Genetic risk factors for sporadic frontotemporal dementia

Abstract

Frontotemporal dementia (FTD) is a complex multifactorial disorder characterized by heterogeneous clinical, pathological and genetic features. FTD is subdivided in familial and sporadic on the basis of the form of inheritance: familial (or Mendelian) cases are those defined by a family history of FTD or closely related neurodegenerative disorders, whilst sporadic cases are those where a family history is not evident. Families are genetically studied to identify genes or genetic markers segregating with (and strongly contributing to) disease through strategies that developed from positional cloning, linkage studies to more recently family-focused whole exome sequencing (WES) approaches. The study of the idiopathic cases is less straightforward: here, besides screening the known candidate (Mendelian) genes (that generally are extremely rare in sporadic cases), the currently most cost-effective strategy is to perform genome-wide association studies (GWAS) to highlight risk-loci. These then need to be further genetically and functionally characterize through, for example, targeted re-sequencing and expression quantitative trait loci (eQTL), to name a few methods. This chapter focuses on the current status of our genetic understanding of sporadic FTD thanks to the GWAS type of approach. This is followed by conclusive critical remarks on the ways ahead, driven by ever-advancing technologies and integrative strategies, for the dissection of complex disorders, including FTD.