The tau H2 haplotype is almost exclusively Caucasian in origin

doi:10.1016/j.neulet.2004.05.119

Neuroscience Letters

Volume 369, Issue 3, 21 October 2004, Pages 183-185

https://doi.org/10.1016/j.neulet.2004.05.119 Get rights and content

Abstract

We have assessed the distribution of the tau H1/H2 haplotype in the publicly available reference series of samples with representatives of most racial groups. This analysis shows that the H2 haplotype is probably exclusively Caucasian in origin and its marginal occurrence in other racial groups is likely to reflect admixture. We discuss this observation in terms of the origin of the H2 haplotype and the epidemiology of the tauopathies.

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Cited by (100)

Genetics of progressive supranuclear palsy in a Chinese population
2022, Neurobiology of Disease
Citation Excerpt :
In our cohort, the MAPT haplotypes of the patients with PSP were all H1/H1. The Caucasian population is almost completely H2, whereas the frequency of the H2 haplotype in the East Asian population is close to zero (Evans et al., 2004). Our results confirmed this finding.
Genetics plays an important role in progressive supranuclear palsy (PSP) and remains poorly understood. A detailed literature search identified 19 PSP-associated genes: MAPT, LRRK2, LRP10, DCTN1, GRN, NPC1, PARK, TARDBP, TBK1, BSN, GBA, STX6, EIF2AK3, MOBP, DUSP10, SLCO1A2, RUNX2, CXCR4, and APOE. To date, genetic studies on PSP have focused on Caucasian population. The gaps in PSP genetic study on East Asian populations need to be filled.
Exon and flanking regions of the PSP-associated genes were sequenced in 104 patients with PSP and 488 healthy controls. Common variant-based association analysis and gene-based association tests of rare variants were performed using PLINK 1.9 and the sequence kernel association test-optimal, respectively. Additionally, the association of APOE and MAPT genotypes with PSP was evaluated. The above association analyses were repeated among probable PSP patients. Finally, PLINK 1.9 was used to test variants associated with the onset age of PSP.
A rare non-pathogenic variant of MAPT (c.425C > T,p.A142V) was detected in a PSP patient. No common variants were significantly associated with PSP. In both the rare-variant and the rare-damaging-variant groups, the combined effect for GBA reached statistical significance (p = 1.43 × 10⁻³, p = 4.98 × 10⁻⁴). The result between APOE, MAPT genotypes and PSP risk were inconsistent across all PSP group and probably PSP group.
The pathogenic variant in MAPT were uncommon in PSP patients. Moreover, GBA gene was likely to increase the risk of PSP, and GBA-associated diseases were beyond α-synucleinopathies. The association between APOE, MAPT and PSP is still unclear among the non-Caucasian population.
Comparing fluid biomarkers of Alzheimer's disease between African American or Black African and white groups: A systematic review and meta-analysis
2021, Journal of the Neurological Sciences
Citation Excerpt :
Other explanations for the observed differences in levels of CSF tau may arise from knowledge of genetics. For example, in a study of the gene encoding microtubule associated protein tau (MAPT), it was found that the H2 haplotype appeared to exist exclusively amongst those who were white in origin, and rare in African, Asian or Native American populations [29]. To this end, it has also been observed that genetic variation of MAPT influences CSF tau levels and expression of tau mRNA, however, the effect is observed only with Aβ deposition [53].
Biomarker research for Alzheimer's disease (AD) has grown rapidly in recent years, ensuing the integration of the AD fluid biomarker profile: Aβ1-42, t-tau, and p-tau₁₈₁, into clinical and research criteria. However, current insights of AD arise almost exclusively from studies on white individuals. Some studies have revealed that epidemiology, clinical features, and genetics of AD show variations between individuals from black and white backgrounds, conveying the importance of ethnoracial differences, and the possibility of such differences also influencing AD biomarker levels. This systematic review explored whether AD fluid biomarker levels differ between African American (AA) or Black African and white groups.
To compare AD fluid biomarkers (Aβ1-42, p-tau₁₈₁, and t-tau) levels between AA or Black Africans and white individuals.
PubMed, Scopus, and other sources were explored for studies that quantified AD biomarkers in biological fluid from whites and AA or Black African groups. Meta-analyses were performed to find the standardized mean difference for biomarkers that were quantified in ≥3 studies.
Five studies were included; studies on Black Africans were not found. The meta-analyses found CSF t-tau and p-tau₁₈₁ were consistently lower in AA than white individuals, in samples with normal cognition or with mild cognitive impairment/dementia.
The meta-analyses found significant differences for CSF tau between AA and white individuals with normal cognition and within the dementia spectrum, expressing the importance of taking into account ethnoracial factors when interpreting CSF AD biomarkers levels. However, the generalisability of these differences is restricted by small samples' size, lack of unified methodologies and recruitment's biases within studies; further large multicentre studies with harmonized protocols and sufficient power are imperative to investigate the extent of ethnoracial differences across the spectrum of cognitive decline, with vaster efforts necessary to diversify recruitment.
Screening non-MAPT genes of the Chr17q21 H1 haplotype in Parkinson's disease
2020, Parkinsonism and Related Disorders
The microtubule-associated protein tau (MAPT) gene is considered a strong genetic risk factor for Parkinson's disease (PD) in Caucasians. MAPT is located within an inversion region of high linkage disequilibrium designated as H1 and H2 haplotype, and contains eight other genes which have been implicated in neurodegeneration. The aim of the current study was to identify common coding variants in strong linkage disequilibrium (LD) within the associated loci on chr17q21 harboring MAPT.
Sanger sequencing of coding exons in 90 Caucasian late-onset PD (LOPD) patients was performed. Specific gene sequencing for LRRC37A, LRRC37A2, ARL17A and ARL17B was not possible given the high homology, presence of pseudogenes and copy number variants that are in the region, and therefore four genes (NSF, KANSL1, SPPL2C, and CRHR1) were included in the analysis. Coding variants from these four genes that did not perfectly tag (r² = 1) the MAPT H1/H2 haplotype were genotyped in an independent replication series of Caucasian PD cases (N = 851) and controls (N = 730).
In the 90 LOPD cases we identified 30 coding variants. Eleven non-synonymous variants tagged the MAPT H1/H2 haplotype, including two SPPL2C variants (rs12185233 and rs12373123) that had high pathogenic combined annotation dependent depletion (CADD) scores of >20. In the replication series, the non-synonymous KANSL1 rs17585974 variant was in very strong LD with MAPT H1/H2 and had a high CADD score of 24.7.
We have identified several non-synonymous variants across neighboring genes of MAPT that may warrant further genetic and functional investigation within the biological etiology of PD.
Interaction of APOE4 alleles and PET tau imaging in former contact sport athletes
2020, NeuroImage: Clinical
Citation Excerpt :
Earlier studies reported that African Americans and Hispanics have an increased frequency of AD regardless of their APOE genotype, however the most recent literature showed that APOE4 has a weak association with AD incidence amongst African Americans and Hispanics, in comparison to white populations [Tang et al., 11, Blue et al., 2019, Rajabli et al., 2018, Yu et al., 2017, KB Rajan et al., 2019]. With regards to MAPT, the H2 haplotype was reported to be almost exclusively Caucasian in origin [Evans et al., 21]. Finally, the use of cerebellar grey matter as a PET reference region has been widely studied and established for use in AD, but not in concussion.
Genetic polymorphisms like apolipoprotein E (APOE) and microtubule-associated protein tau (MAPT) genes increase the risk of neurodegeneration.
38 former players (age 52.63±14.02) of contact sports underwent neuroimaging, biofluid collection, and comprehensive neuropsychological assessment. The [F-18]AV-1451 tracer signal was compared in the cortical grey matter between APOE4 allele carriers and non-carriers as well as carriers of MAPT H1H1 vs non-H1H1. Participants were then divided into the high (N = 13) and low (N = 13) groups based on cortical PET tau standard uptake value ratios (SUVRs) for comparison.
Cortical grey matter PET tau SUVR values were significantly higher in APOE4 carriers compared to non-carriers (p = 0.020). In contrast, there was no significant difference in SUVR between MAPT H1H1 vs non-H1H1 carrier genes (p = 1.00). There was a significantly higher APOE4 allele frequency in the high cortical grey matter PET tau group, comparing to low cortical grey matter PET tau group (p = 0.048). No significant difference in neuropsychological function was found between APOE4 allele carriers and non-carriers.
There is an association between higher cortical grey matter tau burden as seen with [F-18]AV-1451 PET tracer SUVR, and the APOE4 allele in former professional and semi-professional players at high risk of concussions. APOE4 allele may be a risk factor for tau accumulation in former contact sports athletes at high risk of neurodegeneration.
Toronto General and Western Hospital Foundations; Weston Brain Institute; Canadian Consortium on Neurodegeneration in ageing; Krembil Research Institute. There was no role of the funders in this study.
Analysis of frontotemporal dementia, amyotrophic lateral sclerosis, and other dementia-related genes in 107 Korean patients with frontotemporal dementia
2018, Neurobiology of Aging
Citation Excerpt :
The C9orf72 repeat expansion has been reported to be the most common genetic cause of familial or sporadic ALS-FTD, ALS, and FTD in North Americans, Europeans, and Australians but is rare or absent in Asian populations (DeJesus-Hernandez et al., 2011; Majounie et al., 2012). All participants in this study had an H1/H1 tau haplotype, consistent with previous reports on ethnic variations of the tau genotype showing no H2 alleles in the East Asian population (Evans et al., 2004). Blauwendraat et al. (2018) recently found 24 pathogenic or likely pathogenic variants involving 10 distinct genes and 63 VUS in 121 subjects of Caucasian ancestry with FTD by using an unbiased combined sequencing approach.
To identify pathogenic variants in 107 Korean patients with sporadic frontotemporal dementia (FTD), 46 genes related to FTD, amyotrophic lateral sclerosis, and other dementias were screened by next-generation sequencing. Hexanucleotide repeats in C9orf72 gene were also tested by repeat-primed polymerase chain reaction. Next-generation sequencing revealed one known pathogenic variant (c.708+1G>A) in the GRN gene in a patient with behavioral variant FTD (bvFTD). In addition, a novel in-frame deletion (c.2675_2683del) in the CSF1R gene was identified in a patient with bvFTD who had severe bifrontal atrophy with frontal subcortical white matter changes. Novel compound heterozygous variants in the AARS2 gene, c.1040+1G>A and c.636G>A (p.Met212Ile), were found in a patient with bvFTD. Forty-six variants of uncertain significance were detected in other patients. None of the patients had expanded hexanucleotide repeats in C9orf72. These results show that pathogenic variants of known FTD genes are rare in Korean FTD patients but the CSF1R and AARS2 genes should be screened for a genetic diagnosis of FTD or other dementias.
The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes
2024, Alzheimer's and Dementia

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View full text

The tau H2 haplotype is almost exclusively Caucasian in origin

Abstract

Neurosci. Lett.

Neurosci. Lett.

Association of an extended haplotype in the tau gene with progressive supranuclear palsy

Hum. Mol. Genet.

A human genome diversity cell line panel

Science

Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD

Neurology

Amyotrophic lateral sclerosis, Parkinson's disease, and the amyotrophic lateral sclerosis–Parkinsonism–dementia complex on Guam: a review and summary of attempts to demonstrate infection as the aetiology

J. Clin. Pathol. Suppl. (R. Coll. Pathol.)