Cognitive Endophenotypes Inform Genome-Wide Expression Profiling in Schizophrenia

Supplemental Materials Cognitive Endophenotypes Inform Genome-Wide Expression Profiling in Schizophrenia

by A. B. Zheutlin et al., 2015, Neuropsychology http://dx.doi.org/10.1037/neu0000244

Tables

S1. Genome-Wide Gene Expression Analysis of CVLT

S2. Mean Expression Levels by Diagnostic Status for CVLT-Associated Genes in Swedish Sample

S3. Mean Expression Levels by Diagnostic Status for CVLT-Associated Genes in Finnish Sample

S4. Functional Annotation Clustering of Genes Associated with CVLT and Diagnostic Status

Figures

S1. Genome-Wide Gene Expression in Schizophrenia Patients vs. Controls 2

Table S1

Genome-Wide Gene Expression Analysis of CVLT

Partial R2 Partial R2 Illumina Probe Gene Symbol t df p Bon (full sample) (no probands) ILMN_1751072 SRPRB 6.16 177.01 < .0001 0.177 0.098 ILMN_1775522 MAGED1 6.14 178.43 < .0001 0.174 0.135 ILMN_1673991 ATIC 5.92 187.94 0.0003 0.157 0.111 ILMN_1686871 PARP1 5.70 168.60 0.0010 0.161 0.107 ILMN_1730077 RPUSD2 5.52 179.27 0.0022 0.145 0.134 ILMN_1689953 CD81 5.49 183.50 0.0024 0.141 0.097 ILMN_1685580 CBLB 5.47 184.39 0.0027 0.140 0.100 ILMN_1662364 AARS 5.49 168.92 0.0028 0.151 0.102 ILMN_1787461 RUNX3 5.46 186.37 0.0029 0.138 0.077 ILMN_1761479 ZC3HC1 5.49 156.95 0.0029 0.161 0.079 ILMN_1689652 RNMTL1 5.44 161.15 0.0036 0.155 0.097 ILMN_1727098 PPP1R16B 5.38 185.83 0.0042 0.135 0.107 ILMN_2224143 MCM3 5.35 167.21 0.0053 0.146 0.084 ILMN_1676745 ZNF142 5.32 187.98 0.0053 0.131 0.121 ILMN_1678140 NA 5.36 157.70 0.0055 0.154 0.061 ILMN_1750800 ACO1 5.33 174.07 0.0055 0.140 0.081 ILMN_2097793 ZBTB4 5.32 177.36 0.0057 0.138 0.133 ILMN_1671257 DKC1 5.33 169.07 0.0057 0.144 0.059 ILMN_1733696 IMP3 5.32 164.72 0.0062 0.147 0.100 ILMN_2412549 GAR1 5.31 173.46 0.0062 0.140 0.071 ILMN_1766010 YARS 5.31 172.45 0.0063 0.140 0.092 ILMN_1665943 MAP4K1 5.29 187.88 0.0064 0.129 0.099 ILMN_1721978 CARD11 5.27 183.58 0.0070 0.131 0.112 ILMN_1744068 ELP3 5.25 173.50 0.0080 0.137 0.098 ILMN_1662334 DNAJA3 5.24 170.74 0.0085 0.139 0.096 ILMN_1663954 NELFCD 5.18 185.13 0.0106 0.127 0.081 ILMN_1761159 ESYT1 5.18 187.96 0.0107 0.125 0.105 ILMN_2334296 IL18BP 5.17 187.67 0.0108 0.125 0.102 ILMN_1751338 NUP133 5.20 167.84 0.0109 0.139 0.070 ILMN_1753745 HDDC2 5.17 187.70 0.0113 0.124 0.035 ILMN_1795678 POLR3C 5.19 167.58 0.0113 0.138 0.081 ILMN_1754149 LETMD1 5.15 185.48 0.0122 0.125 0.075 ILMN_1801348 GOT2 5.15 178.21 0.0128 0.129 0.107 ILMN_1752111 SMARCAL1 5.15 171.82 0.0130 0.134 0.088 ILMN_2343097 NCALD 5.12 188.00 0.0142 0.122 0.089 ILMN_1774196 URM1 5.13 175.50 0.0143 0.130 0.119 ILMN_1693664 POMGNT1 5.11 177.12 0.0153 0.128 0.116 ILMN_1753885 YTHDF1 5.05 185.90 0.0191 0.121 0.118 ILMN_1763080 QARS 5.05 183.63 0.0193 0.122 0.087 3

ILMN_2073012 TMEM203 5.05 173.37 0.0201 0.128 0.075 ILMN_1701731 AKR1B1 5.04 182.99 0.0208 0.122 0.113 ILMN_1813836 DARS 5.05 174.39 0.0208 0.127 0.096 ILMN_1774547 MPRIP 5.03 185.01 0.0216 0.120 0.097 ILMN_1728298 SBK1 5.03 178.74 0.0219 0.124 0.091 ILMN_1763460 NHP2L1 5.02 183.07 0.0225 0.121 0.099 ILMN_1777740 THEM6 5.02 183.32 0.0229 0.121 0.094 ILMN_1751400 SKAP1 5.02 174.31 0.0230 0.127 0.126 ILMN_1708328 RAB11FIP3 5.01 185.32 0.0231 0.119 0.084 ILMN_1786024 POLR3H 5.00 182.79 0.0242 0.121 0.120 ILMN_2306189 MAGED1 4.99 187.34 0.0252 0.117 0.130 ILMN_1788538 NCALD 4.99 187.95 0.0253 0.117 0.077 ILMN_1670948 TSR2 4.98 185.88 0.0263 0.118 0.090 ILMN_1796235 CIRH1A 5.00 170.20 0.0265 0.128 0.098 ILMN_2183687 LIME1 4.98 183.23 0.0274 0.119 0.091 ILMN_1713454 ZNF671 4.99 169.74 0.0277 0.128 0.074 ILMN_1779185 SPECC1L 4.99 162.99 0.0283 0.133 0.101 ILMN_2044453 LPAR5 4.96 187.39 0.0289 0.116 0.071 ILMN_1740265 ACOT7 4.96 185.07 0.0294 0.117 0.095 ILMN_1696375 TTC31 4.96 173.73 0.0313 0.124 0.101 ILMN_2110167 POLR1E 4.97 164.34 0.0315 0.130 0.115 ILMN_1793203 SMCR7L 4.95 168.63 0.0328 0.127 0.113 ILMN_2392635 ABCF1 4.92 175.17 0.0366 0.121 0.088 ILMN_1764764 MUM1 4.92 173.84 0.0373 0.122 0.116 ILMN_1657204 SAE1 4.94 155.52 0.0376 0.135 0.093 ILMN_1658289 WDR54 4.90 182.55 0.0386 0.116 0.105 ILMN_1679476 GART 4.94 150.17 0.0387 0.140 0.086 ILMN_2249920 FYN 4.90 187.60 0.0390 0.113 0.075 ILMN_1743049 PWP1 4.91 167.28 0.0392 0.126 0.045 ILMN_2361695 BAG5 4.90 167.09 0.0420 0.126 0.100 ILMN_2162989 TMEM189 4.88 187.02 0.0424 0.113 0.116 ILMN_2153787 ARRDC5 4.87 185.73 0.0432 0.113 0.102 ILMN_1810334 COMMD7 4.88 173.51 0.0449 0.121 0.073 ILMN_1700604 RBM14 4.88 172.74 0.0451 0.121 0.092 ILMN_1785198 POLE3 4.88 162.22 0.0463 0.128 0.073 ILMN_1748894 GTPBP3 4.87 173.16 0.0467 0.120 0.068 ILMN_1776080 GTPBP6 4.85 186.43 0.0477 0.112 0.081

Note. Seventy-six genes were associated with CVLT after correcting for multiple comparisons (p < 2.69 × 10-6).

The effect of each probe on CVLT adjusted for age and sex in the Swedish discovery sample is reported. Partial

R2 values for the probe effect in the full sample (N = 190) and in a subsample excluding schizophrenia and bipolar patients (probands; N = 131) are also listed. 4

Table S2

Mean Expression Levels by Diagnostic Status for CVLT-Associated Genes in Swedish Sample

SZ-CT Control SZ vs. SZ-CT SZ vs. controls SZ expression expression expression Partial Partial Illumina probe Gene symbol t df p t df P Mean [95% CIs] Mean [95% CIs] Mean [95% CIs] R 2 R 2 ILMN_1752111 SMARCAL1 2.68 62 0.009 0.10 3.38 86 0.001 0.12 8.74 [8.67, 8.81] 8.87 [8.81, 8.92] 8.89 [8.84, 8.95] 10.37 [10.25, 10.52 [10.43, 10.61 [10.54, ILMN_2224143 MCM3 1.88 62 0.065 0.05 3.53 86 0.001 0.13 10.5] 10.61] 10.69] 9.88 [9.75, 10.11 [10.01, 10.12 [10.04, ILMN_1728298 SBK1 2.76 62 0.008 0.11 3.31 86 0.001 0.11 10.02] 10.2] 10.2] ILMN_1777740 THEM6 2.59 62 0.012 0.10 3.29 86 0.001 0.11 8.87 [8.78, 8.97] 9.02 [8.95, 9.1] 9.07 [9, 9.13] ILMN_1750800 ACO1 2.31 62 0.024 0.08 3.33 86 0.001 0.11 8.61 [8.54, 8.67] 8.71 [8.65, 8.77] 8.76 [8.7, 8.82] 9.94 [9.81, 10.07 [9.99, 10.15 [10.09, ILMN_2073012 TMEM203 1.79 62 0.079 0.05 3.39 86 0.001 0.12 10.07] 10.14] 10.21] ILMN_1676745 ZNF142 2.31 62 0.024 0.08 3.31 86 0.001 0.11 8.66 [8.58, 8.73] 8.77 [8.69, 8.84] 8.81 [8.76, 8.85] 11.9 [11.72, 12.12 [12.03, 12.13 [12.06, ILMN_1787461 RUNX3 2.70 62 0.009 0.11 3.09 86 0.003 0.10 12.08] 12.21] 12.2] ILMN_1775522 MAGED1 1.62 62 0.111 0.04 3.26 86 0.002 0.11 9.59 [9.48, 9.7] 9.7 [9.61, 9.78] 9.8 [9.73, 9.88] ILMN_2412549 GAR1 1.81 62 0.075 0.05 3.24 86 0.002 0.11 9.46 [9.36, 9.56] 9.58 [9.5, 9.65] 9.66 [9.59, 9.74] 12.62 [12.49, 12.78 [12.69, 12.83 [12.76, ILMN_1689953 CD81 2.34 62 0.023 0.08 3.13 86 0.002 0.10 12.76] 12.87] 12.9] 10.51 [10.36, 10.64 [10.57, 10.72 [10.66, ILMN_1701731 AKR1B1 1.69 62 0.096 0.04 3.12 86 0.002 0.10 10.66] 10.71] 10.79] 10.38 [10.25, 10.52 [10.45, 10.58 [10.51, ILMN_1686871 PARP1 1.82 62 0.074 0.05 3.06 86 0.003 0.10 10.52] 10.59] 10.65] ILMN_1786024 POLR3H 2.74 62 0.008 0.11 2.44 86 0.017 0.06 8.49 [8.43, 8.55] 8.62 [8.54, 8.69] 8.61 [8.55, 8.67] 11.22 [11.07, 11.37 [11.31, 11.39 [11.34, ILMN_1733696 IMP3 2.18 62 0.033 0.07 2.96 86 0.004 0.09 11.36] 11.43] 11.45] ILMN_1721978 CARD11 2.78 62 0.007 0.11 2.35 86 0.021 0.06 9.53 [9.42, 9.63] 9.7 [9.62, 9.79] 9.67 [9.6, 9.73] ILMN_1700604 RBM14 2.77 62 0.007 0.11 2.40 86 0.018 0.06 10.5 [10.36, 10.68 [10.6, 10.64 [10.58, 5

10.63] 10.77] 10.7] 10.12 [9.99, 10.24 [10.16, 10.3 [10.24, ILMN_2097793 ZBTB4 1.65 62 0.103 0.04 2.96 86 0.004 0.09 10.26] 10.31] 10.35] 10.1 [9.95, 10.27 [10.16, 10.32 [10.25, ILMN_1673991 ATIC 1.96 62 0.054 0.06 2.88 86 0.005 0.09 10.26] 10.37] 10.4] 10.19 [10.07, 10.34 [10.28, 10.35 [10.29, ILMN_1766010 YARS 2.30 62 0.025 0.08 2.74 86 0.007 0.08 10.31] 10.41] 10.41] ILMN_2162989 TMEM189 2.42 62 0.019 0.09 2.54 86 0.013 0.07 8.95 [8.86, 9.04] 9.07 [9.02, 9.12] 9.07 [9.02, 9.13] 10.67 [10.5, 10.84 [10.71, 10.9 [10.83, ILMN_1665943 MAP4K1 1.88 62 0.065 0.05 2.82 86 0.006 0.08 10.83] 10.97] 10.98] ILMN_2334296 IL18BP 2.49 62 0.015 0.09 2.42 86 0.018 0.06 9.53 [9.41, 9.65] 9.68 [9.55, 9.8] 9.69 [9.62, 9.75] ILMN_2044453 LPAR5 1.96 62 0.054 0.06 2.76 86 0.007 0.08 9.09 [8.96, 9.21] 9.22 [9.09, 9.34] 9.29 [9.22, 9.36] ILMN_2153787 ARRDC5 1.83 62 0.072 0.05 2.79 86 0.006 0.08 8.62 [8.52, 8.72] 8.72 [8.65, 8.8] 8.79 [8.73, 8.85] ILMN_1788538 NCALD 2.10 62 0.040 0.07 2.67 86 0.009 0.08 9.15 [9.02, 9.27] 9.33 [9.2, 9.46] 9.36 [9.28, 9.45] ILMN_1670948 TSR2 2.12 62 0.038 0.07 2.60 86 0.011 0.07 9.23 [9.12, 9.33] 9.33 [9.28, 9.39] 9.35 [9.3, 9.4] ILMN_1671257 DKC1 1.70 62 0.094 0.04 2.70 86 0.008 0.08 9.73 [9.63, 9.84] 9.85 [9.77, 9.92] 9.9 [9.83, 9.98] ILMN_1663954 NELFCD 1.28 62 0.206 0.03 2.71 86 0.008 0.08 9.46 [9.35, 9.56] 9.53 [9.46, 9.61] 9.62 [9.55, 9.68] ILMN_1761479 ZC3HC1 2.05 62 0.044 0.06 2.55 86 0.013 0.07 9.01 [8.93, 9.09] 9.13 [9.06, 9.19] 9.15 [9.08, 9.21] 11.38 [11.21, 11.62 [11.46, 11.59 [11.51, ILMN_2183687 LIME1 2.37 62 0.021 0.08 2.36 86 0.020 0.06 11.56] 11.77] 11.66] ILMN_1801348 GOT2 2.21 62 0.031 0.07 2.41 86 0.018 0.06 9.69 [9.58, 9.79] 9.84 [9.74, 9.94] 9.85 [9.77, 9.92] 10.1 [9.99, 10.23 [10.16, 10.22 [10.16, ILMN_1779185 SPECC1L 2.36 62 0.022 0.08 2.25 86 0.027 0.06 10.21] 10.3] 10.28] ILMN_1753885 YTHDF1 1.51 62 0.136 0.04 2.60 86 0.011 0.07 9.7 [9.58, 9.83] 9.79 [9.74, 9.84] 9.84 [9.79, 9.89] ILMN_1740265 ACOT7 1.88 62 0.065 0.05 2.52 86 0.014 0.07 8.44 [8.37, 8.51] 8.58 [8.47, 8.68] 8.61 [8.53, 8.69] ILMN_2306189 MAGED1 0.95 62 0.348 0.01 2.56 86 0.012 0.07 8.31 [8.26, 8.37] 8.37 [8.28, 8.45] 8.45 [8.39, 8.51] ILMN_1748894 GTPBP3 1.76 62 0.083 0.05 2.54 86 0.013 0.07 8.9 [8.8, 9] 9 [8.93, 9.07] 9.04 [8.98, 9.11] ILMN_1685580 CBLB 1.88 62 0.064 0.05 2.47 86 0.016 0.07 9.36 [9.25, 9.46] 9.49 [9.38, 9.6] 9.54 [9.45, 9.62] ILMN_2343097 NCALD 1.76 62 0.083 0.05 2.53 86 0.013 0.07 8.63 [8.52, 8.74] 8.76 [8.64, 8.89] 8.81 [8.73, 8.89] ILMN_1708328 RAB11FIP3 1.76 62 0.083 0.05 2.52 86 0.014 0.07 9.01 [8.92, 9.09] 9.11 [9.02, 9.19] 9.15 [9.08, 9.21] ILMN_1751338 NUP133 1.35 62 0.183 0.03 2.57 86 0.012 0.07 8.89 [8.82, 8.96] 8.96 [8.89, 9.03] 9.02 [8.96, 9.09] ILMN_1744068 ELP3 1.58 62 0.119 0.04 2.51 86 0.014 0.07 9.45 [9.35, 9.56] 9.55 [9.49, 9.6] 9.6 [9.53, 9.66] 6

10.65 [10.49, 10.79 [10.7, 10.82 [10.76, ILMN_1763460 NHP2L1 1.85 62 0.069 0.05 2.45 86 0.016 0.07 10.8] 10.88] 10.88]

Note. For CVLT-associated genes related to diagnostic status, fixed effect comparisons between SZ and each nonpatients group (i.e., SZ-CT and controls) were reported along with group mean expression values in the discovery sample. Separate mixed linear effect models were run between SZ-

CT and controls, and no significant differences were found. SZ = schizophrenia patients; SZ-CT = unaffected co-twins of schizophrenia patients.

Boldface type reflects significance (p < .05). 7

Table S3

Mean Expression Levels by Diagnostic Status for CVLT-Associated Genes in Finnish Sample

SZ-CT Control SZ vs. SZ-CT SZ vs. controls SZ expression expression expression Gene Partial Partial Illumina probe t df p t df p Mean [95% CIs] Mean [95% CIs] Mean [95% CIs] symbol R 2 R 2 11.45 [11.21, ILMN_2224143 MCM3 1.82 42 0.075 0.07 2.14 42 0.038 0.10 11 [10.67, 11.33] 11.41 [11, 11.82] 11.68] 10.51 [10.17, 11.01 [10.76, ILMN_1728298 SBK1 2.01 42 0.051 0.09 2.10 42 0.042 0.09 11 [10.51, 11.49] 10.86] 11.26] 12.54 [12.22, 12.92 [12.53, 12.98 [12.74, ILMN_1787461 RUNX3 1.80 42 0.078 0.07 2.11 42 0.041 0.10 12.86] 13.32] 13.22] 10.62 [10.18, 10.66 [10.42, ILMN_1775522 MAGED1 1.98 42 0.054 0.09 2.29 42 0.027 0.11 10.17 [9.87, 10.47] 11.06] 10.89] 10.34 [10.11, ILMN_2412549 GAR1 1.91 42 0.063 0.08 2.16 42 0.037 0.10 9.9 [9.61, 10.19] 10.3 [9.9, 10.71] 10.56] 10.85 [10.51, 11.28 [10.85, 11.3 [11.05, ILMN_1686871 PARP1 1.82 42 0.076 0.07 2.06 42 0.045 0.09 11.19] 11.71] 11.55] 10.47 [10.05, 10.47 [10.24, ILMN_1721978 CARD11 2.00 42 0.052 0.09 2.18 42 0.035 0.10 10.03 [9.77, 10.29] 10.88] 10.71] 10.63 [10.22, 10.6 [10.36, ILMN_2097793 ZBTB4 1.95 42 0.057 0.08 1.98 42 0.054 0.09 10.2 [9.92, 10.48] 11.04] 10.85] 10.52 [10.28, 10.96 [10.56, 10.94 [10.72, ILMN_1673991 ATIC 2.13 42 0.039 0.10 2.22 42 0.032 0.10 10.77] 11.35] 11.17] 10.58 [10.29, 10.95 [10.55, 11.02 [10.79, ILMN_1766010 YARS 1.80 42 0.079 0.07 2.18 42 0.035 0.10 10.87] 11.36] 11.24] 10.41 [9.99, 10.47 [10.23, ILMN_1801348 GOT2 1.89 42 0.066 0.08 2.17 42 0.035 0.10 10.02 [9.76, 10.28] 10.83] 10.7] ILMN_2306189 MAGED1 1.79 42 0.081 0.07 2.19 42 0.034 0.10 8.73 [8.54, 8.93] 9.03 [8.7, 9.37] 9.08 [8.9, 9.26] ILMN_1748894 GTPBP3 1.79 42 0.081 0.07 2.07 42 0.044 0.09 9.29 [9.01, 9.56] 9.66 [9.26, 9.7 [9.47, 9.92] 8

10.07] ILMN_2343097 NCALD 1.59 42 0.120 0.06 2.17 42 0.036 0.10 9.16 [8.87, 9.45] 9.54 [9.09, 9.99] 9.64 [9.39, 9.89]

Note. Of the 43 CVLT-associated genes related to diagnostic status in the Swedish sample, 14 were significantly associated with diagnostic status in the Finnish sample. For those genes, fixed effect comparisons between SZ and each nonpatients group (i.e., SZ-CT and controls) were reported along with group mean expression values in the replication sample. Separate mixed linear effect models were run between SZ-CT and controls, and no significant differences were found. SZ = schizophrenia patients; SZ-CT = unaffected co-twins of schizophrenia patients. Boldface type reflects significance (p < .05). 9

Table S4

Functional Annotation Clustering of Genes Associated with CVLT and Diagnostic Status

Cluster Database Category Term No. genes p Enrichment score Cluster 1: RNA processing 2.53 SP-PIR-Keywords rRNA processing 4 0.00020 Gene Onotology BP ribosome biogenesis 5 0.00021 Gene Onotology BP ncRNA metabolic process 6 0.00022 Gene Onotology CC nucleolus 8 0.00028 SP-PIR-Keywords RNA-binding 7 0.00045 Gene Onotology BP ribonucleoprotein complex biogenesis 5 0.00092 Gene Onotology BP ncRNA processing 5 0.0011 Gene Onotology BP rRNA processing 4 0.0014 Gene Onotology BP rRNA metabolic processing 4 0.0016 Gene Onotology BP RNA processing 7 0.0019 SP-PIR-Keywords ribosome biogenesis 3 0.0036 Gene Onotology CC nucleoplasm part 6 0.0039 Gene Onotology CC intracellular organelle lumen 10 0.0048 Gene Onotology CC nuclear lumen 9 0.0049 Gene Onotology CC organelle lumen 10 0.0056 Gene Onotology CC nucleoplasm 7 0.0060 Gene Onotology MF RNA binding 7 0.0063 Gene Onotology CC membrane-enclosed lumen 10 0.0064 SP-PIR-Keywords nucleus 16 0.0071 SP-PIR-Keywords ribonucleoprotein 4 0.015 Gene Onotology CC ribonucleoprotein complex 5 0.017 Gene Onotology CC intracellular non-membrane-bounded organelle 9 0.012 Gene Onotology CC non-membrane-bounded organelle 9 0.012 Cluster 2: DNA Replication 1.60 10

Gene Onotology CC nucleoplasm 7 0.063 Gene Onotology BP DNA matabolic process 5 0.034 Gene Onotology BP DNA replication 3 0.078 Cluster 3: Regulation of Cell Proliferation and Death 0.60 Gene Onotology BP regulation of cell proliferation 5 0.12 Gene Onotology BP regulation of apoptosis 4 0.31 Gene Onotology BP regulation of programmed cell death 4 0.32 Gene Onotology BP regulation of cell death 4 0.32 Cluster 4: Nucleotide and ATP Binding 0.58 Gene Onotology MF nucleotide binding 9 0.15 SP-PIR-Keywords nucleotide-binding 6 0.20 SP-PIR-Keywords ATP-binding 5 0.23 Gene Onotology MF purine ribonucleotide binding 7 0.27 Gene Onotology MF ribonucleotide binding 7 0.27 UP-SEQ-Feature nucleotide phosphate-binding region: ATP 4 0.27 Gene Onotology MF ATP binding 6 0.27 Gene Onotology MF adenyl ribonucleotide binding 6 0.28 Gene Onotology MF purine nucleotide binding 7 0.30 Gene Onotology MF adenyl nucleotide binding 6 0.32 Gene Onotology MF purine nucleoside binding 6 0.33 Gene Onotology MF nucleoside binding 6 0.34 Cluster 5: Regulation of Transcription 0.56 Gene Onotology BP regulation of transcription 10 0.17 SP-PIR-Keywords transcription regulation 7 0.17 Gene Onotology MF transcription activator activity 3 0.26 regulation of transcription fron RNA polymerase II Gene Onotology BP 4 0.26 promoter Gene Onotology MF transcription regulator activity 6 0.29 Gene Onotology BP regulation of transcription, DNA-dependent 6 0.44 Gene Onotology BP regulation of RNA metabolic process 6 0.46 Cluster 6: Calcium Ion Binding 0.54 11

INTERPRO EF-Hand type 3 0.083 SP-PIR-Keywords Calcium 3 0.45 Gene Onotology MF calcium ion binding 3 0.66 Cluster 7: Ion Binding 0.45 SP-PIR-Keywords Transcription 8 0.082 Gene Onotology BP regulation of transcription 10 0.17 SP-PIR-Keywords transcription regulation 7 0.17 SP-PIR-Keywords zinc-finger 6 0.22 Gene Onotology BP transcription 8 0.24 SP-PIR-Keywords metal-binding 8 0.32 SP-PIR-Keywords zinc 6 0.39 SP-PIR-Keywords DNA-binding 5 0.47 Gene Onotology MF DNA binding 7 0.49 Gene Onotology MF transition metal ion binding 8 0.51 Gene Onotology MF zinc ion binding 6 0.67 Gene Onotology MF metal ion binding 10 0.70 Gene Onotology MF cation binding 10 0.71 Gene Onotology MF ion binding 10 0.73 Cluster 8: Catabolic Processes 0.34 SP-PIR-Keywords ubl conjugation pathway 3 0.25 modification-dependent macromolecule catabolic Gene Onotology BP 3 0.41 process Gene Onotology BP modification-dependent protein catabolic process 3 0.41 Gene Onotology BP proteolysis involved in cellular protein catabolic process 3 0.43 Gene Onotology BP cellular protein catabolic process 3 0.44 Gene Onotology BP protein catabolic process 3 0.45 Gene Onotology BP cellular macromolecular catabolic process 3 0.53 Gene Onotology BP macromolecule catabolic process 3 0.58 Gene Onotology BP proteolysis 3 0.74 Cluster 9: Protein Localization and Transport 0.31 Gene Onotology BP protein localization 4 0.37 12

Gene Onotology BP protein transport 3 0.56 Gene Onotology BP establishment of protein localization 3 0.57 Cluster 10: Phosphorylation 0.21 Gene Onotology BP protein amino acid phosphorylation 3 0.49 Gene Onotology BP phosphorylation 3 0.59 Gene Onotology BP phosphorus metabolic process 3 0.70 Gene Onotology BP phosphate metabolic process 3 0.70 Cluster 11: Cell Membrane 0.06 SP-PIR-Keywords cell membrane 4 0.79 Gene Onotology CC plasma membrane 6 0.90 SP-PIR-Keywords membrane 9 0.94 Cluster 12: Membrane 0.01 SP-PIR-Keywords membrane 9 0.94 UP-SEQ-Feature topological domain: extracellular 3 0.97 UP-SEQ-Feature transmembrane region 5 0.99 SP-PIR-Keywords transmembrane 5 0.99 UP-SEQ-Feature topoloical domain: cytoplasmic 3 0.99 Gene Onotology CC intregral to membrane 6 0.99 Gene Onotology CC intrinsic to membrane 6 1.00

Note. Forty-one genes (mapped from 43 probes) were clustered into 12 groups of related annotation terms. Enrichment scores for each cluster are reported along with all terms included for each cluster, the number of genes corresponding to each term, and respective p-values. BP = biological process; CC = cellular component; MF = molecular function 13

Figure S1. Genome-wide gene expression in schizophrenia patients vs. controls. Patients’ expression levels were normalized to the mean and standard deviation of the control sample for each probe remaining after quality control (N = 18,559). The x-axis reflects the control mean for each probe. Bars below the x-axis represent genes for which patients showed underexpression relative to controls (71.5% of all probes); bars above the x-axis reflect patient overexpression (28.5%).