RGD Reference Report - Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples. - Rat Genome Database

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Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples.

Authors: Yang, Bao-Zhu  Kranzler, Henry R  Zhao, Hongyu  Gruen, Jeffrey R  Luo, Xingguang  Gelernter, Joel 
Citation: Yang BZ, etal., Hum Mol Genet. 2007 Dec 1;16(23):2844-53. doi: 10.1093/hmg/ddm240. Epub 2007 Aug 30.
RGD ID: 405866369
Pubmed: PMID:17761687   (View Abstract at PubMed)
DOI: DOI:10.1093/hmg/ddm240   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
NCAM1Humanalcohol dependence susceptibilityIAGP DNA:SNPs:exon:RGD 
Ncam1Ratalcohol dependence susceptibilityISONCAM1 (Homo sapiens)DNA:SNPs:exon:RGD 
Ncam1Mousealcohol dependence susceptibilityISONCAM1 (Homo sapiens)DNA:SNPs:exon:RGD 
TTC12Humanalcohol dependence susceptibilityIAGP DNA:SNPs:introns and exon:RGD 
Ttc12Ratalcohol dependence susceptibilityISOTTC12 (Homo sapiens)DNA:SNPs:introns and exon:RGD 
Ttc12Mousealcohol dependence susceptibilityISOTTC12 (Homo sapiens)DNA:SNPs:introns and exon:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ncam1  (neural cell adhesion molecule 1)
Ttc12  (tetratricopeptide repeat domain 12)

Genes (Mus musculus)
Ncam1  (neural cell adhesion molecule 1)
Ttc12  (tetratricopeptide repeat domain 12)

Genes (Homo sapiens)
NCAM1  (neural cell adhesion molecule 1)
TTC12  (tetratricopeptide repeat domain 12)


Additional Information