Intronic variants in the dopa decarboxylase (DDC) gene are associated with smoking behavior in European-Americans and African-Americans.

We report here a study considering association of alleles and haplotypes at the DOPA decarboxylase (DDC) locus with the DSM-IV diagnosis of nicotine dependence (ND) or a quantitative measure for ND using the Fagerstrom Test for Nicotine Dependence (FTND). We genotyped 18 single nucleotide polymorphisms (SNPs) spanning a region of approximately 210 kb that includes DDC and the genes immediately flanking DDC in 1,590 individuals from 621 families of African-American (AA) or European-American (EA) ancestry. Evidence of association (family-based tests) was observed with several SNPs for both traits (0.0002<or=P<or=0.04). The most significant result was obtained for the relationship of FTND score to SNP rs12718541 (AA families: P=0.002; EA families: P=0.03; all families: P=0.0002) which is in the same intron as the splice site for a neuronal isoform of human DDC lacking exons 10-15. Haplotype analysis did not reveal any SNP combination with stronger evidence for association than rs12718541 alone. Although sequence analysis suggests that rs12718541 may be an intronic splicing enhancer, further studies are needed to determine whether a direct link exists between an alternatively spliced form of DDC and predisposition to ND. These findings confirm a previous report of association of DDC with ND, localize the causative variants to the 3' end of the coding region and extend the association to multiple population groups.

[1]  Hongyu Zhao,et al.  Genomewide linkage scan for opioid dependence and related traits. , 2006, American journal of human genetics.

[2]  N. Martin,et al.  The Implications of Simultaneous Smoking Initiation for Inferences about the Genetics of Smoking Behavior from Twin Data , 2006, Behavior genetics.

[3]  A. Boulton,et al.  Aromaticl-amino acid decarboxylase: A neglected and misunderstood enzyme , 1996, Neurochemical Research.

[4]  Alisha R Pollastri,et al.  Diagnostic reliability of the Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA). , 2005, Drug and alcohol dependence.

[5]  V. Hesselbrock,et al.  Genomewide linkage scan for cocaine dependence and related traits: Significant linkages for a cocaine‐related trait and cocaine‐induced paranoia , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[6]  Gonneke Willemsen,et al.  Heritability of Smoking Initiation and Nicotine Dependence , 2005, Behavior genetics.

[7]  Ming D. Li,et al.  Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence. , 2005, Human molecular genetics.

[8]  D. Wang,et al.  Mapping and verification of susceptibility loci for smoking quantity using permutation linkage analysis , 2005, The Pharmacogenomics Journal.

[9]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[10]  M. Jarvis,et al.  The scientific case that nicotine is addictive , 2005, Psychopharmacology.

[11]  Gene W. Yeo,et al.  Variation in sequence and organization of splicing regulatory elements in vertebrate genes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Sullivan,et al.  A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence , 2004, Psychological Medicine.

[13]  D. C. Sideris,et al.  Identification and Characterization of a Novel Form of the Human L-Dopa Decarboxylase mRNA , 2004, Neurochemical Research.

[14]  Yan Shen,et al.  No association between polymorphisms in the DDC gene and paranoid schizophrenia in a northern Chinese population , 2004, Psychiatric genetics.

[15]  V. Hesselbrock,et al.  Results of a genomewide linkage scan: Support for chromosomes 9 and 11 loci increasing risk for cigarette smoking , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[16]  N. Martin,et al.  Defining nicotine dependence for genetic research: evidence from Australian twins , 2004, Psychological Medicine.

[17]  J. Gerberding,et al.  Actual causes of death in the United States, 2000. , 2004, JAMA.

[18]  Xin Xu,et al.  Family‐based tests for associating haplotypes with general phenotype data: Application to asthma genetics , 2004, Genetic epidemiology.

[19]  L. Bierut,et al.  A genomic scan for habitual smoking in families of alcoholics: Common and specific genetic factors in substance dependence , 2004, American journal of medical genetics. Part A.

[20]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[21]  Ming D. Li.  The genetics of smoking related behavior: a brief review. , 2003, The American journal of the medical sciences.

[22]  Majid Ezzati,et al.  Estimates of global mortality attributable to smoking in 2000 , 2003, The Lancet.

[23]  S. Kuersten,et al.  The power of the 3′ UTR: translational control and development , 2003, Nature Reviews Genetics.

[24]  R. Darnell,et al.  Nova Regulates GABAA Receptor γ2 Alternative Splicing via a Distal Downstream UCAU-Rich Intronic Splicing Enhancer , 2003, Molecular and Cellular Biology.

[25]  P. McKeigue,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Problems of Reporting Genetic Associations with Complex Outcomes , 2022 .

[26]  D. Collier,et al.  Possible parent‐of‐origin effect of Dopa decarboxylase in susceptibility to bipolar affective disorder , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[27]  U. Högberg,et al.  The World Health report 2002. , 2003, Midwifery.

[28]  S. Cichon,et al.  Association study between two variants in the DOPA decarboxylase gene in bipolar and unipolar affective disorder. , 2002, American journal of medical genetics.

[29]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[30]  R. Myers,et al.  Candidate-gene approaches for studying complex genetic traits: practical considerations , 2002, Nature Reviews Genetics.

[31]  Peter E. Hilsenrath,et al.  The World Health Report 2000 , 2002 .

[32]  G. Uhl,et al.  The Fagerstrom Test for Nicotine Dependence and the Diagnostic Interview Schedule: do they diagnose the same smokers? , 2002, Addictive behaviors.

[33]  M. Hampson,et al.  Dopa decarboxylase genotypes may influence age at onset of schizophrenia , 2001, Molecular Psychiatry.

[34]  M. Gill,et al.  Dopa decarboxylase gene polymorphisms and attention deficit hyperactivity disorder (ADHD): no evidence for association in the Irish population , 2001, Molecular Psychiatry.

[35]  N. Laird,et al.  The family based association test method: strategies for studying general genotype–phenotype associations , 2001, European Journal of Human Genetics.

[36]  K. Kendler,et al.  Tobacco consumption in Swedish twins reared apart and reared together. , 2000, Archives of general psychiatry.

[37]  Brandt En,et al.  Effects of smoking on health care costs. , 2000 .

[38]  T. Niu,et al.  Nicotine dependence and its familial aggregation in Chinese. , 2000, International journal of epidemiology.

[39]  E. Brandt,et al.  Effects of smoking on health care costs. , 2000, The Journal of the Oklahoma State Medical Association.

[40]  T. G. Bruun,et al.  Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder , 1999, Molecular Psychiatry.

[41]  M. Bleavins,et al.  High throughput genotyping for the detection of a single nucleotide polymorphism in NAD(P)H quinone oxidoreductase (DT diaphorase) using TaqMan probes. , 1999, Molecular pathology : MP.

[42]  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.

[43]  P. Sullivan,et al.  The genetic epidemiology of smoking. , 1999, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[44]  G. Dockray,et al.  Novel form of L‐aromatic amino acid decarboxylase mRNA in rat antral mucosa , 1998, Experimental physiology.

[45]  J R O'Connell,et al.  PedCheck: a program for identification of genotype incompatibilities in linkage analysis. , 1998, American journal of human genetics.

[46]  K. O’Malley,et al.  The Human Aromatic l‐Amino Acid Decarboxylase Gene Can Be Alternatively Spliced To Generate Unique Protein Isoforms , 1995, Journal of neurochemistry.

[47]  J. Hirsh,et al.  cis-regulatory sequences responsible for alternative splicing of the Drosophila dopa decarboxylase gene , 1994, Molecular and cellular biology.

[48]  P. Blackman.  Actual causes of death in the United States. , 1994, JAMA.

[49]  McGinnis Jm,et al.  Actual causes of death in the United States. , 1993 .

[50]  H. Ichinose,et al.  Tissue-specific alternative splicing of the first exon generates two types of mRNAs in human aromatic L-amino acid decarboxylase. , 1992, Biochemistry.

[51]  H. Ichinose,et al.  Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis. , 1992, Biochemistry.

[52]  I. Craig,et al.  Localisation of the gene for human aromatic L-amino acid decarboxylase (DDC) to chromosome 7p13-->p11 by in situ hybridisation. , 1992, Cytogenetics and cell genetics.

[53]  L. Kozlowski,et al.  The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. , 1991, British journal of addiction.

[54]  W. A. Johnson,et al.  A neuron-specific enhancer of the Drosophila dopa decarboxylase gene. , 1989, Genes & development.

[55]  S. Udenfriend,et al.  On the identity of DOPA decarboxylase and 5-hydroxytryptophan decarboxylase (immunological titration-aromatic L-amino acid decarboxylase-serotonin-dopamine-norepinephrine). , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[56]  J. Stephenson.  World health report. , 2004, Lancet.