Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk

Abstract Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn’s disease via altered methylation and expression of EPHB4—a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10−4), Crohn’s disease (rg = 0.097 ± 0.06, P = 3.27 × 10−3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10–3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10−3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10–3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10–3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.

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202 In African Americans, NOD2, SLC22A5 and ATG16L1 But Not Il23R or IRGM Are Genetic Risk Factors for Crohn's Disease

Gastroenterology ◽

10.1016/s0016-5085(09)60173-6 ◽

2009 ◽

Vol 136 (5) ◽

pp. A-38

Author(s):

Ming-Hsi Wang ◽

Toshihiko Okazaki ◽

Kim L. Isaacs ◽

James D. Lewis ◽

Duane T. Smoot ◽

...

Keyword(s):

Risk Factors ◽

Crohn’S Disease ◽

African Americans ◽

Crohn's Disease ◽

Genetic Risk ◽

Genetic Risk Factors

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rs224136 on Chromosome 10q21.1 and Variants in PHOX2B, NCF4 and FAM92B Are Not Major Genetic Risk Factors for Susceptibility to Crohn's Disease in the German Population

The American Journal of Gastroenterology ◽

10.1038/ajg.2008.65 ◽

2009 ◽

Vol 104 (3) ◽

pp. 665-672 ◽

Cited By ~ 15

Author(s):

Jürgen Glas ◽

Julia Seiderer ◽

Giulia Pasciuto ◽

Cornelia Tillack ◽

Julia Diegelmann ◽

...

Keyword(s):

Risk Factors ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Genetic Risk ◽

Genetic Risk Factors ◽

German Population

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Genetic risk factors predict disease progression in Crohn’s disease patients of the Swiss inflammatory bowel disease cohort

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820959252 ◽

2020 ◽

Vol 13 ◽

pp. 175628482095925

Author(s):

Felicitas Ditrich ◽

Sena Blümel ◽

Luc Biedermann ◽

Nicolas Fournier ◽

Jean-Benoit Rossel ◽

...

Keyword(s):

Risk Factors ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Progression ◽

Genetic Risk ◽

Treatment Options ◽

Genetic Risk Factors ◽

Disease Course ◽

Nucleotide Polymorphisms ◽

Predict Disease Progression

Background: Crohn’s disease (CD) may progress from an inflammatory to a stricturing or penetrating disease phenotype. The aim of our study was to identify single nucleotide polymorphisms (SNPs) that predict disease progression in patients of the Swiss IBD Cohort Study (SIBDCS). Methods: We applied a multi-state Markov model for progression behavior of CD with three behavioral states according to the Montreal classification. The model considered transition from B1 to B2/B3 or from B2 to B3 stage. Model dynamics were summarized with transition intensities by including the effect of SNPs and calculating transition intensities for each SNP. Results: We included 1276 CD patients [669 (52.4%) B1, 248 (19.4%) B2, 359 (28.1%) B3 patients] with a median follow-up of 6.8 (interquartile range = 3.6–9.1; range 0–11.6) years. Probability for a B1 patient to develop a stenosis (B1 to B2, q = 0.033) was twice as much as compared to developing a penetrating complication (B3) during the disease course. In contrast, the probability of entering B3 stage was similar regardless of whether antecedent stricture was present (B2 to B3, q = 0.016) or not (B1 to B3, q = 0.016). We identified SNPs within the gene loci encoding ZMIZ1, LOC105373831 and KSR1 as carrying the highest risk for progression to B3, while the presence of SNPs within gene loci TNFSF15 and CEBPB-PTPN1 protected from progression to B2 or B3. Conclusion: We identified new genetic risk factors that can predict disease course in CD patients. A closer understanding on the functional impact of these genetic variations might improve our treatment options finally to prevent disease progression in CD patients.

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New genetic risk factors identified for Crohn's disease

Nature Clinical Practice Gastroenterology &#38 Hepatology ◽

10.1038/ncpgasthep0835 ◽

2007 ◽

Vol 4 (7) ◽

pp. 361-361

Keyword(s):

Risk Factors ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Genetic Risk ◽

Genetic Risk Factors

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Cross-disorder analysis of schizophrenia and 19 immune diseases reveals genetic correlation

10.1101/068684 ◽

2016 ◽

Author(s):

Jennie G Pouget ◽

Buhm Han ◽

Yang Wu ◽

Emmanuel Mignot ◽

Hanna M Ollila ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genetic Correlation ◽

Lupus Erythematosus ◽

Genetic Variants ◽

Genetic Risk ◽

Risk Scores ◽

Phenotypic Correlation ◽

Biliary Cirrhosis ◽

Genome Wide ◽

Shared Genetic

AbstractEpidemiological studies indicate that many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenotypic correlation between immune diseases and schizophrenia might be explained by shared genetic risk factors (genetic correlation). We used data from a large genome-wide association study (GWAS) of schizophrenia (N=35,476 cases and 46,839 controls) to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified three variants with pleiotropic effects, located in regions associated with both schizophrenia and immune disease. Our analyses provided the strongest evidence of pleiotropy at rs1734907 (∼85kb upstream ofEPHB4), a variant which was associated with increased risk of both Crohn’s disease (OR = 1.16, P = 1.67×10−13) and schizophrenia (OR = 1.07, P = 7.55×10−6). Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using polygenic risk scores (PRS) and cross-trait LD Score regression (LDSC). PRS revealed significant genetic overlap with schizophrenia for narcolepsy (p=4.1×10−4), primary biliary cirrhosis (p=1.4×10−8), psoriasis (p=3.6×10−5), systemic lupus erythematosus (p=2.2×10−8), and ulcerative colitis (p=4.3×10−4). Genetic correlations between these immune diseases and schizophrenia, estimated using LDSC, ranged from 0.10 to 0.18 and were consistent with the expected phenotypic correlation based on epidemiological data. We also observed suggestive evidence of sex-dependent genetic correlation between schizophrenia and multiple sclerosis (interaction p=0.02), with genetic risk scores for multiple sclerosis associated with greater risk of schizophrenia among males but not females. Our findings suggest that shared genetic risk factors contribute to the epidemiological co-occurrence of schizophrenia and certain immune diseases, and suggest that in some cases this genetic correlation is sex-dependent.Author SummaryImmune diseases occur at different rates among patients with schizophrenia compared to the general population. While the reasons for this phenotypic correlation are unclear, shared genetic risk (genetic correlation) has been proposed as a contributing factor. Prior studies have estimated the genetic correlation between schizophrenia and a handful of immune diseases, with conflicting results. Here, we performed a comprehensive cross-disorder investigation of schizophrenia and 19 immune diseases. We identified three individual genetic variants associated with both schizophrenia and immune diseases, including a variant nearEPHB4– a gene whose protein product guides the migration of lymphocytes towards infected cells in the immune system and the migration of neuronal axons in the brain. We demonstrated significant genome-wide genetic correlation between schizophrenia and narcolepsy, primary biliary cirrhosis, psoriasis, systemic lupus erythematosus, and ulcerative colitis. Finally, we identified a potential sex-dependent pleiotropic effect between schizophrenia and multiple sclerosis. Our findings point to shared genetic risk for schizophrenia and at least a subset of immune diseases, which likely contributes to their epidemiological co-occurrence. These results raise the possibility that the same genetic variants may exert their effects on neurons or immune cells to influence the development of psychiatric and immune disorders, respectively.

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