| Title |
Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci
|
|---|---|
| Published in |
Acta Neuropathologica, April 2016
|
| DOI | 10.1007/s00401-016-1576-7 |
| Pubmed ID | |
| Authors |
Mariet Allen, Jeremy D. Burgess, Travis Ballard, Daniel Serie, Xue Wang, Curtis S. Younkin, Zhifu Sun, Naomi Kouri, Saurabh Baheti, Chen Wang, Minerva M. Carrasquillo, Thuy Nguyen, Sarah Lincoln, Kimberly Malphrus, Melissa Murray, Todd E. Golde, Nathan D. Price, Steven G. Younkin, Gerard D. Schellenberg, Yan Asmann, Tamas Ordog, Julia Crook, Dennis Dickson, Nilüfer Ertekin-Taner |
| Abstract |
To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3' region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci. |
X Demographics
The data shown below were collected from the profiles of 3 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 33% |
| France | 1 | 33% |
| Unknown | 1 | 33% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 3 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 65 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 1 | 2% |
| Unknown | 64 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 10 | 15% |
| Researcher | 10 | 15% |
| Student > Bachelor | 5 | 8% |
| Student > Doctoral Student | 4 | 6% |
| Professor > Associate Professor | 4 | 6% |
| Other | 13 | 20% |
| Unknown | 19 | 29% |
| Readers by discipline | Count | As % |
|---|---|---|
| Neuroscience | 13 | 20% |
| Biochemistry, Genetics and Molecular Biology | 9 | 14% |
| Medicine and Dentistry | 8 | 12% |
| Agricultural and Biological Sciences | 7 | 11% |
| Engineering | 2 | 3% |
| Other | 5 | 8% |
| Unknown | 21 | 32% |
Attention Score in Context
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#17,799,386
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Outputs from Acta Neuropathologica
#2,173
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Outputs of similar age from Acta Neuropathologica
#26
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