Document Detail


Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples.
MedLine Citation:
PMID:  17761687     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
There have been many conflicting reports concerning the association of the DRD2 locus with alcohol dependence (AD). To investigate whether these findings could be reconciled by considering the genomic region of DRD2 in greater detail, we conducted two separate association studies of AD in 1220 European-American subjects using family-based (488 subjects) and case-control (318 cases and 414 controls) designs, and 43 single nucleotide polymorphisms mapped to the gene cluster of NCAM1, TTC12, ANKK1 and DRD2. We used a generalized linear model and haplotype score tests for the case-control sample, and the family-based association test for the family sample. Haplotype associations centered on TTC12 exon 3 [rs1893699-rs723077; optimal individual haplotype simulated P-value (P(oihs)) = 0.00021] in both independent samples (family and case-control). Additional AD-associated haplotypes centered around NCAM1 exon 12 in the family sample (P(oihs) = 0.0032), and at exons 2 and 5 of ANKK1 in the case-control sample (P(oihs) = 0.00058). LD contrasts between cases and controls support selection at TTC12 exon 3 and ANKK1 exon 2. The armadillo repeat domains encoded by TTC12 and dopamine interact in the Wnt pathway and may have effects on dopamine cell development in the ventral midbrain. We conclude that risk for AD is attributable in part to variants in four regions within this cluster: exon 3 of TTC12, exon 12/intron13 of NCAM1 and exons 2 and 5 of ANKK1. The complexity of these relationships, many of which replicate between our independent samples, may explain prior inconsistent results.
Authors:
Bao-Zhu Yang; Henry R Kranzler; Hongyu Zhao; Jeffrey R Gruen; Xingguang Luo; Joel Gelernter
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-08-30
Journal Detail:
Title:  Human molecular genetics     Volume:  16     ISSN:  0964-6906     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-11-05     Completed Date:  2008-01-22     Revised Date:  2012-10-12    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  2844-53     Citation Subset:  IM    
Affiliation:
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Alcoholism / genetics*
Antigens, CD56
Case-Control Studies
Chromosomes, Human, Pair 11 / genetics
Family
Female
Genetic Variation
Haplotypes
Humans
Linkage Disequilibrium
Male
Middle Aged
Multigene Family
Neural Cell Adhesion Molecules / genetics*
Polymorphism, Single Nucleotide
Protein-Serine-Threonine Kinases / genetics*
Proteins / genetics*
Receptors, Dopamine D2 / genetics*
Grant Support
ID/Acronym/Agency:
K08 AA13732/AA/NIAAA NIH HHS; K24 AA13736/AA/NIAAA NIH HHS; K24 DA015105/DA/NIDA NIH HHS; K24 DA15105/DA/NIDA NIH HHS; M01 RR06192/RR/NCRR NIH HHS; P50 AA012870/AA/NIAAA NIH HHS; P50 AA12870/AA/NIAAA NIH HHS; R01 AA011330/AA/NIAAA NIH HHS; R01 AA016015/AA/NIAAA NIH HHS; R01 AA11330/AA/NIAAA NIH HHS; R01 DA012690/DA/NIDA NIH HHS; R01 DA012849/DA/NIDA NIH HHS; R01 DA12690/DA/NIDA NIH HHS; R01 DA12849/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD56; 0/NCAM1 protein, human; 0/Neural Cell Adhesion Molecules; 0/Proteins; 0/Receptors, Dopamine D2; 0/TTC12 protein, human; EC 2.7.11.1/ANKK1 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases

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