Determine the haplotype and cell type specific differences in gene regulation resulting from the H1/H2 inversion mediate risk for sporadic Tauopathies and differences in the effects of MAPT mutations in inherited forms of FTD

Understanding the pathophysiology of dementia is often confounded by the uncertain causal roles of observed pathological phenotypes, even when highly correlated with disease. Genetic findings overcome these limitations by providing a causal anchor from which to begin mechanistic studies. In this regard, the genetic association between 17q21.31 and increased risk for tauopathies, including Progressive Supranuclear Palsy (PSP), is well-established1–3, while dominant rare mutations in MAPT are causal for several Frontotemporal lobar degeneration (FTLD) disorders. Despite this well-replicated association, little is known regarding mechanisms driving the differences in risk between the two major haplotypes, H1 and H2. This is largely because this locus encompasses a genomic inversion of 970 KB, leading to a 1.5 Mb region where strong LD confounds the identification of causal variants and understanding of the gene regulatory mechanisms contributing to disease.

The overall goal of the CWOW is to use multi-omics and functional genomics CRISPR screens to understand the molecular and cellular differences in gene expression and cellular function as a consequence of the H1/H2 haplotype inversion, and the resulting effects on risk for sporadic and familial tauopathies, leading to novel therapeutic targets for treatment of tauopathies.

The center’s researchers aim to address three fundamental questions:

  1. What are the cell type-specific impact of H1/H2 haplotypes on 17q21.31 gene expression and regulation in human brain?
  2. What determines cell type specific impact of H1/H2 haplotypes on 17q21.31 gene expression and regulation in iPSC-derived neural cells?
  3. How can we integrate data across projects and compare with publicly available data to develop models of disease pathogenesis


We envision that our research will improve our understanding of the molecular mechanisms of genetic risk factor in sporadic and inherited forms of Frontotemporal dementias. We hope our findings will spur future work in neurodegenerative research and ultimately lead to therapies for these diseases.



Advancing research in Frontotemporal dementias with the ultimate goal of improving the lives of patients.


Integrating complementary and differing perspectives into our work.


Promoting diversity, inclusion and equity. Our research program studies both genetic risk in the context of European and African genetic ancestry.


Recognizing and empowering women in science.


Enabling rapid data sharing.

This research was supported by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, National Institutes of Health, grant U54NS123746.