Autoimmune Disease Associated CLEC16A Variants Convey Risk of Parkinson’s Disease in Han Chinese

Abstract

CLEC16A is a membrane-associated endosomal protein implicated in regulating autophagy and antigen presentation. Its genetic variants are broadly associated with multiple autoimmune diseases. Parkinson’s disease (PD), which undergoes autophagy disruption and neuroinflammation, has been clinically observed, for an extensive amount of time, to be associated with autoimmune diseases. In this study, we aimed to understand whether the autoimmune disease associated CLEC16A variants pleiotropically modulate PD risk. Five of such CLEC16A variants, including rs6498169, rs12708716, rs12917716, rs7200786, and rs2903692, were selected and analyzed in a Han Chinese cohort comprising 515 sporadic PD patients and 504 controls. Results showed that rs6498169 and rs7200786 were significantly associated with PD susceptibility (p = 0.005 and 0.004, respectively; recessive model, p = 0.002 and 0.001, respectively). Rs6498169 was also associated with the PD subtype of postural instability/gait difficulty (p = 0.002). Haplotype analysis showed that the AAG module in order of rs6498169, rs12708716, and rs2903692 was associated with the highest risk for PD (p = 0.0047, OR = 1.42, 95% CI = 1.11–1.82). Functional annotation analyses suggested that rs6498169 had high probability to affect transcription factor binding and target gene expression. In summary, the current study demonstrates that the autoimmune disease associated CLEC16A variants convey risk of PD in Han Chinese. Our findings suggest a pleiotropic role of CLEC16A and strengthen the link between PD and autoimmune diseases.

CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment

“…Several studies have shown consistent association of heterozygous CLEC16A SNPs with auto-immune disorders, particularly multiple sclerosis (International Multiple Sclerosis Genetics Consortium 2009;International Multiple Sclerosis Genetics Consortium et al 2007;Nischwitz et al 2011), type-1 diabetes (Hakonarson et al 2007;Wellcome Trust Case Control Consortium 2007), and Crohn's disease (Marquez et al 2009), and that CLEC16A plays a role in the neurodegeneration of Parkinson disease (Fan et al 2022; 7a) and corrected for total protein (Supplementary Fig. 7b).…”

“…Unlike other CLEC proteins, CLEC16A lacks an active/full length carbohydrate recognition domain and functions as an E3-ubiquitin ligase involved in the regulation of autophagy and mitophagy (Kim et al 2010Pearson et al 2018;Redmann et al 2016;Soleimanpour et al 2014). Despite the absence of a functional carbohydrate recognition domain, several GWAS studies have shown a link between CLEC16A and the human immune system by associating the CLEC16A locus with susceptibility to auto-immune diseases, including type-1 diabetes (Hakonarson et al 2007;Wellcome Trust Case Control Consortium 2007), multiple sclerosis (International Multiple Sclerosis Genetics Consortium 2009;International Multiple Sclerosis Genetics Consortium et al 2007;Nischwitz et al 2011), primary biliary cholangitis (Hirschfield et al 2012), Addison disease (Skinningsrud et al 2008), juvenile idiopathic arthritis (Skinningsrud et al 2010), and neurodegenerative disorders like Parkinson disease (Fan et al 2022;Strafella et al 2021). CLEC16A is thought to regulate immune tolerance via the endosome-lysosome trafficking by stimulating autophagy of thymic epithelial cells and lowering of the antigen-presenting function (Schuster et al 2015), by the regulation of HLA class-II antigen expression via late endosome biogenesis in antigen-presenting cells and by participating in retrograde transport of HLA-II containing compartments in myeloid cells (Li et al 2015;Rijvers et al 2020;van Luijn et al 2015).…”

“…However, increased ER stress levels lead to neurodegeneration as well as neuronal loss during embryonic development (Hetz and Saxena 2017;Murao and Nishitoh 2017;Passemard et al 2019). In humans, the only link between CLEC16A and neurological disease is made by the association between its locus and susceptibility to neurological disorders, like multiple sclerosis (MS) (International Multiple Sclerosis Genetics Consortium et al 2007;Mero et al 2011) and Parkinson disease (Fan et al 2022;Strafella et al 2021). Despite these observations, the role of CLEC16A in human brain development and neurodegeneration remains poorly understood.…”

Gene-wide significant association analyses of DNMT1 genetic variants with Parkinson’s disease

“…The variants were annotated for functions as previously described ( Fan et al, 2022 ). In brief, potential causal links to diseases were annotated using HaploReg ( http://pubs.broadinstitute.org/mammals/haploreg/haploreg.php ).…”

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…To some extent this is evident in all people, but it is classified as an autoimmune disease when this self-reactivity leads to tissue damage (either systemic or local). There are numerous well-established 'autoimmune' (or immunemediated) diseases, such as multiple sclerosis, type 1 diabetes (T1DM) and rheumatoid arthritis as well as a growing number of diseases that have an important autoimmune aspect to their pathophysiology, such as Parkinson's disease [18], amyotrophic lateral sclerosis (ALS) [19] and Alzheimer's disease [20], with developing treatments now being shaped by the 'autoimmune aspects' of these classical neurodegenerative conditions [21].…”