Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data

Abstract

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.

Keywords: C-reactive protein; Crohn's disease; Tourette syndrome; allergy; anorexia nervosa; attention deficit-hyperactivity disorder; autoimmune disorder; bipolar disorder; celiac disease; childhood ear infection; genetic correlation; genome-wide association; hypothyroidism; major depression; neuroticism; obsessive schizophrenia; primary biliary cirrhosis; rheumatoid arthritis; smoking; systemic lupus erythematosus; tuberculosis susceptibility; type 1 diabetes; ulcerative colitis.

Figure 1

A heatmap depicting LDSC genome-wide genetic correlations between psychiatric and immune-related conditions such that red reflects more positive correlation coefficients while blue reflects more negative coefficients. Correlation coefficients are provided within each cell, with full details provided in Supplementary Table 2. Correlations reaching trend-level significance (0.05 < uncorrected p < 0.10) are depicted as colored panels, while relationships surpassing uncorrected p < 0.05 are additionally denoted with *, and relationships surpassing BH-p < 0.05 (for the total number of tests depicted in the figure) are denoted with **. The rows and columns of the heatmap are hierarchically clustered based on correlation coefficients. Abbreviations: Attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD).

Figure 2

This figure depicts the HESS local genetic correlation data with respect to the genome and previously reported genome-wide association signals for respective disorders. A model genome using HG19 coordinates is depicted in grey. Moving outward from the center of the plot, the first track containing a red histogram depicts loci significantly associated with SZ (GWAS p < 5×10⁻⁸), with larger peaks indicating more significance (plotted as -log(p-value)). The second track (labeled SZ-CD) depicts regions of genetic correlation between SZ and CD, such that blue reflects uncorrected p < 0.05 and red reflects BH corrected p < 0.05. The next track (labeled CD Hits) contains a histogram depicting CD GWAS signal as described previously. The next pair of tracks depict genetic correlations for SZ-PBC and PBC GWAS signal, respectively. The third pair of tracks depicts this information for SZ-SLE (with SLE GWAS signal). The fourth pair of tracks depicts this information for SZ-UC and UC GWAS signal, respectively. In the center of the plot, we identify several GWAS candidate genes using colored text and arrows to indicate the pertinent locus; colored text and arrows are used to indicate the relevant phenotype-pairs, such that green = SZ-CD, orange = SZ-PBC, yellow = SZ-SLE, brown = SZ-PBC/SLE, and purple = SZ/BD-CD/PBC/UC.