Results of a genomewide linkage scan: Support for chromosomes 9 and 11 loci increasing risk for cigarette smoking

Abstract

Cigarette smoking is highly destructive to individuals and society, and is moderately heritable. We completed a genomewide linkage scan to map loci increasing risk for cigarette smoking in a set of families originally identified because they segregate panic disorder (PD). One hundred forty two genotyped individuals in a total of 12 families were studied (214 subjects analyzed, including non-genotyped individuals). Of these individuals, 69 were 'affected' with habitual cigarette smoking (i.e., they smoked more than one pack per day for at least a year, or at least 1/2 pack per day for at least 10 years), 49 were 'unaffected' (i.e., they smoked less than 1/2 pack per day for less than 1 year), and 24 were scored as 'unknown.' Nine families from the panic series were excluded from these analyses because they lacked multiple affected individuals with habitual cigarette smoking. In an initial genomewide scan, we genotyped a total of 416 markers (398 autosomal, 18 X-chromosome) with an average spacing of less than 10 cM, spanning the genome. Linkage analysis (pairwise, or single-point, and multi-point) was performed using ALLEGRO. An additional 14 markers were genotyped in a high-density panel to follow-up on an identified region of interest on chromosome 11p. The three highest multi-point Zlr scores (3.43, 3.04, and 3.01; P = 0.0003, P = 0.0012, and P = 0.0013, respectively), which each reflect 'suggestive' evidence for linkage, were observed in multi-point linkage analyses using Allegro on chromosomes 11p and 9, near markers D11S4046, D9S283, and D9S1677, respectively. D11S4046 is in a region where linkage to alcohol dependence and linkage disequilibrium to substance dependence have previously been identified. The chromosome 9 region we identified as possibly linked to cigarette smoking in anxiety families, was previously identified as significantly linked to PD in Icelandic pedigrees. We also identified evidence supporting linkage (Zlr score > 2.3, P < 0.01) to regions of chromosomes 14, 16, and X. There was a significant phenotypic association between PD and cigarette smoking (P < 0.001). Conclusions: We identified evidence for two loci increasing risk for cigarette smoking that map to chromosomes 9 and 11. There is now evidence supporting linkage or association of chromosome 11 markers with alcohol dependence, illegal drug abuse and dependence, and cigarette smoking. Interestingly, one of our most promising linkage regions, includes a region previously identified as linked to PD