Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway

Jenni Hällfors, Teemu Palviainen, Ida Surakka, Richa Gupta, Jadwiga Buchwald, Anu Raevuori, Samuli Ripatti, Tellervo Korhonen, Pekka Jousilahti, Pamela A.F. Madden, Jaakko Kaprio, Anu Loukola

Research output: Contribution to journalArticle

Abstract

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction—smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 × 10 −9 ), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-κB transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 × 10 −9 ), and on 11p15 (P = 6.6 × 10 −8 ) in an intron of AP2A2, and P = 4.2 × 10 −7 for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 × 10 −8 ) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.

Original languageEnglish
Pages (from-to)549-561
Number of pages13
JournalAddiction Biology
Volume24
Issue number3
DOIs
StatePublished - May 2019

Keywords

  • Finnish population-based imputation reference panel
  • genome-wide association analysis
  • neurotrophin signaling pathway
  • nicotine addiction
  • nicotine withdrawal
  • smoking behavior
  • smoking quantity

Fingerprint Dive into the research topics of 'Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway'. Together they form a unique fingerprint.

  • Cite this

    Hällfors, J., Palviainen, T., Surakka, I., Gupta, R., Buchwald, J., Raevuori, A., Ripatti, S., Korhonen, T., Jousilahti, P., Madden, P. A. F., Kaprio, J., & Loukola, A. (2019). Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway. Addiction Biology, 24(3), 549-561. https://doi.org/10.1111/adb.12618