Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples.
We conducted a genomewide linkage screen of a simple heavy-smoking quantitative trait, the maximum number of cigarettes smoked in a 24-h period, using two independent samples: 289 Australian and 155 Finnish nuclear multiplex families, all of which were of European ancestry and were targeted for DNA analysis by use of probands with a heavy-smoking phenotype. We analyzed the trait, using a regression of identity-by-descent allele sharing on the sum and difference of the trait values for relative pairs. Suggestive linkage was detected on chromosome 22 at 27-29 cM in each sample, with a LOD score of 5.98 at 26.96 cM in the combined sample. After additional markers were used to localize the signal, the LOD score was 5.21 at 25.46 cM. To assess the statistical significance of the LOD score in the combined sample, 1,000 simulated genomewide screens were conducted, resulting in an empirical P value of .006 for the LOD score of 5.21. This linkage signal is driven mainly by the microsatellite marker D22S315 (22.59 cM), which had a single-point LOD score of 5.41 in the combined sample and an empirical P value <.001 from 1,000 simulated genomewide screens. This marker is located within an intron of the gene ADRBK2, encoding the beta-adrenergic receptor kinase 2. Fine mapping of this linkage region may reveal variants contributing to heaviness of smoking, which will lead to a better understanding of the genetic mechanisms underlying nicotine dependence.
Saccone
Scott F
SF
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. saccones@msnotes.wustl.edu
Pergadia
Michele L
ML
Loukola
Anu
A
Broms
Ulla
U
Montgomery
Grant W
GW
Wang
Jen C
JC
Agrawal
Arpana
A
Dick
Danielle M
DM
Heath
Andrew C
AC
Todorov
Alexandre A
AA
Maunu
Heidi
H
Heikkila
Kauko
K
Morley
Katherine I
KI
Rice
John P
JP
Todd
Richard D
RD
Kaprio
Jaakko
J
Peltonen
Leena
L
Martin
Nicholas G
NG
Goate
Alison M
AM
Madden
Pamela A F
PA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D005260:Female; D005387:Finland; D008040:Genetic Linkage; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D040641:Quantitative Trait Loci; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*