A Pilot Study for Discovering Candidate Genes of Chromosome 18q21 in Methamphetamine Abusers: Case-control Association Study

Objective It was previously suggested that the malic enzyme 2 (ME2) as the candidate gene for psychosis in fine mapping of chromosome 18q21. Chromosome 18q21 is also one of the possible regions that can contribute to addiction. Methods We performed a pilot study for discovering candidate gene of chromosome 18q21 in the methamphetamine abusers for elucidating the candidate gene for methamphetamine addiction leading to psychosis. We have selected 30 unrelated controls (16 males, 14 females; age=59.8±10.4) and 37 male methamphetamine abusers (age=43.3±7.8). We analyzed 20 single nucleotide polymorphisms (SNPs) of 7 neuronal genes in chromosome 18q21 for DNA samples that was checked for the data quality and genotype error. The association between the case-control status and each individual SNP was measured using multiple logistic regression models (adjusting for age and sex as covariates). And we controlled false discovery rate (FDR) to deal with multiple testing problem. Results We found 3 significant SNPs of 2 genes in chromosome 18q21 (p-value<0.05; adjusting for age as covariate) in methamphetamine abusers compared to controls. We also found 2 significant SNPs of 1 gene (p-value<0.05; adjusting for age and sex as covariates) (rs3794899, rs3794901:MAPK4). Two SNPs in MAPK4 gene were significant in both statistical groups. Conclusion MAPK4, the gene for mitogen-activated protein kinase 4, is one of the final 6 candidate genes including ME2 in 18q12-21 in our previous finemapping for psychosis. Our results suggest that MAPK4 can be a candidate gene that contribute to the methamphetamine addiction leading to psychosis.

[1]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[2]  E. Y. Kim,et al.  Frequency of osteoporosis in 46 men with methamphetamine abuse hospitalized in a National Hospital. , 2009, Forensic science international.

[3]  D. Kavanagh,et al.  Impulsivity and positive psychotic symptoms influence hostility in methamphetamine users. , 2009, Addictive behaviors.

[4]  H. Nicolini,et al.  The epsin 4 gene is associated with psychotic disorders in families of Latin American origin , 2008, Schizophrenia Research.

[5]  R. Mcketin,et al.  The rise of methamphetamine in Southeast and East Asia. , 2008, Drug and alcohol review.

[6]  J. Carroll,et al.  Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival , 2008, The EMBO journal.

[7]  H. Orimo,et al.  Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and vitamin K , 2008, European Journal of Epidemiology.

[8]  H. Datta,et al.  Osteoporosis in the aging male: Treatment options , 2007, Clinical interventions in aging.

[9]  J. Blahoš.  Treatment and prevention of osteoporosis , 2007, Wiener Medizinische Wochenschrift.

[10]  J. Bilezikian,et al.  Glucocorticoid-induced osteoporosis: clinical and therapeutic aspects. , 2007, Arquivos brasileiros de endocrinologia e metabologia.

[11]  S. Migliaccio,et al.  Glucocorticoid-induced osteoporosis: an osteoblastic disease. , 2007, Aging clinical and experimental research.

[12]  R. Rawson,et al.  Why do we need an Addiction supplement focused on methamphetamine? , 2007, Addiction.

[13]  H. Raventós,et al.  Malic enzyme 2 and susceptibility to psychosis and mania , 2007, Psychiatry Research.

[14]  Tomas Drgon,et al.  Addiction molecular genetics: 639,401 SNP whole genome association identifies many “cell adhesion” genes , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[15]  M. Gaestel,et al.  MAPKAP kinases — MKs — two's company, three's a crowd , 2006, Nature Reviews Molecular Cell Biology.

[16]  Wei Liu,et al.  Evidence of genetic overlap of schizophrenia and bipolar disorder: Linkage disequilibrium analysis of chromosome 18 in the Costa Rican population , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[17]  H. Manji,et al.  Mood stabilizers target cellular plasticity and resilience cascades , 2005, Molecular Neurobiology.

[18]  O. Almeida,et al.  SMAD pathway mediation of BDNF and TGFβ2 regulation of proliferation and differentiation of hippocampal granule neurons , 2005, Development.

[19]  Steven S. Sharfstein,et al.  The American Psychiatric Association , 2005, International psychiatry : bulletin of the Board of International Affairs of the Royal College of Psychiatrists.

[20]  Kazuya Iwamoto,et al.  Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. , 2005, Human molecular genetics.

[21]  T. Mikalsen,et al.  Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway , 2004, The EMBO journal.

[22]  A. Visel,et al.  Scaffolding by ERK3 regulates MK5 in development , 2004, The EMBO journal.

[23]  P. Zandi,et al.  A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders , 2004, International review of psychiatry.

[24]  Kongpetch Kulsudjarit.  Drug Problem in Southeast and Southwest Asia , 2004, Annals of the New York Academy of Sciences.

[25]  Mi-ae Lim,et al.  Recent Trends of Drug Abuse and Drug‐Associated Deaths in Korea , 2004, Annals of the New York Academy of Sciences.

[26]  J. Blenis,et al.  ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions , 2004, Microbiology and Molecular Biology Reviews.

[27]  G. Galloway,et al.  Psychiatric symptoms in methamphetamine users. , 2004, The American journal on addictions.

[28]  Stephan Heckers,et al.  Molecular evidence for mitochondrial dysfunction in bipolar disorder. , 2004, Archives of general psychiatry.

[29]  S. Bartels,et al.  Medicare and medicaid costs for schizophrenia patients by age cohort compared with costs for depression, dementia, and medically ill patients. , 2003, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[30]  Sorin Drăghici,et al.  Data Analysis Tools for DNA Microarrays , 2003 .

[31]  Francis J McMahon,et al.  Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder. , 2003, The American journal of psychiatry.

[32]  M. Cuccaro,et al.  Identification of MeCP2 mutations in a series of females with autistic disorder. , 2003, Pediatric neurology.

[33]  K. Hornik,et al.  Genome scan for susceptibility loci for schizophrenia and bipolar disorder , 2002, Biological Psychiatry.

[34]  Peter McGuffin,et al.  A twin study of genetic relationships between psychotic symptoms. , 2002, The American journal of psychiatry.

[35]  Jeffrey Ross-Ibarra,et al.  Genetic Data Analysis II. Methods for Discrete Population Genentic Data , 2002 .

[36]  J. Pierri,et al.  Gene Expression Profiling Reveals Alterations of Specific Metabolic Pathways in Schizophrenia , 2002, The Journal of Neuroscience.

[37]  M. Escamilla.  Population isolates: their special value for locating genes for bipolar disorder. , 2001, Bipolar disorders.

[38]  B. Hassel.  Pyruvate carboxylation in neurons , 2001, Journal of neuroscience research.

[39]  C. Dion,et al.  A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes , 2001, Molecular Psychiatry.

[40]  N. Freimer,et al.  Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18. , 2001, American journal of medical genetics.

[41]  H. Möller,et al.  Evidence for a mitochondrial oxidative phosphorylation defect in brains from patients with schizophrenia , 2001, Schizophrenia Research.

[42]  Fumiko Itoh,et al.  Signaling of transforming growth factor‐β family members through Smad proteins , 2000 .

[43]  D. Housman,et al.  Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes , 2000, Molecular Psychiatry.

[44]  S. Siris.  Depression in schizophrenia: perspective in the era of "Atypical" antipsychotic agents. , 2000, The American journal of psychiatry.

[45]  M. Owen,et al.  A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs. , 1999, Human molecular genetics.

[46]  F. McMahon,et al.  Report of the chromosome 18 workshop. , 1999, American journal of medical genetics.

[47]  A. Buffenstein,et al.  Chronic psychotic illness from methamphetamine. , 1999, The American journal of psychiatry.

[48]  P. Sullivan,et al.  Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study , 1999, Molecular Psychiatry.

[49]  Yong Jiang,et al.  PRAK, a novel protein kinase regulated by the p38 MAP kinase , 1998, The EMBO journal.

[50]  J. B. Murray.  Psychophysiological aspects of amphetamine-methamphetamine abuse. , 1998, The Journal of psychology.

[51]  X. Wang,et al.  MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. , 1998, Biochemical and biophysical research communications.

[52]  S. Detera-Wadleigh,et al.  Isolation of a cDNA encoding the rat MAP-kinase homolog of human p63mapk , 1996, Mammalian Genome.

[53]  S. Faraone,et al.  Genetic influences on DSM-III-R drug abuse and dependence: a study of 3,372 twin pairs. , 1996, American journal of medical genetics.

[54]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[55]  A. Farmer,et al.  The Strength of the Genetic Effect , 1994, British Journal of Psychiatry.

[56]  R. Davis,et al.  Genomic loci of human mitogen-activated protein kinases. , 1994, Oncogene.

[57]  J. Weber,et al.  Mutation of human short tandem repeats. , 1993, Human molecular genetics.

[58]  J. Rabe-Jabłońska,et al.  [Affective disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association -- diagnostic and statistical manual of mental disorders]. , 1993, Psychiatria polska.

[59]  R. Davis,et al.  Heterogeneous expression of four MAP kinase isoforms in human tissues , 1992, FEBS letters.

[60]  Nancy Y. Ip,et al.  ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF , 1991, Cell.

[61]  G. Uhl,et al.  "Higher order" addiction molecular genetics: convergent data from genome-wide association in humans and mice. , 2008, Biochemical pharmacology.

[62]  K. Davis,et al.  Mitochondrial enzymes in schizophrenia , 2007, Journal of Molecular Neuroscience.

[63]  G. Dore,et al.  Drug-induced psychosis associated with crystalline methamphetamine. , 2006, Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists.

[64]  S. Moshé,et al.  Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. , 2005, American journal of human genetics.

[65]  R. Yolken,et al.  Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress , 2004, Molecular Psychiatry.

[66]  M. Nakao,et al.  Solution Structure of the Methyl-CpG Binding Domain of Human MBD1 in Complex with Methylated DNA , 2001, Cell.

[67]  M. Goumans,et al.  Signaling of transforming growth factor-beta family members through Smad proteins. , 2000, European journal of biochemistry.

[68]  J C Murray,et al.  Pediatrics and , 1998 .

[69]  O. Mors,et al.  Susceptibility loci for bipolar affective disorder on chromosome 18? A review and a study of Danish families , 1997, Psychiatric genetics.