Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Andries T. Marees; Anke R. Hammerschlag; Lisa Bastarache; Hilde de Kluiver; Florence Vorspan; Wim van den Brink; Dirk J. Smit; Damiaan Denys; Eric R. Gamazon; Ruifang Li-Gao; Elemi J. Breetvelt; Mark C.H. de Groot; Tessel E. Galesloot; Sita H. Vermeulen; Jan L. Poppelaars; Patrick C. Souverein; Renske Keeman; Renée de Mutsert; Raymond Noordam; Frits R. Rosendaal; Najada Stringa; Dennis O. Mook-Kanamori; Ilonca Vaartjes; Lambertus A. Kiemeney; Martin den Heijer; Natasja M. van Schoor; Olaf H. Klungel; Anke H. Maitland-Van der Zee; Marjanka K. Schmidt; Tinca J.C. Polderman; Andries R. van der Leij; Danielle Posthuma; Eske M. Derks

doi:10.1016/j.drugalcdep.2018.03.026

Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Andries T. Marees, Anke R. Hammerschlag, Lisa Bastarache, Hilde de Kluiver, Florence Vorspan, Wim van den Brink, Dirk J. Smit, Damiaan Denys, Eric R. Gamazon, Ruifang Li-Gao, Elemi J. Breetvelt, Mark C.H. de Groot, Tessel E. Galesloot, Sita H. Vermeulen, Jan L. Poppelaars, Patrick C. Souverein, Renske Keeman, Renée de Mutsert, Raymond Noordam, Frits R. RosendaalNajada Stringa, Dennis O. Mook-Kanamori, Ilonca Vaartjes, Lambertus A. Kiemeney, Martin den Heijer, Natasja M. van Schoor, Olaf H. Klungel, Anke H. Maitland-Van der Zee, Marjanka K. Schmidt, Tinca J.C. Polderman, Andries R. van der Leij, Danielle Posthuma, Eske M. Derks

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. Methods: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of “alcoholism” (N = 25,508) and “tobacco use disorder” (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. Results: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10−7) and rs8034191 (p = 6.31 × 10−7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. Discussion: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

Original language	English
Pages (from-to)	94-101
Number of pages	8
Journal	Drug and Alcohol Dependence
Volume	188
Early online date	25 Apr 2018
DOIs	https://doi.org/10.1016/j.drugalcdep.2018.03.026
Publication status	Published - 1 Jul 2018

Funding

ATM and EMD are supported by the Foundation Volksbond Rotterdam , FV is supported by the Investissement d’Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02. B . ARH is supported by The Netherlands Organization for Scientific Research (NWO Brain and Cognition 433-09-228). DOMK is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023 ). DP acknowledges funding from The Netherlands Organization for Scientific Research (NWO VICI 453-14-005). The exome chip data for the NBS were generated in a research project that was financially supported by BBMRI-NL , a Research Infrastructure financed by the Dutch government (NWO 184.021.007). The Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health Welfare and Sports , Directorate of Long-Term Care. ABCS was funded by the Dutch cancer society project grant NKI2009-4363 . Funding for the project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated July 9, 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The funding sources had no involvement in study design; in the collection, analysis and interpretation of the data; in the writing of the report or the decision to submit for publication. Statistical analyses were carried out on the Genetic Cluster Computer ( http://www.geneticcluster.org ) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. ABCS: We are grateful to Frans Hogervorst, Annegien Broeks, and all patients and clinicians involved. The study was funded by the Dutch cancer society project grant NKI2009-4363. LASA: We are very grateful to all participants of the Longitudinal Aging Study Amsterdam for their participation, and to all interviewers, fieldwork coordinators, supporting staff and researchers for their contribution. NBS: Principal investigators of the Nijmegen Biomedical Study are L.A. Kiemeney, M. den Heijer, A.L.M. Verbeek, D.W. Swinkels and B. Franke. NEO: We thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Pat van Beelen, Petra Noordijk and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. www.neostudie.nl. NESCOG: We thank all participating subjects. This research was part of Science Live, the innovative research program of science center NEMO that enables scientists to carry out real, publishable, peer-reviewed research using NEMO visitors as volunteers. Dr. D. Posthuma acknowledges funding from The Netherlands Organization for Scientific Research (NWO VICI 453-14-005). UHP: Leidsche Rijn Julius Gezondheidscentra (LRJG) http://www.lrjg.nl/ UCP: acknowledges all participants and the researchers of the UCP study, Mark C.H. de Groot, Olaf H. Klungel, Anke-Hilse Maitland-Van der Zee, Patrick C Souverein. Funding for the ExomeChip project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated July 9, 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). Appendix A

Funders	Funder number
ATM
Centre National de Génotypage
Dutch Brain Foundation
Dutch Science Organization	916.14.023
Dutch cancer society project	184021007
Dutch Government	NWO 184.021.007
Foundation Volksbond Rotterdam	ANR-11-IDEX-0004-02
Leiden University
Leiden University Medical Center
NWO Brain and Cognition 433-09-228	433-09-228
NWO VICI 453-14-005	VICI 453-14-005
Netherlands Ministry of Health Welfare and Sports , Directorate of Long-Term Care
Netherlands Organization for Scientific Research
Netherlands Scientific Organization
SURFsara
The Netherlands Organization for Scientific Research
VU University Amsterdam
National Bureau of Statistics of China
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Universitetet i Bergen	NKI2009-4363
WorkplaceNL

Keywords

Addiction
Alcohol
Exome
Nicotine
Pathway analysis
PRS
Rare variants
Tobacco

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.drugalcdep.2018.03.026

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Marees, A. T., Hammerschlag, A. R., Bastarache, L., de Kluiver, H., Vorspan, F., van den Brink, W., Smit, D. J., Denys, D., Gamazon, E. R., Li-Gao, R., Breetvelt, E. J., de Groot, M. C. H., Galesloot, T. E., Vermeulen, S. H., Poppelaars, J. L., Souverein, P. C., Keeman, R., de Mutsert, R., Noordam, R., ... Derks, E. M. (2018). Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use. Drug and Alcohol Dependence, 188, 94-101. https://doi.org/10.1016/j.drugalcdep.2018.03.026

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abstract = "Background: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. Methods: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of “alcoholism” (N = 25,508) and “tobacco use disorder” (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. Results: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10−7) and rs8034191 (p = 6.31 × 10−7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. Discussion: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.",

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author = "Marees, {Andries T.} and Hammerschlag, {Anke R.} and Lisa Bastarache and {de Kluiver}, Hilde and Florence Vorspan and {van den Brink}, Wim and Smit, {Dirk J.} and Damiaan Denys and Gamazon, {Eric R.} and Ruifang Li-Gao and Breetvelt, {Elemi J.} and {de Groot}, {Mark C.H.} and Galesloot, {Tessel E.} and Vermeulen, {Sita H.} and Poppelaars, {Jan L.} and Souverein, {Patrick C.} and Renske Keeman and {de Mutsert}, Ren{\'e}e and Raymond Noordam and Rosendaal, {Frits R.} and Najada Stringa and Mook-Kanamori, {Dennis O.} and Ilonca Vaartjes and Kiemeney, {Lambertus A.} and {den Heijer}, Martin and {van Schoor}, {Natasja M.} and Klungel, {Olaf H.} and {Maitland-Van der Zee}, {Anke H.} and Schmidt, {Marjanka K.} and Polderman, {Tinca J.C.} and {van der Leij}, {Andries R.} and Danielle Posthuma and Derks, {Eske M.}",

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doi = "10.1016/j.drugalcdep.2018.03.026",

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Marees, AT, Hammerschlag, AR, Bastarache, L, de Kluiver, H, Vorspan, F, van den Brink, W, Smit, DJ, Denys, D, Gamazon, ER, Li-Gao, R, Breetvelt, EJ, de Groot, MCH, Galesloot, TE, Vermeulen, SH, Poppelaars, JL, Souverein, PC, Keeman, R, de Mutsert, R, Noordam, R, Rosendaal, FR, Stringa, N, Mook-Kanamori, DO, Vaartjes, I, Kiemeney, LA, den Heijer, M, van Schoor, NM, Klungel, OH, Maitland-Van der Zee, AH, Schmidt, MK, Polderman, TJC, van der Leij, AR, Posthuma, D & Derks, EM 2018, 'Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use', Drug and Alcohol Dependence, vol. 188, pp. 94-101. https://doi.org/10.1016/j.drugalcdep.2018.03.026

TY - JOUR

T1 - Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

AU - Marees, Andries T.

AU - Hammerschlag, Anke R.

AU - Bastarache, Lisa

AU - de Kluiver, Hilde

AU - Vorspan, Florence

AU - van den Brink, Wim

AU - Smit, Dirk J.

AU - Denys, Damiaan

AU - Gamazon, Eric R.

AU - Li-Gao, Ruifang

AU - Breetvelt, Elemi J.

AU - de Groot, Mark C.H.

AU - Galesloot, Tessel E.

AU - Vermeulen, Sita H.

AU - Poppelaars, Jan L.

AU - Souverein, Patrick C.

AU - Keeman, Renske

AU - de Mutsert, Renée

AU - Noordam, Raymond

AU - Rosendaal, Frits R.

AU - Stringa, Najada

AU - Mook-Kanamori, Dennis O.

AU - Vaartjes, Ilonca

AU - Kiemeney, Lambertus A.

AU - den Heijer, Martin

AU - van Schoor, Natasja M.

AU - Klungel, Olaf H.

AU - Maitland-Van der Zee, Anke H.

AU - Schmidt, Marjanka K.

AU - Polderman, Tinca J.C.

AU - van der Leij, Andries R.

AU - Posthuma, Danielle

AU - Derks, Eske M.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Background: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. Methods: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of “alcoholism” (N = 25,508) and “tobacco use disorder” (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. Results: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10−7) and rs8034191 (p = 6.31 × 10−7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. Discussion: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

AB - Background: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. Methods: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of “alcoholism” (N = 25,508) and “tobacco use disorder” (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. Results: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10−7) and rs8034191 (p = 6.31 × 10−7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. Discussion: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

KW - Addiction

KW - Alcohol

KW - Exome

KW - Nicotine

KW - Pathway analysis

KW - PRS

KW - Rare variants

KW - Tobacco

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Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

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UN SDGs

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