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 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

Department of Psychiatry, Amsterdam Neuroscience, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; QIMR Berghofer, Translational Neurogenomics Group, Brisbane, Australia. Electronic address: [email protected].
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Center for Precision Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
GGZ inGeest and Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
Assistance Publique-Hôpitaux de Paris, Hôpital Fernand Widal, Département de Psychiatrie et de Médecine Addictologique, 200 Rue du Faubourg Saint-Denis, Paris, France; Inserm umr-s 1144, Université Paris Descartes, Université Paris Diderot, 4 Avenue de l'Observatoire, Paris, France.
Department of Psychiatry, Amsterdam Neuroscience, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Clare Hall, University of Cambridge, Cambridge, CB3 9AL, United Kingdom.
Netherlands Cancer Institute
The Dalglish Family 22q Clinic, Toronto General Hospital, University Health Network, Toronto, Canada; Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Canada.
Radboud University Medical Center
Department of Sociology, VU University, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
Institute for Risk Assessment Science, Utrecht University, Utrecht, The Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
University of Amsterdam
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
Department of Psychiatry, Amsterdam Neuroscience, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; QIMR Berghofer, Translational Neurogenomics Group, Brisbane, Australia.

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
DOIs	https://doi.org/10.1016/j.drugalcdep.2018.03.026
Publication status	Published - 1 Jul 2018

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Addiction
Exome
Rare variants
Tobacco
Nicotine
Alcohol
PRS
Pathway analysis

Access to Document

10.1016/j.drugalcdep.2018.03.026

1-s2.0-S0376871618302266-mainFinal published version, 539 KBLicence: CC BY-NC-ND

Cite this

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

@article{68daedb591a645558d566a45379135dc,

title = "Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use",

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 {\texttimes} 10-7) and rs8034191 (p = 6.31 {\texttimes} 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.",

keywords = "Addiction, Exome, Rare variants, Tobacco, Nicotine, Alcohol, PRS, Pathway analysis",

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\}",

year = "2018",

month = jul,

day = "1",

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

language = "English",

volume = "188",

pages = "94--101",

journal = "Drug and Alcohol Dependence",

issn = "0376-8716",

publisher = "Elsevier Ireland Ltd.",

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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 - Exome

KW - Rare variants

KW - Tobacco

KW - Nicotine

KW - Alcohol

KW - PRS

KW - Pathway analysis

U2 - 10.1016/j.drugalcdep.2018.03.026

DO - 10.1016/j.drugalcdep.2018.03.026

M3 - Article

C2 - 29758381

SN - 0376-8716

VL - 188

SP - 94

EP - 101

JO - Drug and Alcohol Dependence

JF - Drug and Alcohol Dependence

ER -

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

Abstract

UN SDGs

Keywords

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