Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

Luke W Bonham,Iris Broce,Rahul S Desikan,Raffaele Ferrari,Zachary A Miller,John Hardy,Celeste M Karch,William W Seeley,Sergio E Baranzini,Patrick A Lewis ,Maria Luisa Gorno‐Tempini ,Parastoo Momeni,Christopher P Hess,Bruce L Miller,Natalie Wen ,Natasha Z.r Steele ,Claudia Manzoni,Ethan G Geier,Jennifer S Yokoyama

doi:10.1038/s41598-019-46415-1

Abstract

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.

Highlights

Frontotemporal lobar dementia (FTLD) is a heterogeneous family of progressive neurodegenerative disorders characterized by degeneration of the frontal and temporal lobes with corresponding clinical deficits in social processes, language, and executive functioning[1]
Our analyses revealed a polygenic network of 64 semantic variant of primary progressive aphasia (svPPA) risk genes which interact at the protein level
Many of these genes are differentially expressed in pathologically confirmed cases of frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions

Summary

Introduction

Frontotemporal lobar dementia (FTLD) is a heterogeneous family of progressive neurodegenerative disorders characterized by degeneration of the frontal and temporal lobes with corresponding clinical deficits in social processes, language, and executive functioning[1]. This observation is striking when compared to other forms of FTLD in which up to 40% of patients have a positive family history and there are many known, common genetic risk variants[1,7,8] This conundrum suggests, among other possibilities, that svPPA risk is more strongly influenced by environmental or developmental factors such as handedness[9] and/or that svPPA is by nature highly polygenic. Utilizing polygenic strategies to identify risk factors for svPPA presents a unique opportunity, as knowledge gleaned from these analyses could inform other forms of FTLD resulting from TDP-43 pathology

Methods

Results

Conclusion