Genomewide linkage scan for nicotine dependence: identification of a chromosome 5 risk locus.
BACKGROUND
Nicotine dependence (ND) is costly to societies worldwide, moderately heritable, and genetically complex. Risk loci can be identified with genetic linkage analysis independent of prior physiological hypotheses.


METHODS
We completed a genomewide linkage scan to map loci increasing risk for DSM-IV ND and for a quantitative assessment of ND as measured by the Fagerstrom Test for Nicotine Dependence (FTND) in a set of 634 small nuclear families ascertained on the basis of multiple individuals affected with cocaine or opioid dependence. Of these, 507 had at least two subjects affected with ND. There are two distinct populations within this sample, European-Americans (EAs) and African-Americans (AAs).


RESULTS
A region on chromosome 5 was identified as containing a gene that affects risk for ND on the basis of FTND score in the AA part of our sample (logarithm of the odds [lod] score 3.04; empirically determined to be genomewide-significant, p = .0374; point p = .0001). The highest lod score observed in the EA part of the sample was on chromosome 7 (lod score 2.73). Several other "possible" risk loci were identified in either AA or EA subjects, with many of these in proximity to previously suggested risk loci from other clinical samples. Three nominally significant single-nucleotide polymorphism associations were found at the peptidylglycine alpha-amidating monooxygenase (PAM) locus under the chromosome 5 linkage peak, also in the AA part of the sample.


CONCLUSIONS
These data add to the growing evidence for locations for ND risk loci, add a novel statistically significant locus important in AAs, and suggest a gene that might be contributing to this linkage signal.
Gelernter
Joel
J
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA. joel.gelernter@yale.edu
Panhuysen
Carolien
C
Weiss
Roger
R
Brady
Kathleen
K
Poling
James
J
Krauthammer
Michael
M
Farrer
Lindsay
L
Kranzler
Henry R
HR
D002874:Chromosome Mapping / Q000379:methods*; D002895:Chromosomes, Human, Pair 5; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics; D009679:Nuclear Family; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012189:Retrospective Studies; D014029:Tobacco Use Disorder / Q000208:ethnology / Q000235:genetics*
D009097:Multienzyme Complexes; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase