Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8L7CGX)

• DOT Name: PR domain zinc finger protein 2 (PRDM2)
• Synonyms: EC 2.1.1.355; GATA-3-binding protein G3B; Lysine N-methyltransferase 8; MTB-ZF; MTE-binding protein; PR domain-containing protein 2; Retinoblastoma protein-interacting zinc finger protein; Zinc finger protein RIZ
• Gene Name: PRDM2
• Related Disease:
  Acute myelogenous leukaemia
  Childhood kidney Wilms tumor
  Wilms tumor
  Advanced cancer
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Bone osteosarcoma
  Breast carcinoma
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Esophageal squamous cell carcinoma
  Gastric cancer
  Gastric neoplasm
  Glioblastoma multiforme
  Glioma
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Melanoma
  Meningioma
  Metastatic malignant neoplasm
  Obesity
  Osteosarcoma
  Pheochromocytoma
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Epithelial ovarian cancer
  Ovarian cancer
  Alcohol dependence
  Colorectal carcinoma
  Endometrial carcinoma
  Neuroblastoma
  Parkinson disease
  Retinoblastoma
• UniProt ID: PRDM2_HUMAN
• PDB ID: 2JV0; 2QPW
• EC Number: 2.1.1.355
• Pfam ID: PF21549 ; PF00096 ; PF13912
• Sequence:
  MNQNTTEPVAATETLAEVPEHVLRGLPEEVRLFPSAVDKTRIGVWATKPILKGKKFGPFV
  GDKKKRSQVKNNVYMWEVYYPNLGWMCIDATDPEKGNWLRYVNWACSGEEQNLFPLEINR
  AIYYKTLKPIAPGEELLVWYNGEDNPEIAAAIEEERASARSKRSSPKSRKGKKKSQENKN
  KGNKIQDIQLKTSEPDFTSANMRDSAEGPKEDEEKPSASALEQPATLQEVASQEVPPELA
  TPAPAWEPQPEPDERLEAAACEVNDLGEEEEEEEEEDEEEEEDDDDDELEDEGEEEASMP
  NENSVKEPEIRCDEKPEDLLEEPKTTSEETLEDCSEVTPAMQIPRTKEEANGDVFETFMF
  PCQHCERKFTTKQGLERHMHIHISTVNHAFKCKYCGKAFGTQINRRRHERRHEAGLKRKP
  SQTLQPSEDLADGKASGENVASKDDSSPPSLGPDCLIMNSEKASQDTINSSVVEENGEVK
  ELHPCKYCKKVFGTHTNMRRHQRRVHERHLIPKGVRRKGGLEEPQPPAEQAQATQNVYVP
  STEPEEEGEADDVYIMDISSNISENLNYYIDGKIQTNNNTSNCDVIEMESASADLYGINC
  LLTPVTVEITQNIKTTQVPVTEDLPKEPLGSTNSEAKKRRTASPPALPKIKAETDSDPMV
  PSCSLSLPLSISTTEAVSFHKEKSVYLSSKLKQLLQTQDKLTPAGISATEIAKLGPVCVS
  APASMLPVTSSRFKRRTSSPPSSPQHSPALRDFGKPSDGKAAWTDAGLTSKKSKLESHSD
  SPAWSLSGRDERETVSPPCFDEYKMSKEWTASSAFSSVCNQQPLDLSSGVKQKAEGTGKT
  PVQWESVLDLSVHKKHCSDSEGKEFKESHSVQPTCSAVKKRKPTTCMLQKVLLNEYNGID
  LPVENPADGTRSPSPCKSLEAQPDPDLGPGSGFPAPTVESTPDVCPSSPALQTPSLSSGQ
  LPPLLIPTDPSSPPPCPPVLTVATPPPPLLPTVPLPAPSSSASPHPCPSPLSNATAQSPL
  PILSPTVSPSPSPIPPVEPLMSAASPGPPTLSSSSSSSSSSSSFSSSSSSSSPSPPPLSA
  ISSVVSSGDNLEASLPMISFKQEELENEGLKPREEPQSAAEQDVVVQETFNKNFVCNVCE
  SPFLSIKDLTKHLSIHAEEWPFKCEFCVQLFKDKTDLSEHRFLLHGVGNIFVCSVCKKEF
  AFLCNLQQHQRDLHPDKVCTHHEFESGTLRPQNFTDPSKAHVEHMQSLPEDPLETSKEEE
  ELNDSSEELYTTIKIMASGIKTKDPDVRLGLNQHYPSFKPPPFQYHHRNPMGIGVTATNF
  TTHNIPQTFTTAIRCTKCGKGVDNMPELHKHILACASASDKKRYTPKKNPVPLKQTVQPK
  NGVVVLDNSGKNAFRRMGQPKRLNFSVELSKMSSNKLKLNALKKKNQLVQKAILQKNKSA
  KQKADLKNACESSSHICPYCNREFTYIGSLNKHAAFSCPKKPLSPPKKKVSHSSKKGGHS
  SPASSDKNSNSNHRRRTADAEIKMQSMQTPLGKTRARSSGPTQVPLPSSSFRSKQNVKFA
  ASVKSKKPSSSSLRNSSPIRMAKITHVEGKKPKAVAKNHSAQLSSKTSRSLHVRVQKSKA
  VLQSKSTLASKKRTDRFNIKSRERSGGPVTRSLQLAAAADLSENKREDGSAKQELKDFSY
  SLRLASRCSPPAAPYITRQYRKVKAPAAAQFQGPFFKE
• Function: S-adenosyl-L-methionine-dependent histone methyltransferase that specifically methylates 'Lys-9' of histone H3. May function as a DNA-binding transcription factor. Binds to the macrophage-specific TPA-responsive element (MTE) of the HMOX1 (heme oxygenase 1) gene and may act as a transcriptional activator of this gene.
• Tissue Specificity: Highly expressed in retinoblastoma cell lines and in brain tumors. Also expressed in a number of other cell lines and in brain, heart, skeletal muscle, liver and spleen. Isoform 1 is expressed in testis at much higher level than isoform 3.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:HS04042-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Posttranslational Modification	[1]
Childhood kidney Wilms tumor	DIS0NMK3	Definitive	Biomarker	[2]
Wilms tumor	DISB6T16	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Altered Expression	[4]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[6]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[7]
Cervical cancer	DISFSHPF	Strong	Biomarker	[8]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[9]
Colon cancer	DISVC52G	Strong	Genetic Variation	[10]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[11]
Gastric cancer	DISXGOUK	Strong	Biomarker	[12]
Gastric neoplasm	DISOKN4Y	Strong	Genetic Variation	[13]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[14]
leukaemia	DISS7D1V	Strong	Genetic Variation	[15]
Leukemia	DISNAKFL	Strong	Genetic Variation	[15]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[16]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[16]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[16]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[17]
Meningioma	DISPT4TG	Strong	Altered Expression	[18]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[19]
Obesity	DIS47Y1K	Strong	Biomarker	[20]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[5]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[21]
Prostate cancer	DISF190Y	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[19]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[9]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[22]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[23]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[24]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[24]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[25]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[25]
Breast cancer	DIS7DPX1	moderate	Posttranslational Modification	[6]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[26]
Ovarian cancer	DISZJHAP	moderate	Altered Expression	[26]
Alcohol dependence	DIS4ZSCO	Limited	Biomarker	[27]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[28]
Endometrial carcinoma	DISXR5CY	Limited	Biomarker	[29]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[30]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[31]
Retinoblastoma	DISVPNPB	Limited	Biomarker	[32]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	PR domain zinc finger protein 2 (PRDM2) affects the response to substance of Methamphetamine.	[53]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of PR domain zinc finger protein 2 (PRDM2).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of PR domain zinc finger protein 2 (PRDM2).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PR domain zinc finger protein 2 (PRDM2).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PR domain zinc finger protein 2 (PRDM2).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of PR domain zinc finger protein 2 (PRDM2).	[37]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of PR domain zinc finger protein 2 (PRDM2).	[39]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of PR domain zinc finger protein 2 (PRDM2).	[40]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of PR domain zinc finger protein 2 (PRDM2).	[24]
Selenium	DM25CGV	Approved	Selenium increases the expression of PR domain zinc finger protein 2 (PRDM2).	[42]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of PR domain zinc finger protein 2 (PRDM2).	[43]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of PR domain zinc finger protein 2 (PRDM2).	[44]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of PR domain zinc finger protein 2 (PRDM2).	[45]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of PR domain zinc finger protein 2 (PRDM2).	[46]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of PR domain zinc finger protein 2 (PRDM2).	[34]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of PR domain zinc finger protein 2 (PRDM2).	[47]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of PR domain zinc finger protein 2 (PRDM2).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of PR domain zinc finger protein 2 (PRDM2).	[51]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of PR domain zinc finger protein 2 (PRDM2).	[52]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of PR domain zinc finger protein 2 (PRDM2).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of PR domain zinc finger protein 2 (PRDM2).	[48]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of PR domain zinc finger protein 2 (PRDM2).	[49]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of PR domain zinc finger protein 2 (PRDM2).	[50]

References

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• [2] High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome.Blood. 1997 Aug 1;90(3):1217-25.
• [3] PRDM14 promotes malignant phenotype and correlates with poor prognosis in colorectal cancer.Clin Transl Oncol. 2020 Jul;22(7):1126-1137. doi: 10.1007/s12094-019-02239-z. Epub 2019 Nov 18.
• [4] RIZ1 is potential CML tumor suppressor that is down-regulated during disease progression.J Hematol Oncol. 2009 Jul 14;2:28. doi: 10.1186/1756-8722-2-28.
• [5] Silencing of YY1 downregulates RIZ1 promoter in human osteosarcoma.Oncol Res. 2008;17(1):33-41. doi: 10.3727/096504008784046081.
• [6] Identification of a functional estrogen-responsive enhancer element in the promoter 2 of PRDM2 gene in breast cancer cell lines.J Cell Physiol. 2012 Mar;227(3):964-75. doi: 10.1002/jcp.22803.
• [7] Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability.Cancer Res. 2000 Sep 1;60(17):4701-4.
• [8] Combination of RIZ1 Overexpression and Radiotherapy Contributes to Apoptosis and DNA Damage of HeLa and SiHa Cervical Cancer Cells.Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):137-146. doi: 10.1111/bcpt.13008. Epub 2018 Apr 25.
• [9] Aberrant Methylation of the 1p36 Tumor Suppressor Gene RIZ1 in Renal Cell Carcinoma.Asian Pac J Cancer Prev. 2015;16(9):4071-5. doi: 10.7314/apjcp.2015.16.9.4071.
• [10] Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma.Br J Cancer. 2001 Mar 23;84(6):743-7. doi: 10.1054/bjoc.2000.1667.
• [11] Effect of the downregulation of SMYD3 expression by RNAi on RIZ1 expression and proliferation of esophageal squamous cell carcinoma.Oncol Rep. 2014 Sep;32(3):1064-70. doi: 10.3892/or.2014.3307. Epub 2014 Jul 3.
• [12] Biallelic inactivation of the RIZ1 gene in human gastric cancer.Oncogene. 2003 Oct 9;22(44):6954-8. doi: 10.1038/sj.onc.1206403.
• [13] Detection of frameshift mutations of RIZ in gastric cancers with microsatellite instability.World J Gastroenterol. 2004 Sep 15;10(18):2719-22. doi: 10.3748/wjg.v10.i18.2719.
• [14] Methylation Status of the RIZ1 Gene Promoter in Human Glioma Tissues and Cell Lines.Cell Mol Neurobiol. 2017 Aug;37(6):1021-1027. doi: 10.1007/s10571-016-0435-3. Epub 2016 Oct 18.
• [15] Nucleotide alteration of retinoblastoma protein-interacting zinc finger gene, RIZ, in human leukemia.Tohoku J Exp Med. 2002 Mar;196(3):193-201. doi: 10.1620/tjem.196.193.
• [16] Genetic polymorphisms in the Rb-binding zinc finger gene RIZ and the risk of lung cancer.Carcinogenesis. 2007 Sep;28(9):1971-7. doi: 10.1093/carcin/bgm156. Epub 2007 Aug 11.
• [17] Frameshift mutations of RIZ, but no point mutations in RIZ1 exons in malignant melanomas with deletions in 1p36.Oncogene. 2002 May 2;21(19):3038-42. doi: 10.1038/sj.onc.1205457.
• [18] Tissue thioredoxin-interacting protein expression predicted recurrence in patients with meningiomas.Int J Clin Oncol. 2017 Aug;22(4):660-666. doi: 10.1007/s10147-017-1103-4. Epub 2017 Feb 27.
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• [20] Repression of Akt3 gene transcription by the tumor suppressor RIZ1.Sci Rep. 2018 Jan 24;8(1):1528. doi: 10.1038/s41598-018-19943-5.
• [21] Deletions and altered expression of the RIZ1 tumour suppressor gene in 1p36 in pheochromocytomas and abdominal paragangliomas.Int J Oncol. 2005 May;26(5):1385-91.
• [22] Epigenetic abnormalities in cutaneous squamous cell carcinomas: frequent inactivation of the RB1/p16 and p53 pathways.Br J Dermatol. 2006 Nov;155(5):999-1005. doi: 10.1111/j.1365-2133.2006.07487.x.
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• [24] RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma. Cancer. 2006 Dec 15;107(12):2752-9. doi: 10.1002/cncr.22325.
• [25] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [26] Decreased expression of RIZ1 and its clinicopathological significance in epithelial ovarian carcinoma: correlation with epigenetic inactivation by aberrant DNA methylation.Pathol Int. 2007 Nov;57(11):725-33. doi: 10.1111/j.1440-1827.2007.02169.x.
• [27] Reprogramming of mPFC transcriptome and function in alcohol dependence.Genes Brain Behav. 2017 Jan;16(1):86-100. doi: 10.1111/gbb.12344. Epub 2016 Nov 24.
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• [29] RIZ1 is regulated by estrogen and suppresses tumor progression in endometrial cancer.Biochem Biophys Res Commun. 2017 Jul 22;489(2):96-102. doi: 10.1016/j.bbrc.2017.05.095. Epub 2017 May 18.
• [30] Suppression of RIZ in biologically unfavourable neuroblastomas.Int J Oncol. 2010 Nov;37(5):1323-30. doi: 10.3892/ijo_00000784.
• [31] Variants in estrogen-related genes and risk of Parkinson's disease.Mov Disord. 2011 Jun;26(7):1234-42. doi: 10.1002/mds.23604. Epub 2011 Apr 5.
• [32] A deletion polymorphism in the RIZ gene is associated with increased progression of imatinib treated chronic myeloid leukemia patients.Leuk Lymphoma. 2017 Jul;58(7):1694-1701. doi: 10.1080/10428194.2016.1251589. Epub 2016 Nov 10.
• [33] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [34] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [35] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [36] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [37] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [38] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [39] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [40] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
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• [42] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [43] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [44] Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem. 2013 May 31;288(22):16004-15. doi: 10.1074/jbc.M112.432294. Epub 2013 Apr 1.
• [45] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [46] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
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• [49] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
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• [51] Effects of BPA on global DNA methylation and global histone 3 lysine modifications in SH-SY5Y cells: An epigenetic mechanism linking the regulation of chromatin modifiying genes. Toxicol In Vitro. 2017 Oct;44:313-321. doi: 10.1016/j.tiv.2017.07.028. Epub 2017 Jul 29.
• [52] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [53] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.