Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

Quach, B. C.; Bray, M. J.; Gaddis, N. C.; Liu, M.; Palviainen, T.; Minica, C. C.; Zellers, S.; Sherva, R.; Aliev, F.; Nothnagel, M.; Young, K. A.; Marks, J.; Young, H.; Guo, Y.; Waldrop, A.; Sey, N.; Landi, M. T.; McNeil, D. W.; Farrer, L. A.; Markunas, C. A.; Vink, J.; Hottenga, J.-J.; Iacono, W. G.; Kranzler, H. R.; Saccone, N. L.; Neale, M. C.; Madden, P.; Rietschel, M.; Marazita, M. L.; McGue, M.; Won, H.; Winterer, G.; Grucza, R.; Dick, D.; Gelernter, J.; Caporaso, N. E.; Baker, T. B.; Boomsma, D. I.; Kaprio, J.; Hokanson, J. E.; Vrieze, S.; Bierut, L. J.; Johnson, E. O.; Hancock, D. B.

doi:10.1101/2020.01.15.898858

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bioRxiv · 10.1101/2020.01.15.898858

Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

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Abstract

Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerstrom Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 17 other smoking traits (rg=0.40-0.95) and co-morbidities. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

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Quach, B. C., Bray, M. J., Gaddis, N. C., Liu, M., Palviainen, T., Minica, C. C., Zellers, S., Sherva, R., Aliev, F., Nothnagel, M., Young, K. A., Marks, J., Young, H., Guo, Y., Waldrop, A., Sey, N., Landi, M. T., McNeil, D. W., Farrer, L. A., Markunas, C. A., Vink, J., Hottenga, J.-J., Iacono, W. G., Kranzler, H. R., Saccone, N. L., Neale, M. C., Madden, P., Rietschel, M., Marazita, M. L., McGue, M., Won, H., Winterer, G., Grucza, R., Dick, D., Gelernter, J., Caporaso, N. E., Baker, T. B., Boomsma, D. I., Kaprio, J., Hokanson, J. E., Vrieze, S., Bierut, L. J., Johnson, E. O., Hancock, D. B.. 2020-01-15. Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium. https://doi.org/10.1101/2020.01.15.898858

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