Parkinson Disease and Autoimmune Disorders—What Can We Learn From Genome-wide Pleiotropy?

Abstract

Although autoimmune disorders are not widely associated with Parkinson disease (PD), there is increasing evidence for a link between immunity and neurodegenerative disorders. 1 Indeed, innate immunity and adaptive immunity have been implicated in neurodegenerative disorders. One of the more provocative examples is TREM2, a member of the immunoglobulin receptor superfamily expressed in microglia and tissue macrophages, which has gene variants that are linked to an increased risk of Alzheimer disease. 2,3 Other TREM2 variants are linked to the development of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, a dementia associated with bone cystic lesions. 4 Another example with less clear biological significance is the reproducible genetic association between a single-nucleotide polymorphism (SNP) in the MAPT locus and type 1 diabetes. 5 The study by Witoelar et al 6 in this issue of JAMA Neurology provides additional data to support this link. By leveraging existing data sets from genome-wide association studies (GWAS) in PD, as well as from 7 autoimmune disorders, they searched for SNPs in genes that might work in a common genetic pathway in both PD and autoimmune disorders. The authors applied conditional and conjunctional false discovery rate analyses on independent GWAS from PD and the autoimmune disorders, including type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. This method takes advantage of the concept of pleiotropy-one gene may have many functions and, therefore, traits or phenotypes-to identify genomic variants in common between two diseases. The increased power from combining two GWAS of related clinical phenotypes can potentially identify additional genetic variants that typically fall below the level of significance in either of the two isolated studies. This approach can identify not only some of the "missing heritability" in either disorder but also mechanistic pathways in common between the two disorders. A similar approach was taken by Yokohama et al 7 in comparing Alzheimer disease with immune-mediated disorders. Notably, the only overlap between these two studies was identified in the HLA locus.Applying the conjunctional false discovery rate approach, Witoelar et al 6 found 17 pleiotropic loci between the 7 autoimmune disorders and PD. Five of these loci, TRIM10, HLA, LRRK2, SETD1A, and MAPT, were replicated with an independent data set. Some of the genes within these loci, such as LRRK2, HLA, and MAPT, have been separately implicated in PD 8-10 or Crohn disease. 11 These newly associated genetic loci have functions involved in the immune system (TRIM10,

SMetABF: A rapid algorithm for Bayesian GWAS meta-analysis with a large number of studies included

“…PD has been reported to be associated with both genetic variations [17] and environmental factors like personal lifestyles such as smoking and drinking [18,19], but the detailed mechanism remains unclear. Recent studies discuss the potential relationship between PD and autoimmune disorders [20]. To explore the underlying relationships, we conduct a GWAS meta-analysis across PD and three common autoimmune disorders: inflammatory bowel disease, multiple sclerosis, and systemic sclerosis.…”