Objective: To determine how tau network genes overlap with single nucleotide polymorphisms (SNPs) associated with Progressive Supranuclear Palsy (PSP) in a Genome Wide Association Study (GWAS)¹.

Background: PSP is a neurodegenerative tauopathy marked by postural instability resulting in falls, supranuclear ophthalmoparesis, and frontal lobe dysfunction. PSP genetic risk includes microtubule-associated protein tau (MAPT) and possibly genes such as Syntaxin 6 identified in a GWAS. As the genetic risks of PSP are not clearly elucidated, investigating gene networks associated with tau dysfunction could uncover specific PSP genetic risk factors.

Methods: Summary statistics from a previous PSP GWAS¹ were obtained. SNPs from the PSP GWAS were associated to genes using Ensembl. Gene networks associated with tau dysfunction were developed using mRNA gene expression in mice with a highly penetrant tau mutation. mRNA was collected from mouse brain tissue. Tau networks were developed via Weighted Gene Co-expression Network Analysis. Mouse tau network genes were represented as human gene homologs. The over-representation of tau network genes among significant SNP associated genes from the GWAS was analyzed with the Fisher exact test.

Results: Twenty percent (2,327) of the genes from the mice with the highly penetrant tau mutation were determined to be involved in a tau network. Sixteen of the most significant SNPs from the GWAS (p-value less than 6.2×10^-4) were associated with 10 unique genes. Of these 10 genes, 7 were tau network genes (OR 8.8 [2.0-52], p-value 0.001). The most significant SNP was associated with NSF, a gene involved in Golgi vesicle transport. NSF is on the 17q21 chromosome region. MAPT is on this region as well. NSF was a candidate gene for a GWAS of Parkinson’s disease in an Ashkenazi Jewish population. TNXB was also a significant SNP associated gene from the tau network. It is an extracellular matrix glycoprotein with anti-adhesive effects. A transcriptomic study² associated TNXB with Alzheimer’s disease, another tauopathy.

Conclusions: Tau network genes show statistically significant over-representation among SNPs highly correlated with PSP in a GWAS. These genes, including NSF and TNXB, have been associated with Parkinson’s disease and Alzheimer’s disease.

References: 1. Cantwell, L. B. et al., with Höglinger, G. U., PSP Genetics Study Group. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet. 43, 699–705 (2011).

2. Chapuis, J. et al., Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer’s disease. Mol Psychiatry. 14(11), 1104-16 (2009).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tau-network-genes-in-a-genome-wide-association-study-of-progressive-supranuclear-palsy/