PLoS Medicine (Jan 2018)

Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.

  • Iris Broce,
  • Celeste M Karch,
  • Natalie Wen,
  • Chun C Fan,
  • Yunpeng Wang,
  • Chin Hong Tan,
  • Naomi Kouri,
  • Owen A Ross,
  • Günter U Höglinger,
  • Ulrich Muller,
  • John Hardy,
  • International FTD-Genomics Consortium,
  • Parastoo Momeni,
  • Christopher P Hess,
  • William P Dillon,
  • Zachary A Miller,
  • Luke W Bonham,
  • Gil D Rabinovici,
  • Howard J Rosen,
  • Gerard D Schellenberg,
  • Andre Franke,
  • Tom H Karlsen,
  • Jan H Veldink,
  • Raffaele Ferrari,
  • Jennifer S Yokoyama,
  • Bruce L Miller,
  • Ole A Andreassen,
  • Anders M Dale,
  • Rahul S Desikan,
  • Leo P Sugrue

DOI
https://doi.org/10.1371/journal.pmed.1002487
Journal volume & issue
Vol. 15, no. 1
p. e1002487

Abstract

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BackgroundConverging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.Methods and findingsUsing large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate ConclusionsWe show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.