Genome‐wide association studies reveal shared genetic haplotypes of autoimmune rheumatic and endocrine diseases with psychiatric disorders

Abstract Background Several studies have shown that autoimmune diseases are associated with psychiatric diseases like depression and psychosis. Genetic evidence supports this association. The aim of this study was to investigate if genetic variants predisposing to autoimmune diseases and psychiatric disorders are genetically linked, constructing the common haplotypes. Methods All registered single nucleotide polymorphisms (SNPs) in the Genome‐wide association studies (“GWAS catalog”) having been associated with autoimmune rheumatic and endocrine diseases were investigated for being in linkage disequilibrium with any psychiatric disorders’ associated SNPs. Analysis was performed by the LDtrait and LDhap bioinformatics tools. Results Multiple chromosomal regions have been detected containing rheumatic/endocrine diseases’ predisposing SNPs and psychiatric disorders’ predisposing SNPs. The genetic haplotypes have been constructed for some of these genetic regions. Six of the autoimmune rheumatic and endocrine diseases examined here share a common haplotype with psychiatric diseases at the HLA locus 6p21‐22. Conclusion Our study shows that autoimmune diseases and psychiatric diseases are genetically linked. Genetic haplotypes have been constructed, showing in detail this genetic linkage.


TA B L E 1 Genetic loci containing linked SNPs, predisposing for autoimmune and psychiatric diseases
Autoimmune disease Linked psychiatric disease (chromosomic region) (flanking SNPs)

Constructed genetic haplotypes (frequency) Pleiotropic SNPs (diseases)
Hashimoto's disease  (Table S1). We did not exclude any psychiatric traits for this investigation, but most associations in the GWAS catalog are associated with depression, anxiety, bipolar disorder, and schizophrenia.
The PubMed ID and the first author of the GWAS studies that were used for our investigation are found in Table S1. We focused on autoimmune diseases with at least 30 registered associations in the GWAS catalog. Pediatric associations were excluded. Systemic lupus erythematosus and psychiatric comorbidities were investigated in a previous study conducted by our team (Parperis et al., 2022). The LDtrait tool (Lin et al., 2020) was used to detect the SNPs in linkage disequilibrium (R 2 ≥ 0.6). A 1 Mb window was set, upstream and downstream, for linkage disequilibrium analysis. The LDhap tool was used to identify and construct haplotypes containing risk alleles for autoimmune and psychiatric diseases (Machiela & Chanock, 2015). We did not exclude any populational ancestries from our study. On the other hand, most published GWAS studies have been performed in populations of European ancestry. In Table S1, haplotype frequencies can be found for all the human populations together and separately for the European ancestry populations.
The results are summarized in Table 1. To the best of our knowledge, Hashimoto's disease, Graves' disease, ankylosing spondylitis, Sjogren's syndrome, and systemic sclerosis are investigated for the first time for common genetic haplotypes with any psychiatric disease. Evidence for genetic association between thyroid diseases and psychiatric diseases has been previously reported (Mo et al., 2019;Panicker, 2011).
A genetic linkage of diabetes mellitus type 1 with schizophrenia and depression (Table 1) was revealed, an observation that has not been shown by previous studies (Tylee et al., 2022). This association is compatible with published epidemiological studies (Chen et al., 2022).
We also found a genetic linkage between Graves' disease, psoriasis, rheumatoid arthritis, and Sjogren's disease with psychosis and mood disorders, justified by previous epidemiological studies (Jeppesen & Benros, 2019). Three SNPs were found to have a pleiotropic effect (Table 1), predisposing for both an autoimmune and a psychiatric disease (rs4622308 predisposes for rheumatoid arthritis and anorexia nervosa, and two nearby SNPs for schizophrenia and diabetes mellitus type 1, respectively). Based on these findings, we constructed genetic haplotypes, including risk alleles for autoimmune and psychiatric diseases. Unfortunately, the risk alleles are not known for all the registered SNPs in the GWAS catalog, a limitation for constructing all the haplotypes of the chromosomal regions (Table 1). We finally constructed 10 risk haplotypes (Table 1 and Table S1). Some of the constructed haplotypes have a very high frequency in the general population. Notably, these genetic haplotypes cannot explain the high comorbidity of the autoimmune diseases with psychiatric phenotypes alone, but they are just a fraction of this complex phenotype.
All genes lying in the constructed haplotypes can be found in Table   S1. Six of the autoimmune rheumatic and endocrine diseases examined here share a common haplotype with psychiatric diseases at the HLA locus 6p21-22 ( Figure 1 and We plan to continue our research efforts by aiming to generate more genetic haplotypes that could be combined with environmental factors, in order to predict more accurately the risk of developing psychiatric comorbidities in patients with autoimmune diseases.

FUNDING INFORMATION
Not any special funding was received for this research.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are inside the paper and in the accompanied Supplementary Material (online).

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.2955