Objective The brain derived neurotrophic factor (BDNF) locus has been implicated in psychiatric and substance related disorders. Recent genome-wide association studies (GWAS) have shown strong associations between single nucleotide polymorphisms in BDNF, smoking behaviour and high body mass index (BMI). Our aim was to test whether genetic BDNF variation alters the risk of smoking related morbidity and mortality.

Design Cox proportional hazards models were used to relate the BDNF rs4923461(A/G) polymorphisms to all-cause, cancer and cardiovascular mortality and cardiovascular disease (CVD) incidence adjusted for age, sex, BMI, and smoking quantity.

Setting The Malmö Diet and Cancer Study (MDCS), a population based prospective cohort study (n=30 447).

Patients We obtained complete data on 25 071 subjects, of whom 6507 were current smokers and 18 564 were non-smokers who underwent a baseline examination from 1991–1996.

Main outcome measures During a mean follow-up time of 12 years, 1049 deaths (346 cardiovascular deaths and 492 cancer deaths) and 802 incident CVD events occurred among current smokers.

Results The major allele (A) of rs4923461 was significantly associated with ever having smoked (p=0.03) and high BMI (p=0.001). The A-allele was associated with risk of all-cause (HR=1.12, 95% CI 1.00 to 1.25; p<0.05) and CVD (HR=1.23, 95% CI 1.01 to 1.49; p=0.04) mortality. There was no significant association between the rs4923461 and cancer mortality or CVD incidence.

Conclusions Our data suggest that smoking- and obesity-associated variation of the BDNF gene affects the risk of death, especially due to cardiovascular causes, in smokers. Determination of the BDNF genotype in smokers may guide the need for smoking cessation interventions.