Supplementary Information for Human Genetics Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS Qian Wang1,2,3,† · Can Yang 3,4,5,† · Joel Gelernter 2,3,6,7, · Hongyu Zhao1,4,7,8,* † † These authors contributed equally to this work. 1 Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA 2 Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA 3 VA CT Healthcare Center, West Haven, Connecticut, USA 4 Department of Biostatistics, Yale School of Public Health, New Haven, Con- necticut, USA 5 Department of Mathematics, Hong Kong Baptist University, Hong Kong SAR 6 Department of Neurobiology, Yale School of Medicine, New Haven, Connecti- cut, USA 7 Department of Genetics, Yale School of Medicine, West Haven, Connecticut, USA 8 VA Cooperative Studies Program Coordinating Center, West Haven, Con- necticut, USA † hongyu.zhao@yale.edu S1 Fig Number of publications. Number of publications from PubMed search of “Psychiatric disorders AND autoimmune diseases” until Oct. 2014 per year. S2 Fig Conditional Q-Q plot showing the cross-enrichment of SCZ-MS GWAS signal but not BPD-MS GWAS signal. Black dots represent all 287 757 SCZ or BPD GWAS SNPs overlapped with MS GWAS SNPs. The other 4 colored dots represent different subsets of SNPs conditional on MS GWAS p-values smaller than 0.05, 0.01, 0.001, 0.0001, respectively, with the number of SNPs of each subset shown in brackets. Right panel shows Q-Q plot of SCZ GWAS conditional on MS GWAS; left panel shows Q-Q plot of BPD GWAS conditional on MS GWAS. Top panel included all overlapped SNPs; bottom panel have MHC region (25Mbp-34Mbp on Chromosome 6) excluded. It suggests that MS may have strong pleiotropy with SCZ but not BPD, with or without the MHC region. S3 Fig Enrichment of CNS SNPs and immune eQTL with and without the MHC region. Red bars are enrichment ratios estimated using all SNPs genome-wide, blue bars are enrichment ratios estimated with SNPs in the MHC region (25Mbp-34Mbp on Chromosome 6) excluded. S4 Fig Enrichment of immune-eQTLs in SNPs shared between five psychiatric disorders and CD. Red bars 𝑞 represent the enrichment ratio of immune related eQTLs in 5 PGC traits specific SNPs respectively ( 10), 𝑞00 𝑞01 blue bars represent the enrichment ratio of immune related eQTLs in SNPs associated only with CD ( 𝑞00 ), grey bars shows the enrichment ratio of immune related eQTLs in SNPs associated with both CD and the 𝑞 𝑞 corresponding PGC disorder ( 11). Among the immune related eQTLs, the ratios 11 are SCZ-CD 3.9 (s.e. 𝑞00 𝑞00 0.06), BPD-CD 4.4(s.e. 0.09), ASD-CD 3.4 (s.e. 0.2), MDD-CD 4.6(s.e. 0.18), and ADHD-CD 2.1(s.e. 𝑞 𝑞 𝑞 𝑞 0.45). The fact that 11> 10 and 11> 01, suggests the shared genetic components between the five 𝑞00 𝑞00 𝑞00 𝑞00 psychiatric disorders and CD are closely related to immune function. S5 Fig Enrichment of DNase-peak located SNPs in SCZ GWAS signal from 98 ENCODE cell lines. 98 cell lines ordered by enrichment ratios; cell lines from blood and brain are colored red and blue respectively. S6 Fig Enrichment of H3K9ac in GWAS traits across different tissues. H3K9ac histone marker information was collected from ROADMAP for eight tissues: blood, brain, breast, fat, heart, lung, muscle and skin. Each bar represent the enrichment of a certain cell with the color indicating the tissue it belongs to. X-axis indicates the 17 GWASs and y-axis shows the enrichment ratio. Both psychiatric disorders (top panel) and immune-related disorders (middle panel) have the highest enrichment for H3K9ac markers in blood, while educational traits (both years of education and colleges completion) have the highest enrichment for H3K9ac markers in brain. S7 Fig Conditional Q-Q plot showing enrichment of SNPs having same effect direction between SCZ and CD. Black dots for all 928 987 SNPs, and the other three lines are different subsets of SNPs, selected by: blue for 472 165 SNPs that have same effect direction for SCZ and CD; red for 7 414 SNPs with p<0.001 in CD GWAS; green for the intersection of blue and red. S8 Fig Trend of consistent effect directions for shared SNPs of SCZ-RA and BPD-RA disease pairs. For each disease pair, SNPs are assigned to 10 groups based on their posterior probability of being associated with both diseases, and then the proportion of alleles having the same effect direction for the disease pair was calculated within each of the ten SNP groups. Left, SCZ-RA; right, BPD-RA. Blue represents the same effect direction, and red represents the opposite direction, x-axis represents proportion of SNPs. S9 Fig LD block grouped SNP effect direction, posterior probability and block size. For each trait pair, all overlapped SNPs were grouped into 20 573 LD blocks. Each LD block was represented by a circle positioned with x-axis being the maximum posterior probability of being associated with both traits, and yaxis being the proportion of SNPs having the same effect direction for two traits. The radiation of each circle was scaled to be proportional to the square root of number of SNPs in a LD block. Top left: SCZheight; top right: SCZ-CD; bottom left: BPD-height; bottom right: BPD-CD. LD blocks with high maximum posterior probability are more likely to have higher proportion of SNPs with same effect direction for SCZ-CD and BPD-CD, while more random for SCZ-height and BPD-height. S10 Fig LocusZoom showing distribution of posterior probability in cytoband 1p13.2. Posterior probability of being associated with both diseases in eight disease pairs between SCZ, BPD, MDD, ASD, and RA, T1D, are shown separately. Only region 1p13.2 is shown. SNP with the highest posterior is labeled, and SNPs in LD with it are colored. Figures plotted using LocusZoom. S11 Fig Protein-protein interaction enrichment. Constructed using the top 1000 SNPs, with color indicating significance level. S12 Fig Posterior of SNPs being associated with both diseases for 28 disease pairs. Posterior of all shared SNPs of a disease pair is plotted against 22 genomic positions. Red line indicates posterior=0.8. S13 Fig The frequencies of top SNPs (posterior probability > 0.8) appearing in 28 disease pairs. A total of 4 149 SNPs have posterior probability > 0.8 of being associated with at least one disease pair. Histogram showing the number of disease pairs that these 4 149 SNPs are associated with (with posterior probability > 0.8). S1 Table Strength of pleiotropy within and across two disorder classes: 5 psychiatric disorders and 7 autoimmune disorders. S2 Table A description of 98 ENCODE cell lines, and the enrichment ratio of DNase-peak located SNPs in SCZ GWAS signals from each cell line. S3 Table Number of SNPs in effect direction analysis and proportions of SNPs in each direction combination categories. S4 Table Genomic information and effect direction of 85 SNPs, whose posterior probability of being associated with both SCZ and CD above 0.9. S5 Table Significance of cross-disorder cytoband enrichment tests. S6 Table Genome annotation enrichment results (adjusted p-value > 0.05), including gene ontology terms and KEGG pathways. S7 Table A complete list of central nervous system (CNS) genes.