Journal article
Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
PLoS medicine, Vol.15(1), e1002487
01/09/2018
DOI: 10.1371/journal.pmed.1002487
PMCID: PMC5760014
PMID: 29315334
Abstract
Converging 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.
Using 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 < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal.
We 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.
Details
- Title: Subtitle
- Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
- Creators
- Iris Broce - University of California, San FranciscoCeleste M Karch - Washington University in St. LouisNatalie Wen - Washington University in St. LouisChun C Fan - University of California, San DiegoYunpeng Wang - Oslo University HospitalChin Hong Tan - University of California, San FranciscoNaomi Kouri - Mayo Clinic in FloridaOwen A Ross - Mayo Clinic in FloridaGünter U Höglinger - German Center for Neurodegenerative DiseasesUlrich Muller - University of GiessenJohn Hardy - University College LondonParastoo Momeni - Texas Tech University Health Sciences CenterChristopher P Hess - University of California, San FranciscoWilliam P Dillon - University of California, San FranciscoZachary A Miller - University of California, San FranciscoLuke W Bonham - University of California, San FranciscoGil D Rabinovici - University of California, San FranciscoHoward J Rosen - University of California, San FranciscoGerard D Schellenberg - University of PennsylvaniaAndre Franke - Kiel UniversityTom H Karlsen - Oslo University HospitalJan H Veldink - University Medical Center UtrechtRaffaele Ferrari - University College LondonJennifer S Yokoyama - University of California, San FranciscoBruce L Miller - University of California, San FranciscoOle A Andreassen - University of OsloAnders M Dale - University of California, San DiegoRahul S Desikan - University of California, San FranciscoLeo P Sugrue - University of California, San FranciscoInternational FTD-Genomics ConsortiumTimothy Griffiths (Contributor) - Psychological and Brain Sciences
- Resource Type
- Journal article
- Publication Details
- PLoS medicine, Vol.15(1), e1002487
- DOI
- 10.1371/journal.pmed.1002487
- PMID
- 29315334
- PMCID
- PMC5760014
- ISSN
- 1549-1277
- eISSN
- 1549-1676
- Grant note
- P01 AG003991 / NIA NIH HHS MC_U105597119 / Medical Research Council K01 AG046374 / NIA NIH HHS K01 AG049152 / NIA NIH HHS U24 DA041123 / NIDA NIH HHS MC_U123160651 / Medical Research Council G0502157 / Medical Research Council P01 AG017586 / NIA NIH HHS P01 AG026276 / NIA NIH HHS P50 AG005681 / NIA NIH HHS G1100540 / Medical Research Council MC_U123160657 / Medical Research Council MC_UU_00005/12 / Medical Research Council G0400074 / Medical Research Council MC_UU_00024/9 / Medical Research Council G0900652 / Medical Research Council MC_UU_00024/1 / Medical Research Council
- Language
- English
- Date published
- 01/09/2018
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984627192502771
Metrics
4 Record Views