Supplementary Material

Localizing regions in the genome contributing to ADHD, aggressive and antisocial behavior

Running title: Genetic overlap between ADHD, aggression and antisocial behavior

Mariana Lizbeth Rodríguez López1, Barbara Franke1,2*, Marieke Klein1,3

1 Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands

2 Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Nijmegen, The Netherlands

3 University Medical Center Utrecht, UMC Utrecht Brain Center, Department of Psychiatry, Utrecht, the Netherlands

Supplementary Tables: 5 Supplementary Figures: 2

Supplementary Table 1 | Category traits from LDHub GWAS-ss database. Category Number of traits Aging 3 Anthropometric 22 Autoimmune 11 Bone 5 Brain Volume 7 Cancer 5 Cardiometabolic 2 Cognitive 1 Education 5 Glycemic 8 Haemotological 3 Hormone 2 Kidney 6 Lipids 4 Lung Function 8 Metabolites 107 Metal 2 Neurological 3 Other 1 Personality 4 Psychiatric 11 Reproductive 4 Sleeping 5 Smoking 4 Behaviour Uric Acid 1 Total 234

A list of all categories from all the traits LDHub platform. We performed genetic correlation analyses for all traits with both AGG and ASB, giving a total of 234 rg scores for each one of our two traits.

Supplementary Table 2 | Summary of data from GTEx project (https://gtexportal.org/home/).

GTEx - expression in 12 brain-related tissues Anterior Caudate Frontal cingulate (basal Cerebellar Cortex Nucleus Substantia Tissues Amygdala cortex ganglial) Hemisphere Cerebellum Cortex (BA9) Hippocampus Hypothalamus accumbens Putamen nigra

Group 1 PBXIP1 83.295 92.11 136.3 42.495 50.13 86.42 72.98 51.38 83.98 135.9 95.535 103.7 PYGO2 19.865 23.33 22.93 58.905** 57.1** 30.665 30.97 19.49 28.93 26.55 18.26 20.235 KCNT2 1.2525 1.856 0.8475 0.3605 0.85 2.4595 3.221* 1.539 2.246 1.142 0.7494 1.1555 CFHR1 0.03493 0.0595 0.016485 0 0 0.029725 0.03561 0.05782 0.1552 0.01877 0.01452 0.09924 F13B 0 0 0 0 0 0 0 0 0 0 0 0 ZBTB41 4.0555 4.681 4.0645 21.005** 19.24** 5.2035 7.079 4.327 5.938 4.999 3.072 4.5755 ZC3H8 3.987 5.256 4.829 16.335** 12.05** 5.8525 7.851* 4.174 5.688 6.062 3.81 4.5175 ZC3H6 2.258 2.435 2.835 9.2065** 8.476* 3.323 3.629 2.639 2.979 3.42 2.303 2.648 TTL 6.8825 6.923 7.939 6.637 6.429 8.809** 9.624** 8.117* 6.115 8.315* 8.3165* 7.1635 TBC1D14 11.735 13.8 12.445 12.505 14.12 14.94 15.41 10.51 12.38 15.09 8.727 11.15 C5orf51 8.315 9.273 9.3295 23.25** 17.05 8.183 12.66 9.085 11.75 10.41 7.2935 10.67 FBXO4 2.5295 2.412 2.405 5.5165 4.776 2.481 2.712 2.412 3.399 2.987 2.1895 2.682 GHR 0.6335 0.8804 0.6436 0.3533 0.4992 0.77815 0.9152 0.6902 1.715 0.8455 0.507 1.1485 CCDC152 3.024 1.502 2.888 0.77565 0.9818 1.872 1.943 2.848 4.652 2.928 2.261 3.594 SEPP1 25.305 13.02 34.605 11.75 21.34 17.61 17.42 38.15 27.07 23.3 31.23 69.42 ZNF131 4.107 4.919 4.843 20.61** 16.16** 5.59 7.157 4.49 5.125 5.408 3.692 4.4385 HMGCS1 26.14 38.67 17.27 37.37 30.48 43.64 62.84* 25 44.03 22.86 13.29 21.655 NKAIN2 16.775* 15.88* 9.8155 13.125* 8.768 10.87* 17.97** 23.25** 13.4* 9.397 9.199 23.99** GATA4 0.01081 0.009618 0.01293 0.014995 0.02724 0.014875 0.01265 0.01436 0.01566 0.01179 0.010335 0.01081 TMEM71 0.38965 0.3923 0.443 0.2385 0.234 0.3438 0.3669 0.4123 0.584 0.3732 0.43025 0.47885 TG 1.02 0.5413 0.4633 0.5515 0.717 0.541 0.4967 0.7798 0.4466 0.4407 0.3571 0.4067 SLA 2.6845 2.208 2.0815 1.2075 1.307 1.253 1.376 2.968 2.232 2.725 1.494 3.165 CHUK 4.0345 3.989 4.9745 10.76* 10.03 3.918 4.755 4.255 6.679 4.882 4.2505 5.2315 CWF19L1 4.8505 6.225 5.869 21.69** 18.36* 8.19 9.456 5.533 7.615 7.45 5.029 6.0695 BLOC1S2 35.795 42.05* 28.775 49.665** 39.27 40.46 58.26** 33.11 48.46** 35.55 26.53 45.475* ATRNL1 5.4335* 10.27** 4.1875 0.85805 2.225 18.255** 25.43** 4.859 3.722 5.022 3.125 1.903 KCNK18 0 0.0276* 0.16495** 0 0 0.034725* 0.05654** 0 0.07626** 0.1824** 0.03221* 0 TMEM132B 7.937* 12.46** 8.6615* 1.7025 1.323 14.795** 17.8** 7.022* 4.371* 11.73** 6.917* 3.3505 MLLT6 33.17 41.72 27.875 96.45* 103.6* 52.765 46.42 28.87 26.22 31.24 24.98 25.86 PCGF2 12.515 16.2 12.455 54.53 54.1 21.69 20.86 11.7 18.3 15.2 11.02 10.7 ANKRD54 13.155 15.42 12.6 32.335** 32.58** 17.85 18.08 12.63 18.47 13.93 11.08 12.03 TMEM184B 33.285 47.09 30.875 58.175* 76.82** 66.08** 57.05 36.68 40.53 34.47 29.73 36.585 GTPBP1 12.1 13.6 12.655 39.09* 41.08** 18.73 17.15 13.16 14.21 15.6 10.955 12.095 SUN2 36.555 22.13 47.785 48.02 55.66 40.12 35.58 49.63 32.79 30.4 46.46 46.79

Group 2 DAB1 3.487* 4.671* 1.1335 24.035** 18.68 ** 3.73* 4.35* 4.86** 3.439* 1.432 0.8718 2.5095 F13B 0 0 0 0 0 0 0 0 0 0 0 0 RBM43 1.7745 1.542 2.121 0.7295 0.833 1.354 1.712 1.418 2.189 2.418 1.4555 1.7525 NMI 3.3705 2.543 3.1935 1.1825 1.421 2.403 2.298 2.922 3.216 2.854 2.817 3.987 SHOX2 0.01234 0.01641 0.010064 0.02929 0.02808 0.023865 0.0188 0.009096 0.136 0.02091 0.010615 0.074495 RSRC1 4.481 5.631 5.3415 17.26** 11.09** 5.625 9.453* 4.501 6.478 6.062 3.7855 5.326 HMGCS1 26.14 38.67 17.27 37.37 30.48 43.64 62.84* 25 44.03 22.86 13.29 21.655 CCL28 0.6247 0.6295 0.3163 0.100535 0.144 0.86005 1.027 0.4091 0.625 0.2951 0.174 0.4703 MSRA 6.2405 8.598 6.1115** 29.7** 28.09 10.08 11.05* 7.369 5.962 6.695 4.88 6.181 PRSS55 0.1154 0.1309 0.11825 0.57605 0.5789 0.14815 0.141 0.1179 0.05924 0.1043 0.11545 0.08649 FAM167A 14.395* 19.29** 14.09* 7.613 12.58 19.525** 16.77* 9.731 11.33 12.71 11.785 10.905 BLK 0.01749 0.01973 0.016935 0.08194 0.1098 0.026865 0.02019 0.03163 0.04851 0.01234 0.0171 0.035155 GATA4 0.01081 0.009618 0.01293 0.014995 0.02724 0.014875 0.01265 0.01436 0.01566 0.01179 0.010335 0.01081 NEIL2 20.405 21.24 18.465 28.14** 26.35* 24.005 27.17* 17.57 28.91** 24.13* 15.95 22.915 FDFT1 30.84 34.31 24.1 39.735 37.45 41.945 49.73 31.45 43.87 27.17 20.88 35.09 CTSB 65.295 89.44 88.39 104.6 93.59 119.65 142.7 68.3 104.2 91.24 70.485 98.18 DEFB136 0 0 0 0 0 0 0 0 0 0 0 0 DEFB134 0.075625 0.06506 0.11595 0.5516 0.5019 0.097625 0.08884 0.02926 0.08835 0.09981 0.058605 0 USP17L7 0 0.02502 0.04138 0.07753 0.1282 0.027565 0.02539 0.01203 0 0.03694 0.02931 0 KIAA1456 1.475 3.078 2.946 105.9** 92.84** 3.525* 4.485** 2.366 2.776 3.115* 1.705 1.6125 NOX4 0.1155 0.06863 0.15025 0.036925 0.04916 0.11765 0.1186 0.1321 0.159 0.09159 0.1528 0.2001 LRP1 0 0 0 0 0 0 0 0 0.02956 0 0 0.016335 NXPH4 1.5055 1.937 0.7042 28.445** 31.54** 1.563 1.725 0.9111 2.86* 0.4112 0.7665 1.0036 STAC3 1.6805 1.695 1.842 4.2185 4.353 1.7835 1.701 1.769 1.781 1.713 1.7585 1.8685 R3HDM2 21.13 27.33 21.83 83.45** 80.54** 42.855 43.62* 20.9 23.26 25.5 18.29 20.485 INHBC 0.06522 0.07656 0.059665 0.6836 0.7682 0.097185 0.09135 0.04705 0.0478 0.08805 0.065755 0.0623 INHBE 0.115 0.2444 0.1075 1.2605 1.29 0.2567 0.2883 0.07665 0.2749 0.2486 0.06807 0.2074 ARHGEF40 13.52 12.13 13.145 31.395 35.83 13.22 9.816 11.27 15.91 13.19 11.51 14.32 ATP5G1 80.29 98.44 94.955 100.7 88.54 99.605 132.3** 80.51 87.83 108.9* 81.8 81.525 UBE2Z 24.55 30.01 22.435 53.51 47.08 39.355 45.63 27.55 33.21 29.55 19.425 25.575 SNF8 14.515 17.22 16.65 27.275 24.38 19.185 21.23 14.52 17.62 18.5 15.22 17.215 GIP 0 0 0 0 0 0 0 0 0 0 0 0 C19orf66 25.295 31.29 29.63 54.805 57.75 45.24 41.33 25.97 37.12 31.77 25.76 21.31 BCL3 3.375 3.374 2.8825 1.7795 2.944 5.2995 4.1 2.908 5.248 2.613 2.266 5.2565 KLC3 0.07445 0.2325 0.40385 0.045445 0.05787 0.2108 0.2143 0.07716 0.1107 0.5094 0.2935 0.07667 ERCC2 8.8075 10.89 8.445 14.18* 16.12* 14.135* 12.93 7.96 9.207 10.52 7.2585 7.3945 IGLON5 12.49* 20.93* 6.529 127.8** 131.6** 27.85** 28.63** 15.6* 32.96** 9.206 6.0315 19.79* VSIG10L 1.728 2.634 1.8855 7.122 6.86 2.5915 3.004 2.167 3.497 2.411 1.4695 3.37 ETFB 24.075 26.57 28.12 21.525 20.28 25.56 28.38 24.41 24.93 33.8* 27.555 32.19

Group 3 SRSF10 1.36 1.55 1.812 5.4905 4.688 1.585 1.983 1.522 1.928 1.863 1.2575 1.666 RCAN3 1.331 1.176 2.1395 59.835** 39.96** 1.072 1.386 1.719 7.823 2.149 2.1295 4.5765 Results show the median Transcripts Per Million (TPM) for each gene from the candidate loci across 12 brain-related tissues. Table is divided into groups (Group1-3). Scores with double asterisk (**) indicate a tissue (column) within the top five tissues (from 53) that most strongly express a gene (row). Scores with single asterisk (*) indicate the ones within the top ten of highest expression.

Supplementary Table 3 | Summary of spatio-temporal gene regulation results.

Spatio-temporal gene regulation Group 1 Group 2 Group 3 Region Enriched Co-Expr. Region Co-Expr. Region Co-Expr. DEX Network Enriched Network Enriched Network genes modules Genes DEX genes modules Genes DEX genes modules PBXIP1 - M2 DAB1 - - SRSF10 - - PYGO2 - - F13B - - RCAN3 - M20 KCNT2 - - RBM43 - M2 CFHR1 - - NMI - M2 F13B - - SHOX2 MD M9* ZBTB41 - M20 RSRC1 - - ZC3H8 - - HMGCS1 - - ZC3H6 - - CCL28 - - TTL - - MSRA - - TBC1D14 - - PRSS55 - - C5orf51 - M20 FAM167A - - FBXO4 - - BLK - - GHR - M2 GATA4 - - CCDC152 - - NEIL2 - M2 SEPP1 - M2 FDFT1 - - ZNF131 - M20 CTSB - M2 HMGCS1 - - DEFB136 - - NKAIN2 - - DEFB134 - - GATA4 - - USP17L7 - - TMEM71 - - KIAA1456 - - TG - - NOX4 - M1 SLA - - LRP1 - - CHUK - - NXPH4 CBC - CWF19L1 - - STAC3 - - BLOC1S2 - M20 R3HDM2 - - ATRNL1 - - INHBC - - KCNK18 - - INHBE - - TMEM132B - - ARHGEF40 - - MLLT6 - - ATP5G1 - - PCGF2 - M20 UBE2Z - - ANKRD54 - - SNF8 - - TMEM184B - - GIP - - GTPBP1 - - C19orf66 - M2 SUN2 - - BCL3 - - KLC3 - - ERCC2 - - IGLON5 - - VSIG10L - - ETFB - M2 Co-expression modules were based on results of a previous study (Kang, et al., 2011). Results provide an overview on brain regions in which a gene is differentially expressed (Region Enriched DEX genes) and the relevant module number, in the co-expression by region and time of development with other genes (Co-Expr. Network modules). No results were obtained for the majority of genes (indicated by dash). Asterisk indicates a gene which was found to be a hub in the network for that module. MD (mediodorsal nucleus of the thalamus). CBC (cerebellar cortex). Table is divided in groups (Group 1-3).

Supplementary Table 4 | Results of gene-based association analyses.

ENIGMA – Gene-based association with regional brain volumes Tissues Accumbens Amygdala Caudate Hippocampus ICV Pallidum Putamen Thalamus

Group 1 PBXIP1 0.21161 0.44826 0.18413 0.93961 0.20896 0.97573 0.9034 0.13225 PYGO2 0.38515 0.94401 0.32104 0.3947 0.0051737* 0.6337 0.022814* 0.54902 KCNT2 0.16288 0.087444 0.1027 0.8835 0.75205 0.14774 0.00012407** 0.61553 CFHR1 ------F13B 0.8006 0.80823 0.16633 0.89822 0.13509 0.0048719* 0.085054 0.18427 ZBTB41 0.83084 0.98232 0.19726 0.95173 0.11276 0.02318* 0.17741 0.44882 ZC3H8 0.4724 0.74427 0.63767 0.79892 0.27217 0.5775 0.90326 0.3113 ZC3H6 0.48784 0.88877 0.85578 0.83631 0.22464 0.60742 0.97887 0.73771 TTL 0.49848 0.88058 0.20541 0.2604 0.54183 0.079305 0.40044 0.55723 TBC1D14 0.40534 0.75219 0.80117 0.7311 0.62347 0.29058 0.74179 0.02246* C5orf51 0.715 0.45781 0.74684 0.17509 0.092003 0.88147 0.62521 0.42926 FBXO4 0.78999 0.2837 0.77998 0.14038 0.17862 0.88528 0.79424 0.39207 GHR 0.26344 0.33156 0.9318 0.94885 0.67347 0.27147 0.65257 0.92875 CCDC152 0.59331 0.16822 0.91315 0.82071 0.52824 0.74439 0.81028 0.63021 SEPP1 0.59769 0.16475 0.96128 0.71323 0.73398 0.86846 0.80393 0.53398 ZNF131 0.18554 0.049901* 0.69852 0.77005 0.87339 0.046282* 0.74476 0.3249 HMGCS1 0.082638 0.46499 0.97927 0.11585 0.10153 0.019882* 0.15007 0.073896 NKAIN2 0.7256 0.64993 0.85364 0.78248 0.020037* 0.91942 0.62273 0.68472 GATA4 0.036933* 0.041591* 0.4057 0.011621* 0.29588 0.85057 0.011928* 0.056181 TMEM71 0.80232 0.73943 0.65731 0.54991 0.27448 0.89121 0.27701 0.6836 TG 0.037086* 0.56367 0.54181 0.443 0.46333 0.97435 0.50244 0.76341 SLA 0.024368* 0.41026 0.62162 0.20355 0.81976 0.98249 0.44209 0.6541 CHUK 0.29297 0.43975 0.34955 0.34223 0.56154 0.18334 0.60848 0.62788 CWF19L1 0.34031 0.3336 0.39491 0.27714 0.646 0.22597 0.69725 0.67788 BLOC1S2 0.36694 0.42634 0.24414 0.38066 0.28711 0.17551 0.50294 0.64041 ATRNL1 0.035902* 0.7447 0.86932 0.1597 0.34123 0.066613 0.64843 0.84338 KCNK18 0.16016 0.70416 0.39522 0.80844 0.13324 0.379 0.80764 0.17052 TMEM132B 0.48487 0.83914 0.93959 0.79296 0.48104 0.82125 0.0001765** 0.1628 MLLT6 0.34946 0.40398 0.65922 0.69046 0.44456 0.63232 0.71295 0.81814 PCGF2 0.51929 0.34925 0.90248 0.17481 0.77691 0.84982 0.73835 0.37944 ANKRD54 0.02844* 0.51578 0.31338 0.3176 0.63245 0.21636 0.21607 0.022613* TMEM184B 0.49941 0.64461 0.63497 0.035166* 0.4087 0.53941 0.81635 0.33889 GTPBP1 0.95382 0.85585 0.44659 0.81522 0.24546 0.8792 0.50832 0.8189 SUN2 0.67517 0.71056 0.58969 0.72392 0.1527 0.52563 0.32754 0.70924

Group 2 DAB1 0.91206 0.58183 0.1512 0.74726 0.89868 0.23683 0.13587 0.70879 F13B 0.8006 0.80823 0.16633 0.89822 0.13509 0.0048719* 0.085054 0.18427 RBM43 0.53078 0.13556 0.17695 0.46581 0.26064 0.10531 0.28648 0.032736* NMI 0.81171 0.28832 0.22939 0.50209 0.10671 0.1955 0.52618 0.048308* SHOX2 0.166 0.87014 0.60647 0.2337 0.50126 0.21412 0.79026 0.88932 RSRC1 0.033118* 0.71597 0.88089 0.46366 0.72728 0.4359 0.0044312* 0.40778 HMGCS1 0.082638 0.46499 0.97927 0.11585 0.10153 0.019882* 0.15007 0.073896 CCL28 0.031499* 0.37896 0.88297 0.16075 0.43554 0.1321 0.064248 0.10896 MSRA 0.26826 0.49417 0.4905 0.60015 0.64696 0.73263 0.069253 0.3439 PRSS55 0.74121 0.095639 0.26715 0.25093 0.34283 0.24263 0.31452 0.24547 FAM167A 0.27837 0.54746 0.89429 0.024375* 0.17447 0.62057 0.82112 0.50793 BLK 0.19217 0.11071 0.77733 0.48911 0.74399 0.73208 0.55752 0.062565 GATA4 0.036933* 0.041591* 0.4057 0.011621* 0.29588 0.85057 0.011928* 0.056181 NEIL2 0.73395 0.043893* 0.0049753* 0.39748 0.16443 0.92791 0.052827 0.83444 FDFT1 0.0036397* 0.067626 0.12658 0.35978 0.38121 0.9221 0.080898 0.12759 CTSB 0.071055 0.13537 0.076408 0.58655 0.54773 0.91524 0.16989 0.74303 DEFB136 0.042153* 0.19675 0.31656 0.12029 0.72698 0.93463 0.2071 0.24012 DEFB134 0.0079314* 0.17603 0.21715 0.018014* 0.35157 0.38781 0.040374* 0.66334 USP17L7 ------KIAA1456 0.024757* 0.11516 0.25715 0.45462 0.8337 0.79877 0.70039 0.10999 NOX4 0.095026 0.91156 0.50106 0.66818 0.12015 0.39359 0.73429 0.052164 LRP1 0.53353 0.66511 0.068879 0.067096 0.64364 0.0065021* 0.31727 0.68684 NXPH4 0.3497 0.15506 0.44744 0.55853 0.11139 0.12225 0.13521 0.41009 STAC3 0.3587 0.6888 0.75919 0.72142 0.18362 0.70134 0.77234 0.59551 R3HDM2 0.72401 0.70075 0.88257 0.75836 0.45715 0.17689 0.2158 0.5567 INHBC 0.802 0.69167 0.65066 0.67078 0.51009 0.13695 0.1866 0.71445 INHBE 0.7505 0.8723 0.8921 0.8265 0.243 0.5468 0.6965 0.657 ARHGEF40 0.89332 0.82968 0.79835 0.46769 0.76117 0.49766 0.98487 0.70776 ATP5G1 0.034686* 0.39381 0.030269* 0.22197 0.92601 0.61232 0.30747 0.30769 UBE2Z 0.058423 0.54127 0.012682* 0.13863 0.77287 0.72029 0.10666 0.50028 SNF8 0.074245 0.28979 0.010277* 0.18145 0.78125 0.60266 0.08246 0.58711 GIP 0.01651* 0.25931 0.011026* 0.34617 0.82283 0.4401 0.21078 0.41895 C19orf66 0.48806 0.12777 0.081029 0.51632 0.4948 0.355 0.0098846* 0.48685 BCL3 0.43156 0.79678 0.02922* 0.60467 0.34056 0.50992 0.91489 0.25164 KLC3 0.80216 0.28566 0.88343 0.66968 0.31951 0.3684 0.86702 0.28146 ERCC2 0.85799 0.59436 0.80777 0.25717 0.15836 0.39027 0.92543 0.24311 IGLON5 0.096981 0.11054 0.20816 0.22231 0.68956 0.57566 0.75808 0.2447 VSIG10L 0.40114 0.45288 0.78229 0.11307 0.62745 0.45554 0.13357 0.30855 ETFB 0.80065 0.073964 0.58754 0.61358 0.5099 0.67287 0.93347 0.14925

Group 3 SRSF10 ------RCAN3 0.34922 0.85251 0.2208 0.15733 0.66026 0.95717 0.80963 0.78402

For the eight subcortical brain volumes, data from the ENIGMA2 consortium was used (Hiber, et al., 2015). Significant (Bonferroni corrected) gene-based associations p-values are marked with double asterisk (thresholds change according to group. Group1 (** p < 0.05/41), Group 2 (** p < 0.05/46), Group3 (** p < 0.05/8)). Nominally significant gene-based associations are marked with a single asterisk. ICV=Intracranial volume

Supplementary Table 6 | Summary of data obtained from GeneCards Human Gene Database (https://www.genecards.org) for biological annotation of all candidate genes. Biological annotation of candidate genes Gene Full name Biological function Molecular function Related Diseases

Group1 -Beta-catenin -Chromatin binding transactivating complex -Oligospermia Pygopus Family PHD -Histone acetyltransferase PYGO2 (deactivation) -Treacher Collins Finger 2 regulator activity -Signaling by GPCR Syndrome 1 -Metal ion binding -Wnt pathway Zinc Finger And BTB -Transcriptional regulation -DNA binding ZBTB41 - Domain Containing 41 (possible) -Metal ion binding -Development and organogenesis, as well as in the function of the adult -DNA-binding transcription ZNF131 Zinc Finger 131 -Joubert Syndrome 1 CNS. (possible) factor activity -ESR1/ER-alpha signaling -Metal ion binding (possible repressor) -Interacts with the beta Sodium/Potassium subunit of a NKAIN2 Transporting ATPase -Transmembrane protein -Lymphoma sodium/potassium- Interacting 2 transporting ATPase Biogenesis Of -BLOC-1 complex -Protein binding BLOC1S2 Lysosomal Organelles - (component) -Gamma-tubulin binding Complex 1 Subunit 2 -Melanocortin signaling ATRNL1 Attractin-Like Protein 1 -Carbohydrate binding - pathways (possible role) -Calcium-activated potassium channel activity Potassium Two Pore -Member of the -Outward rectifier -Migraine with/without KCNK18 Domain Channel superfamily potassium potassium channel activity aura Subfamily K Member 18 channel -Potassium ion leak channel activity Transmembrane TMEM132B -Transmembrane protein - - Protein 132B

Group2 -Neural development (adapter molecule) -Spinocerebellar -SIAH1 activity (possible ataxia 37 DAB1 DAB Adaptor Protein 1 regulator) -Phosphatidylinositol 3 -Lissencephaly with -Guidance coues and kinase binding cerebellar hypoplasia growth cone motility pathway -Schizophrenia (possible association) -Intellectual developmental Arginine And Serine -Pre-mNA constitutive and RSRC1 -Protein binding disorder Rich Coiled-Coil 1 alternative splicing -Autosomal Recessive 70 -Cone-rid dystrophy and hearing loss 2 -Protein repair inactivated Sulfoxide -Mycobacterium MSRA by oxidation -Oxidoreductase activity Reductase A Abscessus -Metabolism of -Occult Macular Dystrophy -Maturity-Onset Family With Sequence Diabetes of the FAM167A Similarity 167 Member - -Protein binding young, type 11 A -Rheumatic disease -Associated with -Member of GAA familiy of -DNA binding transcription cardiac septal defects zinc-finger transcription factor activity -Associated with factors (promoters) -Chromatin binding several cancer types -Embryogenesis and in -Zinc ion binding GATA4 GATA Binding Protein 4 -Tetralogy of Fallot myocardial differentiation -Protein kinase binding -Testicular Anomalies (possible regulator) -Metal ion binding with or without -HOP signaling -NFAT protein binding congenital heart -Adipogenesis -Co-SMAD binding disease -Member of the Fpg/Nei family of DNA glycosylases. -Primarly associated with -DNA binding Nei Like DNA DNA repair (damaged by NEIL2 -Catalytic activity - Glycosylase 2 oxidation or mutagenic -Endonuclease activity agents) -Telomere C-strand synthesis -Depyrimidination -Memeber of the C1 family of peptidases -Overexpression -Proteolytic processing of associated with -Peptidase activity amyloid precursor protein esophageal -Collagen binding CTSB Cathepsin B (APP) adenocarcinoma -Hydrolase activity -Activated TLR4 signalling -Keratolytic Winter -Proteoglycan binding -Innate Immune System Erythema -Intracellular degradation -Annular Erythema -Turnover of proteins -Member of the beta -Atrioventricular defensin protein family Septal Defect DEFB134 Defensin Beta 134 -Defense response to -Antimicrobial -Diaphragmatic bacterium Hernia, Congenital -Innate immune response TRNA -tRNA processing -tRNA wobble uridine KIAA1456 Methyltransferase 9B - - modification (Putative) -Tumor suppressor -Neuropeptide signaling -Signaling receptor NXPH4 Neurexophilin 4 -External Ear Disease pathway binding (alpha-neurexins) -Belongs to the IgLON Family Member IGLON5 immunoglobulin - -Sleep disorder 5 superfamiy IgLON

Group3 -Calcineurin-dependent transcriptional responses (inhibator) -RNA binding -CNS development -Calcium-dependent RCAN Family Member (posible role) protein serine/threonine - RCAN3 -Down Syndrome 3 -Calcium-mediated phosphatase regulator signaling activity -GPCR pathway -Troponin I binding -NFAT and Cardiac Hypertrophy Table is divided into groups (Group 1-3). Column 3 describes related pathways, processes or name of biological groups (GeneCards and UniProtKB/Swiss-Prot). Column 4 lists molecular functions ( (GO) project). Column 5 includes related diseases for each gene (MalaCards).

Supplementary Figure 1 | Modified HESS local SNP-based heritability bar plots. For all plots, X-axis describes loci position in the genome, while Y-axis describes their respective local SNP-heritability estimate and different grey used tones distinguish between even or odd numbers. a) ADHD results show two nominally significant loci (colored in red) on and 5. b) AGG and c) ASB showed no significant loci. d) Neuroticism shows eight nominally significant loci, two on chromosome 2, one on chromosome 6, three on , one on chromosome 11 and one on chr 18omosome e) PSC shows two significant loci (p < 0.05 / 1,694, marked with an asterisk): on chromosome 6 and two nominally significant loci on chromosome 3.

Supplementary Figure 2 | Modified ρHESS local genetic covariance and correlation bar plots. This figure includes all ρHESS results. For all plots, X-axis describes loci genomic position, each segment (a-h) contains two plots, the upper bar plots refers to local genetic correlation estimates (Y-axis) while the lower bar plots refer to the local genetic covariance estimates (Y-axis). Blue colored bars represent the loci that got expected correlation values inside the -1 to 1 range and which were used for subsequent analyses. . Different grey tones distinguish between even or odd chromosome numbers. a) ADHD with AGG, b) ADHD with ASB, d) AGG with Neuroticism, e) ASB with Neuroticism, g) AGG with PSC and h) ASB with PSC cross-trait analyses did not show any significant loci. Only c) ADHD with Neuroticism and f) ADHD with PSC showed nominally significant local genetic covariance on loci (red colored bars) located on chr2:164466638-165178840 & chr2:202818637-205799241 for ADHD with Neuroticism and on chr3:49316972-51832015 for ADHD with PSC.