrease, p=2x10^-11; Miyazawa et al., 2023). A third GWAS, including over 200,000 Japanese individuals, identified an association with cardiac arrythmia of unspecified type (A allele: OR=0.94 [CI=0.92-0.96], p=1x10^-8; Ishigaki et al., 2020). Moreover, a study that intergrated data from GWAS, expression quantitative trait loci, and RNA/ATAC sequencing, identified c.-17-19976G>A as a candidate causal variant of atrial fibrillation (Leblanc et al., 2024).

Biological effect
c.-17-19976G>A lies within an evolutionarily conserved region 47kb downstream of the MAPT core promoter and 19 kb upstream of the first coding exon (Myers et al., 2007). It may be a functional variant, with the A allele boosting MAPT transcription and/or altering RNA splicing, but not all studies have detected significant effects.

In plasma, two GWASs identified significant associations between elevated tau levels and c.-17-19976A (Chen et al., 2017; Sarnowski et al., 2022). The larger of the two included nearly 15,000 individuals of European ancestry (β=0.2 unit increase, CI=0.18-0.22 p=9x10^-143; Sarnowski et al., 2022).

Whether c.-17-19976A is associated with elevated tau levels in brain remains unclear. PCR analysis of post-mortem brain tissue from 88 Caucasians revealed a 3- to 4-fold increase in total transcript expression in both AD cases and controls that were H1c homozygotes compared with all other genotypes (Myers et al., 2007). Moreover, an expression GWAS (eGWAS) of tissue from 399 brains of Caucasians with various brain pathologies found significant increases in cerebellum and temporal cortex (Zou et al., 2012). However, in a follow-up study, the same group failed to identify significant associations between the H1c subhaplotype and brain tau levels, although they observed “suggestive associations” with c.-17-19976G>A that varied depending on the sequence of the probes used to detect MAPT mRNA (Allen et al., 2014). In addition, two studies using c.-17-19976G>A to tag the H1c haplotype—one examining post-mortem samples from 222 H1/H1 individuals (Trabzuni 2012) and the other from 39 H1/H2 individuals (Hayesmoore et al., 2009)—found no significant associations.

Several studies using cell-based reporter assays have identified c.-17-19976G>A-mediated effects on transcription. An early study using a luciferase reporter system showed that a 182-bp conserved binding site for transcription factors that includes c.-17-19976G>A, differentially influenced expression depending on the c.-17-19976G>A allele (Rademakers et al., 2005). A subsequent study, testing transcription of various constructs including the MAPT promoter along with upstream and downstream sequences in multiple cell types, concluded that the A allele of c.-17-19976G>A, in the context of subhaplotype H1c, was a key contributor to high MAPT promoter activity (Myers et al., 2007). A follow-up study from the same group identified proteins that bound to transcriptional repressor Region C, a conserved domain including c.-17-19976G>A (Anaya et al., 2011).

However, a global survey of gene expression across the brain found no evidence of c.-17-19976G>A affecting MAPT expression (Höglinger et al., 2011; June 2011 news). The authors identified several single nucleotide polymorphisms in the MAPT locus associated with the gene’s expression, but the associations did not survive correction for the H1/H2 inversion.

Studies that have examined whether c.-17-19976G>A affects the relative levels of spliced tau isoforms have yielded inconsistent results. Although Myers and colleagues found H1c homozygote brains had a large elevation of 4-repeat containing transcripts, which encode the tau isoform that accumulates in PSP, the sample size was small and results were highly variable (Myers et al., 2007). Another small study including 26 PSP cases and 53 controls also yielded inconsistent results (Majounie et al., 2013).

Of note, c.-17-19976G>A, or other variants inherited with c.-17-19976G>A, may affect the expression of genes beyond MAPT. For example, one study identified associations between c.-17-19976G>A and expression levels, as well as methylation patterns, of ADP-ribosylation factor-like (ARF-like) ARL17A and ARL17B (Allen et al., 2016). These two genes encode proteins involved in regulating membrane trafficking and vesicular transport.

This variant’s PHRED-scaled CADD score (19.90), which integrates diverse information in silico, nearly reached 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Aug 2024).

Table

Allelic Associations between c.-17-19976G>A and Neurodegenerative Disorders

Progressive Supranuclear Palsy

^a Meta-analysis
^b controlled for H1/H2
^c pathologically confirmed / predominantly confirmed

Other Primary Taupathies

^a Meta-analysis
^c pathologically confirmed / predominantly confirmed
^d described as “nominally significant” by authors

Alzheimer's Disease

^a Meta-analysis

Parkinson's Disease

^a Meta-analysis

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References

News Citations

1. GWAS Fingers Tau and Other Genes for Parkinsonian Tauopathy 24 Jun 2011
2. Unequal: Some Tau Haplotypes Carry More Risk Than Others 22 Mar 2019

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External Citations

1. Wider et al., 2010

Further Reading