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A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression

Michael D. Gallagher, Marijan Posavi, Peng Huang, Travis L. Unger, Yosef Berlyand, Analise L. Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D. Wells, Struan F.A. Grant, Gerd A. Blobel, Christopher D. Brown, View ORCID ProfileAlice S. Chen-Plotkin
doi: https://doi.org/10.1101/154989
Michael D. Gallagher
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Marijan Posavi
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Peng Huang
2Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Travis L. Unger
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Yosef Berlyand
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Analise L. Gruenewald
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Alessandra Chesi
3Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Elisabetta Manduchi
3Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
4Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA
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Andrew D. Wells
5Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Struan F.A. Grant
2Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
3Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
6Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
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Gerd A. Blobel
2Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Christopher D. Brown
6Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
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Alice S. Chen-Plotkin
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • ORCID record for Alice S. Chen-Plotkin
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ABSTRACT

Neurodegenerative diseases pose an extraordinary threat to the world’s aging population, yet no disease-modifying therapies are available. While genome-wide association studies (GWAS) have identified hundreds of novel risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Indeed, of the many thousands of SNP-trait associations identified by GWAS over the past ~10 years, very few are understood mechanistically. Here, we investigate the association of common genetic variants at the 7p21 locus with risk for the neurodegenerative disease frontotemporal lobar degeneration. We show that variants associated with disease risk correlate with increased brain expression of the 7p21 gene TMEM106B, and no other genes. Furthermore, incremental increases in TMEM106B levels result in incremental increases in lysosomal phenotypes and cell toxicity. We then combine fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, which differentially recruits CTCF, influencing CTCF-mediated long-range chromatin looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWAS to frontotemporal lobar degeneration, nominating a causal variant and a causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk for neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in brain CTCF-binding sites genome-wide, implicating CTCF-mediated gene regulation in risk for neurodegeneration more generally.

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Posted June 24, 2017.
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A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression
Michael D. Gallagher, Marijan Posavi, Peng Huang, Travis L. Unger, Yosef Berlyand, Analise L. Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D. Wells, Struan F.A. Grant, Gerd A. Blobel, Christopher D. Brown, Alice S. Chen-Plotkin
bioRxiv 154989; doi: https://doi.org/10.1101/154989
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A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression
Michael D. Gallagher, Marijan Posavi, Peng Huang, Travis L. Unger, Yosef Berlyand, Analise L. Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D. Wells, Struan F.A. Grant, Gerd A. Blobel, Christopher D. Brown, Alice S. Chen-Plotkin
bioRxiv 154989; doi: https://doi.org/10.1101/154989

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