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

Abstract

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 < 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.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.

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

“…Manhattan plots were constructed based on the ranking of conjunction FDR to illustrate the genomic location of the pleiotropic loci. In all analyses, we controlled for the effects of genomic inflation using intergenic SNPs (see Supplemental and previous reports for additional details [2, 5, 8, 12, 13, 19]).…”

Lipid associated polygenic enrichment in Alzheimer’s disease

“…We evaluated whether there is pleiotropic enrichment in AD as a function of each of the seven CV RFs (see Supplemental Information). These validated methods have been described previously [2,3,6,16,44]. Briefly, for given associated phenotypes A (e.g.…”

“…To account for large blocks of linkage disequilibrium (LD) that may result in spurious genetic enrichment, we applied a random pruning approach, where one random SNP per LD block (defined by an r 2 of 0.8) was used and averaged over 200 random pruning runs. Given prior evidence that several genetic variants within the human leukocyte antigen (HLA) region on chromosome 6 [38,44], microtubule-associated tau protein (MAPT) region on chromosome 17 [9] and the APOE region on chromosome 19 [10] are associated with increased AD risk, one concern is that random pruning may not sufficiently account for these large LD blocks resulting in artificially inflated genetic enrichment [6]. To better account for these large LD blocks, in our genetic enrichment analyses, we removed all SNPs in LD with r 2 > 0.2 within 1Mb of HLA, MAPT and APOE variants (based on 1000 Genomes Project LD structure).…”

Common neurodegeneration-associated proteins are physiologically expressed by antigen-presenting cells and are interconnected via the inflammation/autophagy-related proteins TRAF6 and SQSTM1

“…Extending the functional results mentioned above, genome-wide association studies (GWAS) have unraveled the central position of autoimmunity-related genes in the genetic susceptibility landscape of neurodegenerative diseases (14)(15)(16)(17)(18)(19). This is notably the case for HLA-DRB1 alleles which were recently demonstrated to confer increased risks of developing PD (15) or late-onset AD (14).…”