Nature Genetics: doi: /ng Supplementary Figure 1
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1 Supplementary Figure 1 Relationship of the Icelandic psychosis family to five individuals (X1 X5) who carry the haplotype harboring RBM12 c.2377g>t but not RBM12 c.2377g>t. An asterisk marks whole-genome-sequenced individuals. For individuals with samples, RBM12 c.2377 genotypes are shown.
2 Supplementary Figure 2 Sharing between C1 (the haplotype inherited from B2) and individuals depicted in Supplementary Figure 1. The location of RBM12 c.2377g>t is indicated by a dotted line. Individuals who do not carry c.2377g>t are shown in gray. P, paternal; U, unspecified; M, maternal.
3 Supplementary Figure 3 Western blots. (a) Western blot stained with an antibody that recognizes amino acids of RBM12. (b) Western blot stained with anti- -actin antibody.
4 Supplementary Figure 4 Score on neuropsychological test principal component 1 for c.2377g>t carriers (C1 C5) and non-carriers (NC1 NC6).
5 Supplementary Figure 5 Individual neuropsychological test results for Icelandic controls (n = 763), patients with schizophrenia (n = 198), RBM12 c.2377g>t family non-carriers and c.2377g>t carriers. When the c.2377g>t family non-carriers (NC) are within 0.5 s.d. of the controls, color bars indicate that the carriers are >1.5 s.d. from controls (purple), between 1.5 and 1 s.d. from controls (light blue), between 0.5 and 0 s.d. from controls (green), or between 0 and 0.5 s.d. from controls (yellow). Ctrl, controls; SZ, patients with schizophrenia; NC, non-carriers; C, carriers. The line in the NC and C columns indicates the median.
6 Supplementary Figure 6 Individual neuropsychological test results for the Finnish psychosis family and patients with schizophrenia (n = 142) from the same region. FI-B1, who had a subarachnoid hemorrhage before assessment was carried out, is designated with an x. The line in the fam and car columns indicates the median. SZ, patients with schizophrenia; fam, healthy non-carriers from the Finnish psychosis family; car, c.2532delt carriers with psychosis. Note that the TMT B was not administered for the c.2532delt carriers as it was deemed too difficult for them.
7 Supplementary Figure 7 Odds ratios and standard errors from the regression of psychosis on bipolar and schizophrenia polygenic scores. Left, the Icelandic psychosis family. Comparison of ten patients with psychosis and 18 non-psychotic individuals, all c.2377g>t carriers. Right, the Finnish psychosis family. Comparison of four patients with psychosis carrying c.2532delt and four non-psychotic full-siblings who do not carry c.2532delt. Note that scores were shifted and scaled to have a mean of zero and a standard deviation of 1 in the group unaffected by psychosis in each family.
8 Supplementary Figure 8 Relative intensity of the full-length RBM12 band detected by western blot using two antibodies. Left, relative intensity from two experiments with antibody A, recognizing amino acids at the C terminus of RBM12. Mean relative intensity was lower in carriers (C) than in non-carriers (NC) (P = (t test)). Right, relative intensity from two experiments with antibody B, recognizing amino acids of RBM12. Mean relative intensity was lower in carriers (C) than in non-carriers (NC) (P = 0.14 based on the t test). Note that all values are normalized for β-actin and shifted so that the non-carriers have a mean of 1. Individuals are shown as open circles and the mean for each group is indicated by a blue, filled circle.
9 Supplementary Figure 9 Contribution of carriers to the score depending on affected status. The red line indicates the weight of affecteds and the blue line the weight of unaffecteds.
10 Supplementary Tables for Truncating Mutations in RBM12 Are Associated with Psychosis 1
11 Supplementary Table 1 Clinical information for the Icelandic psychosis family Patient Psychosis diagnosis Age at Pre-morbid functioning Other psychiatric diagnoses onset B3 schizophrenia 40 poor premorbid work and social adjustment - B6 schizophrenia 15 poor premorbid work and social adjustment mild mental retardation B7 schizophrenia 20 poor premorbid work and social adjustment - C1 schizophrenia 25 poor premorbid work and social adjustment - C2 schizophrenia 30 poor premorbid work and social adjustment alcohol dependence C3 bipolar disorder 31 - mild mental retardation C4 bipolar disorder 14 poor premorbid work adjustment mild mental retardation, alcohol dependence C5 schizoaffective disorder C6 schizoaffective disorder 29 poor premorbid social adjustment alcohol and sedative dependence D1 schizophrenia Age at onset refers to the psychosis diagnosis. For students, poor work adjustment refers to failure to keep up with studies. Note that the individuals with bipolar disorder had psychotic symptoms. Supplementary Table 2 Clinical information for the Finnish psychosis family Patient Gender Psychosis diagnosis Age at onset Pre-morbid functioning Other psychiatric diagnoses Non-psychiatric diagnoses FI-B1 M schizophrenia, paranoid type 30 information not available alcohol dependence Subarachnoid hemorrhage (SAH) at age 39 FI-B4 M psychotic disorder not otherwise specified 21 poor premorbid work and social adjustment moderate mental retardation congenital heart defect, dysmorphic features FI-B5 F schizophrenia, 31 poor premorbid work - - undifferentiated type adjustment FI-B7 M schizophrenia, paranoid type 33 poor premorbid work and alcohol dependence - social adjustment FI-B8 M schizoaffective disorder, bipolar type 19 poor premorbid work adjustment - - Age at onset refers to the psychosis diagnosis. For students, poor work adjustment refers to failure to keep up with studies. 2
12 Supplementary Table 3 Psychiatric disorder information from the M.I.N.I. for individuals without psychosis from the Icelandic psychosis family Indiv Any Depr Sui Mani Hypo Anx PTSD Eat ASPD Add NC NC NC NC NC NC C C C C C Results are based on the M.I.N.I. 1 Depression (depr) was scored based on modules A and B, suicidality (sui) using module C, mania (mani) and hypomania (hypo) based on the corresponding items in module D, anxiety (anx) using modules E, F, G, H and O, posttraumatic stress disorder (PTSD) based on module I, eating disorders (eat) using modules M and N, antisocial personality disorder (ASPD) based on module P and addiction (add) using modules J and K. Note that no individual scored positively on module L, psychotic disorders. Any refers to any psychiatric disorder. In all cases, 1 indicates the presence of a disorder and 0 its absence. Supplementary Table 4 Psychiatric disorder information from addiction treatment center and hospital records for individuals without psychosis from the Icelandic psychosis family Group Any Add Depr/Anx ADHD ASD/ID Carriers 16 (0.73) 14 (0.64) 6 (0.27) 3 (0.14) 1 (0.045) Non-carriers 18 (0.43) 14 (0.33) 6 (0.14) 2 (0.048) 0 (0) Number (fraction) of RBM12 c.2377g>t carriers (N = 22) and non-carriers (N = 42) admitted to the addiction treatment center (add) or diagnosed with depression/anxiety (depr/anx), attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder/intellectual disability (ASD/ID). Any refers to any psychiatric disorder. 3
13 Supplementary Table 5 Logistic regression model predicting schizophrenia based on neuropsychological tests and information from the M.I.N.I. Variable Effect P Logical memory I&II 0.97/ e-11 Category fluency 0.24/ SWM Stroop reading task Matrix reasoning Depression or suicidal ideation e-06 Mania or hypomania e-09 The neuropsychological tests considered were Logical memory I&II, Letter fluency, Category fluency, Stroop interference, WCST perseverative errors, SWM, Stroop reading task, WASI vocabulary and WASI matrix reasoning. These were the same tests as in our previous work, with the exceptions that 1) for the WASI, only the vocabulary and matrix reasoning subtests were used as the similarities and block design subtests were not available for the majority of schizophrenia patients and 2) the TMT and RVIP tests were not considered as they were missing for several of the psychosis family individuals. For the M.I.N.I, psychiatric disorder categories (see Supplementary Table 3) with positive responses for at least 10 individuals (depr, sui, mani, hypo, anx and add) were considered. The related phenotypes of depression/suicide and mania/hypomania were combined (when examined separately, the effect of each member of a pair was similar). Only variables having P < 0.05 were retained in the model. When a significant interaction with sex (P < 0.05) was found, the effect is shown for males/females and the P value for the twodegree of freedom test for both sexes is given. In total, 156 schizophrenia patients and 724 controls without missing data were used to create the model. 4
14 References 1. Sheehan, D.V. et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59 Suppl 20, 22-33;quiz (1998). 5
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