Use of Polygenic Risk Scores of Nicotine Metabolism in Predicting Smoking Behaviors

Abstract

Aim: This study tests whether polygenic risk scores (PRSs) for nicotine metabolism predict smoking behaviors in independent data. Materials & methods: Linear regression, logistic regression and survival analyses were used to analyze nicotine metabolism PRSs and nicotine metabolism, smoking quantity and smoking cessation. Results: Nicotine metabolism PRSs based on two genome wide association studies (GWAS) meta-analyses significantly predicted nicotine metabolism biomarkers (R² range: 9.2–16%; minimum p = 7.6 × 10^-8). The GWAS top hit variant rs56113850 significantly predicted nicotine metabolism biomarkers (R² range: 14–17%; minimum p = 4.4 × 10^-8). There was insufficient evidence for these PRSs predicting smoking quantity and smoking cessation. Conclusion: Results suggest that nicotine metabolism PRSs based on GWAS meta-analyses predict an individual’s nicotine metabolism, so does use of the top hit variant. We anticipate that PRSs will enter clinical medicine, but additional research is needed to develop a more comprehensive genetic score to predict smoking behaviors.

Keywords::

• CYP2A6
• nicotine metabolism
• polygenic risk scores
• smoking cessation

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: https://www.tandfonline.com/doi/suppl/10.2217/pgs-2018-0081

Acknowledgements

The authors thank S Fisher, L Fox and N Smock for editorial and data support of the manuscript.

Financial & competing interests disclosure

This research was supported by R01DA036583, P30CA091842, U01HG004422 (LJB), R01DA038076, P30 CA091842-16S2, U19CA203654, K08DA030398, and KL2RR024994 (LSC), P50CA84724, K05CA139871, P50DA19706 (TBB), R01DA026911 (NLS).

The Collaborative Genetic Study of Nicotine Dependence (COGEND; PI: L Bierut) was supported by grant P01CA089392 from the National Cancer Institute. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096.

The Atherosclerosis Risk in Communities Study (ARIC; PI: E Boerwinkle) was obtained from dbGaP through study accession number phs000090. ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research.

MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and CTSA UL1-RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (CA, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetric Genome-Wide Human SNP Array 6.0.

Genotyping services for the UW-TTURC sample were provided by the Center for Inherited Disease Research (CIDR) and DNA extraction supported by the Wisconsin State Laboratory of Hygiene. Funding support for CIDR was provided by NIH grant U01HG004438 and NIH contract HHSN268200782096C to The Johns Hopkins University. Assistance with genotype cleaning was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446).

Glaxo Wellcome provided bupropion at no cost in the UW-TTURC clinical trial. The Wisconsin State Laboratory of Hygiene provided considerable technical assistance in this research effort in the form of DNA extraction, and this research was also aided by the Wisconsin Partnership Program. The authors have no other relevant affiliations or financialinvolvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Conflicts of interest

LJ Bierut is listed as an inventor on issued US patent 8,080,371, ‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction. N Saccone is the spouse of S Saccone who is also listed as an inventor on the above patent. All other authors declare no potential conflict of interest.

Additional information

Funding

This research was supported by R01DA036583, P30CA091842, U01HG004422 (LJB), R01DA038076, P30 CA091842-16S2, U19CA203654, K08DA030398, and KL2RR024994 (LSC), P50CA84724, K05CA139871, P50DA19706 (TBB), R01DA026911 (NLS). The Collaborative Genetic Study of Nicotine Dependence (COGEND; PI: L Bierut) was supported by grant P01CA089392 from the National Cancer Institute. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096. The Atherosclerosis Risk in Communities Study (ARIC; PI: E Boerwinkle) was obtained from dbGaP through study accession number phs000090. ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and CTSA UL1-RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (CA, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetric Genome-Wide Human SNP Array 6.0. Genotyping services for the UW-TTURC sample were provided by the Center for Inherited Disease Research (CIDR) and DNA extraction supported by the Wisconsin State Laboratory of Hygiene. Funding support for CIDR was provided by NIH grant U01HG004438 and NIH contract HHSN268200782096C to The Johns Hopkins University. Assistance with genotype cleaning was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Glaxo Wellcome provided bupropion at no cost in the UW-TTURC clinical trial. The Wisconsin State Laboratory of Hygiene provided considerable technical assistance in this research effort in the form of DNA extraction, and this research was also aided by the Wisconsin Partnership Program. The authors have no other relevant affiliations or financialinvolvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript